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Publisher: John Wiley and Sons   (Total: 1583 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 11, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 53, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 43, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 135, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 24, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 48, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 246, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 4, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 28, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 127, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 30, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 35, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 235, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 116, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 15)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 153)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 204, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 5, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 42, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 92, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 66, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 133, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 48, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 13, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 24, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 204, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 48, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 13)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 319, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 3, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 13, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 7, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 42, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 22, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 16, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 381, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 64, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 3, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 8, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 22, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 2, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 44, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 135, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 17, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 33, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover Archaeological Prospection
  [SJR: 0.922]   [H-I: 21]   [12 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1075-2196 - ISSN (Online) 1099-0763
   Published by John Wiley and Sons Homepage  [1583 journals]
  • LiDAR-guided Archaeological Survey of a Mediterranean Landscape: Lessons
           from the Ancient Greek Polis of Kolophon (Ionia, Western Anatolia)
    • Authors: Benedikt Grammer; Erich Draganits, Martin Gretscher, Ulrike Muss
      Abstract: In 2013, an airborne laser scan survey was conducted in the territory of the Ionian city of Kolophon near the western coast of modern Turkey as part of an archaeological survey project carried out by the Mimar Sinan University of Istanbul (Turkey) and the University of Vienna (Austria). Several light detection and ranging (LiDAR) studies have been carried out in the temperate climate zones of Europe, but only a few in Mediterranean landscapes. Our study is based on the first LiDAR survey carried out for an archaeological purpose in Turkey and one of the first in the Mediterranean that have been planned, measured and filtered especially for archaeological research questions. The interpretation of LiDAR data combined with ground-observations proved extremely useful for the detection and documentation of archaeological remains below Mediterranean evergreen vegetation and dense maquis. This article deals with the methodological aspects of interpreting LiDAR data, using the Kolophon data as a case study. We offer a discussion of the strengths and limitations of LiDAR as an archaeological remote sensing method and suggest a best practice model for interpreting LiDAR data in a Mediterranean context. © 2017 The
      Authors . Archaeological Prospection published by John Wiley & Sons Ltd.
      PubDate: 2017-04-25T23:31:37.510415-05:
      DOI: 10.1002/arp.1572
  • Clinical spectrum of Kabuki-like syndrome caused by HNRNPK
    • Authors: Maria Lisa Dentici; Sabina Barresi, Marcello Niceta, Francesca Pantaleoni, Simone Pizzi, Bruno Dallapiccola, Marco Tartaglia, Maria Cristina Digilio
      Abstract: Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11-year-old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole-exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.
      PubDate: 2017-04-25T21:30:33.773957-05:
      DOI: 10.1111/cge.13029
  • The Mutation p.D313Y is associated with organ manifestation in Fabry
    • Authors: M. du Moulin; A.F. Koehn, A. Golsari, S. Dulz, Y. Atiskova, M. Patten, J. Münch, M. Avanesov, K. Ullrich, N. Muschol
      Abstract: Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.
      PubDate: 2017-04-24T21:01:06.425679-05:
      DOI: 10.1111/cge.13007
  • The investigation of genetic and clinical features in Chinese patients
           with juvenile amyotrophic lateral sclerosis
    • Authors: Z.-J. Liu; H.-X. Lin, G.-L. Liu, Q.-Q. Tao, W. Ni, B.-G. Xiao, Z.-Y. Wu
      Abstract: Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients).
      PubDate: 2017-04-20T21:04:54.232628-05:
      DOI: 10.1111/cge.13015
  • Constitutional LZTR1 mutation presenting with a unilateral vestibular
           schwannoma in a teenager
    • Authors: K.W. Gripp; L. Baker, V. Kandula, J. Piatt, A. Walter, Z. Chen, L. Messiaen
      Abstract: Schwannomatosis is a rare neurofibromatosis clinically diagnosed by age-dependent criteria, with bilateral vestibular schwannoma and/or a constitutional NF2 mutation representing exclusion criteria. Following SMARCB1 germline mutations, constitutional mutations in LZTR1 were discovered. We report on the molecular investigation in a patient presenting at 14 years with a unilateral vestibular schwannoma, ultimately causing blindness and unilateral hearing loss, in the absence of other schwannomas or a positive family history.In DNA derived from frozen tumor tissue, a comprehensive NF2, SMARCB1 and LZTR1 analysis showed an NF2 truncating mutation c.1006_1021delins16; an LZTR1 mutation c.791+1G>A; and a partial 22q deletion including NF2, SMARCB1 and LZTR1. Sequence analysis on peripheral blood derived DNA showed the LZTR1 mutation to be constitutional, but the NF2 mutation and partial 22q deletion were not found, indicating them to be somatic events. RNA-based targeted analysis confirmed missplicing of LZTR1 intron 8, predicted to result in a premature stop codon. This LZTR1 mutation was paternally inherited.While isolated vestibular schwannoma or NF2 may be considered in a young individual with a unilateral vestibular schwannoma, this report suggests that LZTR1-related schwannomatosis be added to this differential diagnosis.
      PubDate: 2017-04-19T02:22:19.888939-05:
      DOI: 10.1111/cge.13013
  • Novel non-contiguous exon duplication in choroideremia
    • Authors: T.L. Edwards; J. Williams, M.I. Patrício, M.P. Simunovic, M. Shanks, P. Clouston, R.E. MacLaren
      Abstract: The importance of establishing a genetic diagnosis in patients with a choroideremia phenotype has been underscored by the advent of gene replacement therapy for this condition. Here, we describe a complex imbalance at the CHM locus in a male patient with classical disease. At the DNA level, this imbalance consists of 2 non-contiguous duplications (exons 1-2 and 9-12). Further characterization suggests the generation of 2 independent CHM transcriptional units, one of which may produce a deleted form of the Rab escort protein 1 protein. Expression of such a type of aberrant protein in photoreceptors may have important implications when considering gene therapy for this disorder.
      PubDate: 2017-04-19T02:22:17.330257-05:
      DOI: 10.1111/cge.13021
  • Second family provides further evidence for causation of Steel syndrome by
           biallelic mutations in COL27A1
    • Authors: S. Kotabagi; H. Shah, A. Shukla, K.M. Girisha
      Abstract: Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus. Homozygous variants in COL27A1 were reported in an extending family from Puerto Rico. Here, we report a 5-year-old girl from a non-consanguineous family with facial dysmorphism, short stature, carpal coalition, dislocation of radial heads, bilateral hip dislocation, scoliosis and vertical talus. Exome sequencing identified 2 novel compound heterozygous variants c.521_528del (p.(Cys174Serfs*34)) and c.2119C>T (p.(Arg707*)) in COL27A1 in this child and the parents were heterozygous carriers. We hence report the second molecularly proven case of Steel syndrome and the first case to be reported among non-Puerto Rican population. Our report further validates the role of COL27A1 mutations in causation of Steel syndrome.
      PubDate: 2017-04-19T02:22:06.979553-05:
      DOI: 10.1111/cge.13006
  • PLA2G6 mutations associated with a continuous clinical spectrum from
           neuroaxonal dystrophy to hereditary spastic paraplegia
    • Authors: B. Ozes; N. Karagoz, R. Schüle, A. Rebelo, M.-J. Sobrido, F. Harmuth, M. Synofzik, S.I.P. Pascual, M. Colak, B. Ciftci-Kavaklioglu, B. Kara, A. Ordóñez-Ugalde, B. Quintáns, M.A. Gonzalez, A. Soysal, S. Zuchner, E. Battaloglu
      Abstract: PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.A, Brain iron accumulation in Turkish patients in association with HSP phenotype and PLA2G6 mutation, B, atrophy of cerebellum in Moroccan and C, Romanian patients with child onset PLAN.
      PubDate: 2017-04-19T02:21:57.428212-05:
      DOI: 10.1111/cge.13008
  • Clinical and mutational spectrum of Japanese patients with
           Charcot-Marie-Tooth disease caused by GDAP1 variants
    • Authors: A. Yoshimura; J.-H. Yuan, A. Hashiguchi, Y. Hiramatsu, M. Ando, Y. Higuchi, T. Nakamura, Y. Okamoto, K. Matsumura, T. Hamano, N. Sawaura, Y. Shimatani, S. Kumada, Y. Okumura, J. Miyahara, Y. Yamaguchi, S. Kitamura, K. Haginoya, J. Mitsui, H. Ishiura, S. Tsuji, H. Takashima
      Abstract: BackgroundMutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan.Materials and MethodsFrom April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing.ResultsWe identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy.ConclusionWe identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.
      PubDate: 2017-04-19T02:21:50.268203-05:
      DOI: 10.1111/cge.13002
  • Confirming the recessive inheritance of SCN1B mutations in developmental
           epileptic encephalopathy
    • Authors: W. Ramadan; N. Patel, S. Anazi, A.Y. Kentab, F.A. Bashiri, M.H. Hamad, L. Jad, M.A. Salih, H. Alsaif, M. Hashem, E. Faqeih, H.E. Shamseddin, F.S. Alkuraya
      Abstract: Dominant SCN1B mutations are known to cause several epilepsy syndromes in humans. Only 2 epilepsy patients to date have been reported to have recessive mutations in SCN1B as the likely cause of their phenotype. Here, we confirm the recessive inheritance of 2 novel SCN1B mutations in 5 children from 3 families with developmental epileptic encephalopathy. The recessive inheritance and early death in these patients is consistent with the Dravet-like phenotype observed in Scn1b−/− mice. The ‘negative’ clinical exome in one of these families highlights the need to consider recessive mutations in the interpretation of variants in typically dominant genes.
      PubDate: 2017-04-19T02:21:42.40745-05:0
      DOI: 10.1111/cge.12999
  • Defining personal utility in genomics: A Delphi study
    • Authors: J.N. Kohler; E. Turbitt, K.L. Lewis, B.S. Wilfond, L. Jamal, H.L. Peay, L.G. Biesecker, B.B. Biesecker
      Abstract: BackgroundIndividual genome sequencing results are valued by patients in ways distinct from clinical utility. Such outcomes have been described as components of “personal utility,” a concept that broadly encompasses patient-endorsed benefits, that is operationally defined as non-clinical outcomes. No empirical delineation of these outcomes has been reported.AimTo address this gap, we administered a Delphi survey to adult participants in a National Institute of Health (NIH) clinical exome study to extract the most highly endorsed outcomes constituting personal utility.Materials and MethodsForty research participants responded to a Delphi survey to rate 35 items identified by a systematic literature review of personal utility.ResultsTwo rounds of ranking resulted in 24 items that represented 14 distinct elements of personal utility. Elements most highly endorsed by participants were: increased self-knowledge, knowledge of “the condition,” altruism, and anticipated coping.DiscussionOur findings represent the first systematic effort to delineate elements of personal utility that may be used to anticipate participant expectation and inform genetic counseling prior to sequencing. The 24 items reported need to be studied further in additional clinical genome sequencing studies to assess generalizability in other populations. Further research will help to understand motivations and to predict the meaning and use of results.
      PubDate: 2017-04-19T02:21:28.409482-05:
      DOI: 10.1111/cge.12998
  • Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a
           cohort of MODY families
    • Authors: L.S. Santana; L.A. Caetano, A.D. Costa-Riquetto, E.P.S. Quedas, M. Nery, P. Collett-Solberg, M.C.S. Boguszewski, M.F. Vendramini, L.G. Crisostomo, F.O. Floh, Z.I. Zarabia, S.K. Kohara, L. Guastapaglia, C.G.B. Passone, L.E. Sewaybricker, A.A.L. Jorge, M.G. Teles
      Abstract: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK-MODY and HNF1A-MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY (GCK/HNF1A) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK-MODY and 55% with suspicion of HNF1A-MODY. Twenty-five different variants were identified in GCK gene (30 probands—61% of positivity), and 7 variants in HNF1A (10 probands—17% of positivity). Fourteen of them were novel (12—GCK/2—HNF1A). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%—GCK/86%—HNF1A) and likely pathogenic (44%—GCK/14%—HNF1A), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.
      PubDate: 2017-04-12T03:26:30.780849-05:
      DOI: 10.1111/cge.12988
  • A novel DNAJB6 mutation causes dominantly inherited distal-onset myopathy
           and compromises DNAJB6 function
    • Authors: P.-C. Tsai; Y.-S. Tsai, B.-W. Soong, Y.-H. Huang, H.-T. Wu, Y.-H. Chen, K.-P. Lin, Y.-C. Liao, Y.-C. Lee
      Abstract: BackgroundMutations in the DNAJB6 gene have been identified as a rare cause of dominantly inherited limb-girdle muscular dystrophy or distal-onset myopathy.Materials and MethodsExome sequencing was performed to investigate a Taiwanese family with a dominantly inherited distal-onset myopathy. Functional effects of the causal mutation were investigated in vitro.ResultsExome sequencing of the two affected individuals in this family identified a heterozygous mutation, c.287C>T (p.Pro96Leu) in the DNAJB6 gene, which co-segregated with the myopathy within all 12 family members. Notably, this mutation is novel and localizes within the glycine and phenylalanine-rich (G/F) domain and alters an amino acid residue previously reported with a different mutation. Furthermore, immunofluorescence analyses and filter trap assay demonstrated that the c.287C>T (p.Pro96Leu) mutation possessed a dominant negative effect on the anti-aggregation function of DNAJB6 protein.ConclusionThis study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy.
      PubDate: 2017-04-12T03:26:03.408376-05:
      DOI: 10.1111/cge.13001
  • Two novel MYLK nonsense mutations causing thoracic aortic
           aneurysms/dissections in patients without apparent family history
    • Authors: I. Luyckx; D. Proost, J.M.H. Hendriks, J. Saenen, E.M. Van Craenenbroeck, T. Vermeulen, N. Peeters, W. Wuyts, I. Rodrigus, A. Verstraeten, L. Van Laer, B.L. Loeys
      PubDate: 2017-04-12T03:25:47.527811-05:
      DOI: 10.1111/cge.13000
  • The new neuromuscular disease related with defects in the ASC-1 complex:
           report of a second case confirms ASCC1 involvement
    • Authors: J. Oliveira; M. Martins, R. Pinto Leite, M. Sousa, R. Santos
      Abstract: Next-generation sequencing technology aided the identification of the underlying genetic cause in a female newborn with a severe neuromuscular disorder. The patient presented generalized hypotonia, congenital bone fractures, lack of spontaneous movements and poor respiratory effort. She died within the first days of life. Karyotyping and screening for several genes related with neuromuscular diseases all tested negative. A male sibling was subsequently born with the same clinical presentation. Whole-exome sequencing was performed with variant filtering assuming a recessive disease model. Analysis focused on genes known to be related firstly with congenital myopathies, extended to muscle diseases and finally to other neuromuscular disorders. No disease-causing variants were identified. A similar disorder was described in patients with recessive variants in two genes: TRIP4 (three families) and ASCC1 (one family), both encoding subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. Our patient was also found to have a homozygous frameshift variant (c.157dupG, p.Glu53Glyfs*19) in ASCC1, thereby representing the second known case. This confirms ASCC1 involvement in a severe neuromuscular disease lying within the spinal muscular atrophy or primary muscle disease spectra.Identification of the second case of a rare neuromuscular disease confirms ASCC1 involvement. Main clinical features include: hypotonia, lack of spontaneous movements, arthrogryposis, bilateral congenital femoral fractures and thin, gracile ribs. A homozygous frame shift variant was identified in ASCC1 using whole-exome sequencing.
      PubDate: 2017-03-31T00:41:26.919873-05:
      DOI: 10.1111/cge.12997
  • Genome-wide linkage and sequence analysis challenge CCDC66 as a human
           retinal dystrophy candidate gene and support a distinct NMNAT1-related
           fundus phenotype
    • Authors: Arif O. Khan; Birgit S. Budde, Peter Nürnberg, Amit Kawalia, Steffen Lenzner, Hanno J. Bolz
      Abstract: To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in two siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted two homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy.Graphical Abstract
      PubDate: 2017-03-30T03:12:30.019073-05:
      DOI: 10.1111/cge.13022
  • SNORD116 deletions cause Prader-Willi syndrome with a mild phenotype and
    • Authors: P. Fontana; M. Grasso, F. Acquaviva, E. Gennaro, M.L. Galli, M. Falco, F. Scarano, G. Scarano, F. Lonardo
      Abstract: Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome.
      PubDate: 2017-03-30T02:50:49.922821-05:
      DOI: 10.1111/cge.13005
  • Clinical and mutation analysis of 24 Chinese patients with ornithine
           transcarbamylase deficiency
    • Authors: Y. Shao; M. Jiang, Y. Lin, H. Mei, W. Zhang, Y. Cai, X. Su, H. Hu, X. Li, L. Liu
      Abstract: The principal aim of this study was to examine the clinical manifestations, biochemical features, and molecular genetic characteristics of Chinese patients with ornithine transcarbamylase deficiency (OTCD) at a single medical center. We retrospectively analyzed 24 patients (17 males and 7 females) diagnosed with OTCD between 2006 and 2015. Five male patients had a neonatal presentation; 12 male patients had late onset disease and 7 female patients presented as symptomatic. Patients with a neonatal presentation had the highest peak plasma ammonia and glutamine levels at diagnosis with a high mortality (80% vs 16% in late onset disease). Most of the male late onset disease cases displayed neurologic damage with a mild elevation in plasma ammonia, and a significant increase in serum glutamine, which was commonly misdiagnosed as intracranial infection. In the symptomatic female group, mortality was abnormally high in China with some patients dying at the time of presentation during the first episode of hyperammonemia. Refractory hyperammonemia, serious hepatic function damage, recurrent infection and lethal mutation are the main reasons for poor clinical outcomes of the symptomatic females. Molecular analyses identified 19 different mutations, including 3 novel mutations (c.103insA, c.591C>A and c.805G>A).
      PubDate: 2017-03-30T02:35:27.687324-05:
      DOI: 10.1111/cge.13004
  • Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia,
           ataxia, and intellectual disability
    • Authors: K.L. Helbig; C. Mroske, D. Moorthy, S.A. Sajan, M. Velinov
      Abstract: DOCK3 encodes the dedicator of cytokinesis 3 protein, a member of the DOCK180 family of proteins that are characterized by guanine-nucleotide exchange factor activity. DOCK3 is expressed exclusively in the central nervous system and plays an important role in axonal outgrowth and cytoskeleton reorganization. Dock3 knockout mice exhibit motor deficiencies with abnormal ataxic gait and impaired learning. We report 2 siblings with biallelic loss-of-function variants in DOCK3. Diagnostic whole-exome sequencing (WES) and chromosomal microarray were performed on a proband with severe developmental disability, hypotonia, and ataxic gait. Testing was also performed on the proband's similarly affected brother. A paternally inherited 458 kb deletion in chromosomal region 3p21.2 disrupting the DOCK3 gene was identified in both affected siblings. WES identified a nonsense variant c.382C>G (p.Gln128*) in the DOCK3 gene (NM_004947) on the maternal allele in both siblings. Common features in both affected individuals include severe developmental disability, ataxic gait, and severe hypotonia, which recapitulates the Dock3 knockout mouse phenotype. We show that complete DOCK3 deficiency in humans leads to developmental disability with significant hypotonia and gait ataxia, probably due to abnormal axonal development.
      PubDate: 2017-03-30T02:25:58.658049-05:
      DOI: 10.1111/cge.12995
  • Genetic testing facilitates prepubertal diagnosis of congenital
           hypogonadotropic hypogonadism
    • Authors: C. Xu; M. Lang-Muritano, F. Phan-Hug, A.A. Dwyer, G.P. Sykiotis, D. Cassatella, J. Acierno, M. Mohammadi, N. Pitteloud
      Abstract: Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both
      PubDate: 2017-03-30T02:25:42.407194-05:
      DOI: 10.1111/cge.12996
  • Experiences in microarray-based evaluation of developmental disabilities
           and congenital anomalies
    • Authors: B. Ozyilmaz; O. Kirbiyik, A. Koc, T.R. Ozdemir, O.O. Kaya, M.S. Guvenc, K.M. Erdoğan, Y.B. Kutbay
      Abstract: BackgroundChromosomal microarray analysis is the first-tier test for the evaluation of developmental disabilities and congenital anomalies. In this report, we present CMA results of 971 patient and 301 parent samples.Materials and MethodsAmong 971 patient samples, 133 (13.6%) had pathogenic variants.ResultsWhile analyzing, an “in-house” variant database was also used besides other databases. Owing to this, we have found chance to report the most frequent benign variants in Turkish population.ConclusionWith the additional data we acquired in this study, we also emphasized the high potential of CMA in revealing single gene disorders and novel gene-phenotype associations as well as copy number variations.
      PubDate: 2017-03-30T02:25:25.156653-05:
      DOI: 10.1111/cge.12978
  • Parents’ attitudes toward genetic testing of children for health
           conditions: A systematic review
    • Authors: Q. Lim; B.C. McGill, V.F. Quinn, K.M. Tucker, D. Mizrahi, A.F. Patenaude, M. Warby, R.J. Cohn, C.E. Wakefield
      Abstract: This review assessed parents’ attitudes toward childhood genetic testing for health conditions, with a focus on perceived advantages and disadvantages. We also evaluated the factors that influence parents’ attitudes toward childhood genetic testing. We searched Medline, Medline In-Process, EMBASE, PsycINFO, Social Work s and CINAHL. We screened 945 abstracts and identified 21 studies representing the views of 3934 parents. Parents reported largely positive attitudes toward childhood genetic testing across different genetic tests with varying medical utility. Parents perceived a range of advantages and disadvantages of childhood genetic testing. Childhood genetic testing was viewed by most as beneficial. Parents’ education level, genetic status, sex and sociodemographic status were associated with reported attitudes. This yielded some conflicting findings, indicating the need for further research. Genetic counseling remains essential to support this population in making well-informed decisions. Targeted interventions tailored to specific families with different sociodemographic characteristics may be useful. Further research on the long-term impact of childhood genetic testing on families is warranted.
      PubDate: 2017-03-30T02:10:32.686657-05:
      DOI: 10.1111/cge.12989
  • PAX9 gene mutations and tooth agenesis: A review
    • Authors: O. Bonczek; V.J. Balcar, O. Šerý
      Abstract: Paired box 9 (PAX9) is one of the best-known transcription factors involved in the development of human dentition. Mutations in PAX9 gene could, therefore, seriously influence the number, position and morphology of the teeth in an affected individual. To date, over 50 mutations in the gene have been reported as associated with various types of dental agenesis (congenitally missing teeth) and other inherited dental defects or variations. The most common consequence of PAX9 gene mutation is the autosomal-dominant isolated (non-syndromic) oligodontia or hypodontia.In the present review, we are summarizing all known PAX9 mutations as well as their nature and precise loci in the DNA sequence of the gene. Where necessary, we have revised the loci of the mutations in line with the reference sequence of the PAX9 gene as it appears in the current DNA databases.
      PubDate: 2017-03-30T02:05:27.501823-05:
      DOI: 10.1111/cge.12986
  • A novel mutation in SLC25A46 causes optic atrophy and progressive limb
           spasticity, with no cerebellar atrophy or axonal neuropathy
    • Authors: R.A. Sulaiman; N. Patel, H. Alsharif, S.T. Arold, F.S. Alkuraya
      PubDate: 2017-03-30T02:00:23.006442-05:
      DOI: 10.1111/cge.12963
  • DEPDC5 mutations in familial and sporadic focal epilepsy
    • Authors: M.-H. Tsai; C.-K. Chan, Y.-C. Chang, Y.-T. Yu, S.-T. Chuang, W.-L. Fan, S.-C. Li, T.-Y. Fu, W.-N. Chang, C.-W. Liou, Y.-C. Chuang, C.-C. Ng, D.-Y. Hwang, K.-S. Lim
      Abstract: Background and AimsMutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.Materials and MethodsWe studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.ResultsWe reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.Discussion and ConclusionsOur finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.
      PubDate: 2017-03-30T01:55:46.205836-05:
      DOI: 10.1111/cge.12992
  • Identification of novel SNORD118 mutations in seven patients with
           leukoencephalopathy with brain calcifications and cysts
    • Authors: Kazuhiro Iwama; Takeshi Mizuguchi, Jun-ichi Takanashi, Hidehiro Shibayama, Minobu Shichiji, Susumu Ito, Hirokazu Oguni, Toshiyuki Yamamoto, Akiko Sekine, Shun Nagamine, Yoshio Ikeda, Hiroya Nishida, Satoko Kumada, Takeshi Yoshida, Tomonari Awaya, Ryuta Tanaka, Ryo Chikuchi, Hisayoshi Niwa, Yu-ichi Oka, Satoko Miyatake, Mitsuko Nakashima, Atsushi Takata, Noriko Miyake, Shuichi Ito, Hirotomo Saitsu, Naomichi Matsumoto
      Abstract: BackgroundLeukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively.Materials and MethodsEight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families.ResultsSeven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (
      PubDate: 2017-03-30T01:40:32.1144-05:00
      DOI: 10.1111/cge.12991
  • Attenuated phenotype of Costello syndrome and early death in a patient
           with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics
    • Authors: K.W. Gripp; V. Kolbe, L.I. Brandenstein, G. Rosenberger
      Abstract: Costello syndrome (CS) is caused by heterozygous germline HRAS mutations. Most patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype. Although many disease-associated HRAS alterations trigger constitutive activation of HRAS-dependent signalling pathways, additional pathological consequences exist. An infant with failure-to-thrive and hypertrophic cardiomyopathy had a novel de novo HRAS mutation (c.179G>T; p.Gly60Val). He showed subtle dysmorphic findings consistent with attenuated CS and died from presumed cardiac cause. Functional studies revealed that amino acid change p.Gly60Val impairs HRAS binding to effectors PIK3CA, phospholipase C1, and RAL guanine nucleotide dissociation stimulator. In contrast, interaction with effector rapidly accelerated fibrosarcoma (RAF) and regulator NF1 GTPase-activating protein was enhanced. Importantly, expression of HRAS p.Gly60Val in HEK293 cells reduced growth factor sensitivity leading to damped RAF-MAPK and phosphoinositide 3-kinases-AKT signalling response. Our data support the idea that a variable range of dysregulated HRAS-dependent signalling dynamics, rather than static activation of HRAS-dependent signal flow, may underlie the phenotypic variability in CS.
      PubDate: 2017-03-30T01:35:36.841659-05:
      DOI: 10.1111/cge.12980
  • Metatarsal bony syndactyly in 2 fetuses with Smith-Lemli-Opitz syndrome:
           An under-recognized part of the clinical spectrum
    • Authors: Shahida Moosa; Bart Loeys, Janine Altmüller, Geert Mortier, Peter Nürnberg, Yun Li, Bernd Wollnik, Ida Vogel
      PubDate: 2017-03-30T01:35:22.809102-05:
      DOI: 10.1111/cge.12990
  • Eye coloboma and complex cardiac malformations belong to the clinical
           spectrum of PUF60 variants
    • Authors: F. Santos-Simarro; E. Vallespin, A. Pozo, K. Ibañez, J.C. Silla, L. Fernandez, J. Nevado, H. González-Pecellín, V.E.F. Montaño, R. Martin, L.I. Alba Valdivia, S. García-Miñaúr, P. Lapunzina, M. Palomares-Bralo
      PubDate: 2017-03-30T01:30:28.004278-05:
      DOI: 10.1111/cge.12965
  • The genotype–phenotype landscape of familial amyotrophic lateral
           sclerosis in Australia
    • Authors: E.P. McCann; K.L. Williams, J.A. Fifita, I.S. Tarr, J. O'Connor, D.B. Rowe, G.A. Nicholson, I.P. Blair
      Abstract: Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype–phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype–phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration.
      PubDate: 2017-03-30T01:25:52.236893-05:
      DOI: 10.1111/cge.12973
  • BMP15 “knockout-like” effect in familial premature ovarian
           insufficiency with persistent ovarian reserve
    • Authors: A. Mayer; B. Fouquet, M. Pugeat, M. Misrahi
      Abstract: Premature ovarian insufficiency (POI) affects 1% to 2% of women under 40 years. Bone morphogenetic protein 15 (BMP15) variants have been described in POI. We studied a family with 2 sisters compound heterozygous for deletions in the BMP15 gene on chromosome Xp11.22 yielding a human “knockout-like” effect: a c.151_152delGA deletion yielded a p.Glu51IlefsTer27 mutation transmitted by the hemizygous father and a c.189_198delAGGGCATTCAinsTG deletion/insertion yielded a p.Glu64AlafsTer12 mutation transmitted by the heterozygous mother. Both deletions resulted in frameshifts with premature stop codons at positions 78 and 76 in the proregion, precluding mature BMP15 production. One sister had primary amenorrhea and the other primo-secondary amenorrhea. No bone abnormality was observed. Despite streak ovaries devoid of follicles on ultrasonography, anti-Mullerian hormone (AMH) levels were low but detectable suggesting the presence of growing follicles. Five years later, AMH was undetectable in both sisters, 1 had received an egg donation. BMP15 did not seem critical for follicles to enter the growth phase. Genetic counselling should be performed and fertility preservation discussed before progressive loss of follicular reserve. The fertile heterozygous mother did not support previous reports of BMP15 haploinsufficiency and gene dosage in humans, as in bovine species. The hemizygous brother had asthenozoospermia, consistent with previous observations in bulls with a variant BMP15.Two sisters (A) compound heterozygous for deletions in the BMP15 gene (B) resulting in frameshifts with premature stop codons at positions 78 and 76 in the proregion (C). One sister had primary amenorrhea and the other primo-secondary amenorrhea. Despite streak ovaries devoid of follicles on ultrasonography, AMH values are compatible with persistent primary follicles reflecting an ovarian reserve. BMP15 did not seem critical for follicles to enter the growth phase. Genetic counselling should be performed and fertility preservation discussed before progressive loss of follicular reserve. The fertility heterozygous mother (A, B) did not support previous reports of BMP15 haploinsufficiency and gene dosage in humans. The hemizygous brother (A, B) had asthenozoospermia, consistent with previous observations in bulls with a variant BMP15.
      PubDate: 2017-03-30T01:25:25.771971-05:
      DOI: 10.1111/cge.12970
  • The Danish HD Registry—a nationwide family registry of HD families
           in Denmark
    • Authors: M. Gilling; E. Budtz-Jørgensen, S.E. Boonen, D. Lildballe, A. Bojesen, J.M. Hertz, S.A. Sørensen
      Abstract: The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.
      PubDate: 2017-03-28T01:25:56.911144-05:
      DOI: 10.1111/cge.12984
  • Prenatal course of metaphyseal anadysplasia associated with homozygous
           mutation in MMP9 identified by exome sequencing
    • Authors: Reuven Sharony; Zvi Borochowitz, Lior Cohen, Atalia Storch, Revital Rosenfeld, Shira Modai, Eyal Reinstein
      Abstract: Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition the finding of homozygous mutation in non-consanguineous parents of Caucasus ancestry may suggest unawareness of such relationship or the occurrence of a founder mutation in this gene.Lateral spine - in the neonatal period showing coronal clefts Lateral spine at 5 months showing hyperlordosis resolving coronal clefts and mild lower lumbar platyspondyly Lower limbs at the neonatal period showing proportionate shortened limbs with mild bowing of tibiae and fibulae with no metaphyseal changes AP of lower limbs at age of 1year showing somewhat short limbs with no other skeletal changes
      PubDate: 2017-03-25T02:50:28.547481-05:
      DOI: 10.1111/cge.13020
  • Use of multigene-panel identifies pathogenic variants in several
           CRC-predisposing genes in patients previously tested for Lynch Syndrome
    • Authors: Maren F. Hansen; Jostein Johansen, Anna E. Sylvander, Inga Bjørnevoll, Bente A. Talseth-Palmer, Liss A. S. Lavik, Alexandre Xavier, Lars F. Engebretsen, Rodney J. Scott, Finn Drabløs, Wenche Sjursen
      Abstract: BackgroundMany families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases.Materials and methodsTo reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed.ResultsWe identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected.ConclusionIn conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach.
      PubDate: 2017-03-22T05:01:00.217064-05:
      DOI: 10.1111/cge.12994
  • Further phenotypic heterogeneity of CoQ10 deficiency associated with
           steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants
    • Authors: M. Gigante; S. Diella, L. Santangelo, E. Trevisson, M.J. Acosta, M. Amatruda, G. Finzi, G. Caridi, L. Murer, M. Accetturo, E. Ranieri, G.M. Ghiggeri, M. Giordano, G. Grandaliano, L. Salviati, L. Gesualdo
      PubDate: 2017-03-22T04:50:39.463678-05:
      DOI: 10.1111/cge.12960
  • Molecular Analysis of Patients with Aniridia in Russian Federation
           Broadens the Spectrum of PAX6 Mutations
    • Authors: Tatyana A. Vasilyeva; Anna A. Voskresenskaya, Barbara Käsmann-Kellner, Olga V. Khlebnikova, Nadezhda A. Pozdeyeva, Gulnara M. Bayazutdinova, Sergey I. Kutsev, Evgeny K. Ginter, Elena V. Semina, Andrey V. Marakhonov, Rena A. Zinchenko
      Abstract: Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia.Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome. The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In three families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 out of 91 probands lacking pathogenic variants in the gene.
      PubDate: 2017-03-21T00:50:46.261811-05:
      DOI: 10.1111/cge.13019
  • Homozygous deletion of RAG1, RAG2 and 5′ region TRAF6 causes severe
           immune suppression and atypical osteopetrosis
    • Authors: M. Weisz Hubshman; L. Basel-Vanagaite, A. Krauss, O. Konen, Y. Levy, B.Z. Garty, P. Smirin-Yosef, I. Maya, I. Lagovsky, E. Taub, D. Marom, D. Gaash, K. Shichrur, S. Avigad, L. Hayman-Manzur, A. Villa, C. Sobacchi, M. Shohat, I. Yaniv, J. Stein
      Abstract: Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5′ region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.Left picture-increased radio density of the long bones of the leg and a pathological fracture suggesting osteopetrosis. Right picture- after about 45 days, note exuberant femoral callus, metaphyseal widening of the distal femur and proximal tibia, with splaying and fraying.
      PubDate: 2017-03-19T23:21:06.306929-05:
      DOI: 10.1111/cge.12916
  • Cartilage-hair hypoplasia with normal height in childhood—4 patients
           with a unique genotype
    • Authors: P. Klemetti; H. Valta, S. Kostjukovits, M. Taskinen, S. Toiviainen-Salo, O. Mäkitie
      Abstract: The manifestations of cartilage-hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (−1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10-nucleotide duplication at position −13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS −1.6 at 14 years and −3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra-skeletal manifestations, emphasizing the need for careful follow-up also in CHH patients with mild-skeletal manifestations.
      PubDate: 2017-03-19T23:11:14.025809-05:
      DOI: 10.1111/cge.12969
  • A recognizable type of syndromic short stature with arthrogryposis caused
           by bi-allelic SEMA3A loss-of-function variants
    • Authors: M. Baumann; E. Steichen-Gersdorf, B. Krabichler, T. Müller, A.R. Janecke
      Abstract: The semaphorins constitute a large family of secreted and membrane-associated proteins that regulate many developmental processes, including neural circuit assembly, bone formation and angiogenesis. Recently, bi-allelic loss-of-function variants in SEMA3A (semaphorin 3A) were identified in a single patient with a particular pattern of multiple congenital anomalies (MCA). Using homozygosity mapping combined with exome sequencing, we identified a homozygous SEMA3A variant causing a premature stop codon in an 8 year old boy with the same pattern of MCA. The phenotype of these patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Motor development is delayed in both patients, and intellectual development is delayed in one patient. Our observation of a second case supports the notion that bi-allelic mutations in SEMA3A cause an autosomal recessive type of syndromic short stature.
      PubDate: 2017-03-19T23:11:08.129137-05:
      DOI: 10.1111/cge.12967
  • Associations of microRNA single nucleotide polymorphisms and disease risk
           and pathophysiology
    • Authors: X. Liu; Z. Han, C. Yang
      Abstract: Single nucleotide polymorphisms (SNPs) are genetic variations that contribute to human phenotypes associated with various diseases. SNPs are involved in the regulation of a broad range of physiological and pathological processes, such as cellular senescence, apoptosis, inflammation, and immune response, by upregulating the expression of classical inflammation markers. Recent studies have suggested that SNPs located in gene-encoding microRNAs (miRNAs) affect various aspects of diseases by regulating the expression or activity of miRNAs. In the last few years, miRNA polymorphisms that increase and/or reduce the risk of developing many diseases, such as cancers, autoimmune diseases, and cardiovascular diseases, have attracted increasing attention not only because of their involvement in the pathophysiology of diseases but also because they can be used as prognostic biomarkers for a variety of diseases. In this review, we summarize the relationships between miRNA SNPs and the pathophysiology and risk of diseases.
      PubDate: 2017-03-19T23:10:50.94954-05:0
      DOI: 10.1111/cge.12950
  • Association of genetic variation with blood pressure traits among East
    • Authors: J. Kayima; J. Liang, Y. Natanzon, J. Nankabirwa, I. Ssinabulya, J. Nakibuuka, A. Katamba, H. Mayanja-Kizza, A. Miron, C. Li, X. Zhu
      Abstract: IntroductionGenetic variation may play explain some of the disparity in prevalence and control of hypertension across Sub-Saharan Africa. However, there have been very few studies to characterize genetic variation of blood pressure traits.AimTo determine whether a set of blood pressure-associated genetic loci can be replicated among samples East African samples.MethodsTwenty-seven blood pressures (BP)-related single nucleotide polymorphisms (SNPs) were genotyped among 2881 samples from participants in the Medical Education Partnership Initiative for Cardiovascular Disease (MEPI-CVD) survey. Associations with known BP variants were evaluated for systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) as continuous variables and for hypertension (HTN) as a binary variable.ResultsEleven SNPS were associated with at least 1 BP trait (P 
      PubDate: 2017-03-19T23:06:05.918972-05:
      DOI: 10.1111/cge.12974
  • Dental and extra-oral clinical features in 41 patients with WNT10A gene
           mutations: A multicentric genotype–phenotype study
    • Authors: C. Tardieu; S. Jung, K. Niederreither, M. Prasad, S. Hadj-Rabia, N. Philip, A. Mallet, E. Consolino, E. Sfeir, B. Noueiri, N. Chassaing, H. Dollfus, M.C. Manière, A. Bloch-Zupan, F. Clauss
      Abstract: WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.
      PubDate: 2017-03-19T23:05:59.092595-05:
      DOI: 10.1111/cge.12972
  • A 15-year-long Southern blotting analysis of FMR1 to detect female
           carriers and for prenatal diagnosis of fragile X syndrome in Taiwan
    • Authors: C.-C. Tzeng; L.-P. Tsai, Y.-K. Chang, Y.-J. Hung, Y.-Y. Chang, Y.-P. Su, J.-J. Jiang, H.-M. Liang
      Abstract: Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15-year period. In total, 725 high-risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low-risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low-risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156-1/539). A total of 100 carriers were found to be in the high-risk group, thus revealing a significantly higher frequency than the low-risk group (100/725 vs 2/3911, P
      PubDate: 2017-03-19T23:00:49.308187-05:
      DOI: 10.1111/cge.12981
  • A duplication in a patient with 46,XX ovo-testicular disorder of sex
    • Authors: T. Ohnesorg; J.A. Bergen, D. Belluoccio, N. Shankara-Narayana, A.-M. Kean, A. Vasilaras, L. Ewans, K.L. Ayers, A.H. Sinclair
      Abstract: A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3′ breakpoint region magnified.
      PubDate: 2017-03-19T23:00:36.894846-05:
      DOI: 10.1111/cge.12976
  • EDA mutation by exome sequencing in non-syndromic X-linked oligodontia
    • Authors: L. Martins; R. A. Machado, D. S. Araujo, P. A. Giovani, P. D. Rebouças, L. P. Rodrigues, L. S. Mofatto, M. M. Ribeiro, L. L. Coutinho, R. M. Puppin-Rontani, R. D. Coletta, F. H. Nociti, K. R. Kantovitz
      PubDate: 2017-03-19T22:55:43.418401-05:
      DOI: 10.1111/cge.12961
  • Mutations in ERGIC1 cause Arthrogryposis Multiplex Congenita, Neuropathic
    • Authors: Eyal Reinstein; Valerie Dersinover, Rona Lotan, Meital Gal-Tanhami, Inbal Bulokin Nachman, Eran Eyal, Jaber Lutfi, Nurit Magal, Mordechai Shohat
      Abstract: Arthrogryposis multiplex congenita (AMC) is heterogeneous group of disorders characterized by non-progressive joint contractures from birth that involve more than one part of the body. There are various etiologies for AMC including genetic and environmental depends on the specific type, however, for most types, the cause is not fully understood. We previously reported large Israeli Arab kindred consisting of 16 patients affected with AMC neuropathic type, and mapped the locus to a 5.5 cM interval on chromosome 5qter. Using whole exome sequencing, we have now identified homozygous pathogenic variant in the ERGIC1 gene within the previously defined linked region. This gene encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. We further show that this mutation was absent in more than 200 samples of healthy unrelated individuals of the Israeli Arab population. Thus, our findings expand the spectrum of hereditary AMC and suggest that abnormalities in protein trafficking may underlie AMC-related disorders.
      PubDate: 2017-03-19T21:55:33.751994-05:
      DOI: 10.1111/cge.13018
  • Genetic profiling of children with advanced cholestatic liver disease
    • Authors: M. Shagrani; J. Burkholder, D. Broering, M. Abouelhoda, T. Faquih, M. El-Kalioby, S.N. Subhani, E. Goljan, R. Albar, D. Monies, N. Mazhar, B.S. AlAbdulaziz, K.A. Abdelrahman, N. Altassan, F.S. Alkuraya
      Abstract: Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.
      PubDate: 2017-03-17T00:05:38.245652-05:
      DOI: 10.1111/cge.12959
  • Novel mutations in KARS cause hypertrophic cardiomyopathy and combined
           mitochondrial respiratory chain defect
    • Authors: D. Verrigni; D. Diodato, M. Di Nottia, A. Torraco, E. Bellacchio, T. Rizza, G. Tozzi, M. Verardo, F. Piemonte, G. Tasca, A. D'Amico, E. Bertini, R. Carrozzo
      Abstract: Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot–Mary–Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
      PubDate: 2017-03-17T00:00:40.602796-05:
      DOI: 10.1111/cge.12931
  • Deletion of the transcription factor SOX4 is implicated in syndromic
    • Authors: A. Trimouille; E. Barouk-Simonet, S. Charron, J. Bouron, J.-C. Bernhard, D. Lacombe, P. Fergelot, C. Rooryck
      PubDate: 2017-03-16T23:51:00.533816-05:
      DOI: 10.1111/cge.12977
  • Reassessing the clinical spectrum associated with Hereditary
           Leiomyomatosis and Renal Cell Carcinoma syndrome in French FH mutation
    • Authors: Marie Muller; Sophie Ferlicot, Marine Guillaud-Bataille, Gwénaël Le Teuff, Catherine Genestie, Sophie Deveaux, Abdelhamid Slama, Nicolas Poulalhon, Bernard Escudier, Laurence Albiges, Nadem Soufir, Marie-Françoise Avril, Betty Gardie, Carolina Saldana, Yves Allory, Anne-Paule Gimenez-Roqueplo, Brigitte Bressac- de Paillerets, Stéphane Richard, Patrick R. Benusiglio
      Abstract: We addressed uncertainties regarding Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate Hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, thirteen were papillary type 2. There were four papillary RCC of unspecified type, three unclassified, two tubulocystic, and one collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining fourteen, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI:11–29). 133 cases (73%) had a history of cutaneous leiomyomas, three developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only two cases had pheochromocytomas/paraganglioma. Our findings have direct implications regarding the identification and management of HLRCC patients.
      PubDate: 2017-03-16T06:46:05.123655-05:
      DOI: 10.1111/cge.13014
  • Geographical and ethnic distribution of MTHFR gene polymorphisms and their
           associations with diseases among Chinese population
    • Authors: B. Yang; S. Fan, X. Zhi, R. Xia, Y. Wang, Q. Zheng, G. Sun
      Abstract: Numerous studies have investigated the distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and their associations with diseases in China. In this study we conducted a systematic review and meta-analysis of these studies (715 eligible studies in total).Results revealed that the frequencies of the MTHFR C677T and A1298C polymorphisms varied markedly in different areas and ethnicities, and even showed geographical gradients. The MTHFR C677T polymorphism was significantly associated with 42 clinical disorders (p < 0.05), mostly relating to the diseases of circulatory system, birth defects and cancers. The association of the A1298C polymorphism with three diseases (coronary heart disease, breast cancer and neural tube defects fathers) was statistically significant (p < 0.05). However, according to the Venice criteria, only the associations of the C677T polymorphism with breast and ovarian cancers were assessed as having strong epidemiological credibility. This is the first study to provide a comprehensive assessment of the current status and gaps in genetic epidemiological study of the two polymorphisms in China, and its findings may be useful for medical and public health practices. Future studies are warranted to focus on the interactions of MTHFR genes with environmental exposure and with other genes, and to improve their methodological quality and reporting of findings.
      PubDate: 2017-03-15T03:41:00.982358-05:
      DOI: 10.1111/cge.12929
  • Mutations in CRLF1 cause familial achalasia
    • Authors: A. Busch; M. Žarković, C. Lowe, M. Jankofsky, R. Ganschow, I. Buers, I. Kurth, H. Reutter, F. Rutsch, C.A. Hübner
      Abstract: We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.
      PubDate: 2017-03-15T03:40:48.73037-05:0
      DOI: 10.1111/cge.12953
  • Systematic approach to understanding the pathogenesis of systemic
    • Authors: Xiaoxia Zuo; Lihua Zhang, Hui Luo, Yisha Li, Honglin Zhu
      Abstract: Systemic sclerosis (SSc) is a complex heterogeneous autoimmune disease. Progressive organ fibrosis is a major contributor to SSc mortality. Despite extensive efforts, the underlying mechanism of SSc remains unclear. Efforts to understand the pathogenesis of SSc have included genomics, epigenetics, transcriptomic, proteomic and metabolomic studies in the last decade.This review focuses on recent studies in SSc research based on multi-omics. The combination of these technologies can help us understand the pathogenesis of SSc. This review aims to provide important information for disease identification, therapeutic targets and potential biomarkers.
      PubDate: 2017-03-15T03:40:41.481522-05:
      DOI: 10.1111/cge.12946
  • Molecular, clinical and neuropsychological study in 31 patients with
           Kabuki syndrome and KMT2D mutations
    • Authors: Natacha Lehman; Anne Claire Mazery, Antoine Visier, Clarisse Baumann, Dominique Lachesnais, Yline Capri, Annick Toutain, Sylvie Odent, Myriam Mikaty, Cyril Goizet, Emmanuelle Taupiac, Marie Line Jacquemont, Elodie Sanchez, Elise Schaefer, Vincent Gatinois, Laurence Faivre, Delphine Minot, Honorine Kayirangwa, Kim-Hanh Le Qang Sang, Nathalie Boddaert, Sophie Bayard, Didier Lacombe, Sébastien Moutton, Isabelle Touitou, Marlène Rio, Jeanne Amiel, Stanislas Lyonnet, Damien Sanlaville, Marie Christine Picot, David Geneviève
      Abstract: Kabuki syndrome (KS - OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with Kabuki syndrome and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI). In addition, molecular data and several clinical symptoms were studied. FSIQ and VCI scores were 10 points lower for patients with a truncating mutation than other types of mutations. In addition, scores for FSIQ, VCI and PRI were lower for children with visual impairment than normal vision. We also identified a discrepancy in indexes characterized by high WMI and VCI and low PRI and PSI. We emphasize the importance of early identification and intensive care of visual disorders in patients with Kabuki syndrome and recommend individual assessment of intellectual profile.
      PubDate: 2017-03-14T21:45:28.300831-05:
      DOI: 10.1111/cge.13010
  • CNVs analysis in a cohort of isolated and syndromic DD/ID reveals novel
           genomic disorders, position effects and candidate disease genes
    • Authors: Eleonora Di Gregorio; Evelise Riberi, Elga Fabia Belligni, Elisa Biamino, Malte Spielmann, Ugo Ala, Alessandro Calcia, Irene Bagnasco, Diana Carli, Giorgia Gai, Mara Giordano, Andrea Guala, Roberto Keller, Giorgia Mandrile, Carlo Arduino, Antonella Maffè, Valeria Giorgia Naretto, Fabio Sirchia, Lorena Sorasio, Silvana Ungari, Andrea Zonta, Giulia Zacchetti, Flavia Talarico, Patrizia Pappi, Simona Cavalieri, Elisa Giorgio, Cecilia Mancini, Marta Ferrero, Alessandro Brussino, Elisa Savin, Marina Gandione, Alessandra Pelle, Daniela Francesca Giachino, Mario De Marchi, Gabriella Restagno, Paolo Provero, Margherita Cirillo Silengo, Enrico Grosso, Joseph D. Buxbaum, Barbara Pasini, Silvia De Rubeis, Alfredo Brusco, Giovanni Battista Ferrero
      Abstract: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect Copy Number Variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries likely affecting the regulatory landscape.In conclusion, we show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
      PubDate: 2017-03-14T21:20:24.713408-05:
      DOI: 10.1111/cge.13009
  • A nonsense mutation in CEP55 defines a new locus for a Meckel-like
           syndrome, an autosomal recessive lethal fetal ciliopathy
    • Authors: Marie-Louise Bondeson; Katharina Ericson, Sanna Gudmundsson, Adam Ameur, Fredrik Pontén, Jan Wesström, Carina Frykholm, Maria Wilbe
      Abstract: Mutations in genes involved in the cilium–centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family.CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.
      PubDate: 2017-03-14T20:40:28.917884-05:
      DOI: 10.1111/cge.13012
  • Debunking Occam's razor: Diagnosing multiple genetic diseases in families
           by whole-exome sequencing
    • Authors: T.B. Balci; T. Hartley, Y. Xi, D.A. Dyment, C.L. Beaulieu, F.P. Bernier, L. Dupuis, G.A. Horvath, R. Mendoza-Londono, C. Prasad, J. Richer, X.-R. Yang, C.M. Armour, E. Bareke, B.A. Fernandez, H.J. McMillan, R.E. Lamont, J. Majewski, J.S. Parboosingh, A.N. Prasad, C.A. Rupar, J. Schwartzentruber, A.C. Smith, M. Tétreault, , , A.M. Innes, K.M. Boycott
      Abstract: BackgroundRecent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown.AimsWe set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada.Materials & MethodsWe retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives.ResultsOf the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family.ConclusionOur findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.
      PubDate: 2017-03-13T22:45:29.415954-05:
      DOI: 10.1111/cge.12987
  • Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor
           protein gene, cause short-rib polydactyly type I, Saldino–Noonan type
    • Authors: N. Badiner; S.P. Taylor, K. Forlenza, R. S. Lachman, , M. Bamshad, D. Nickerson, D. H. Cohn, D. Krakow
      Abstract: The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I–IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino–Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.
      PubDate: 2017-03-13T04:51:25.898585-05:
      DOI: 10.1111/cge.12947
  • Maternal uniparental disomy of chromosome 16 [upd(16)mat]: clinical
           features are rather caused by (hidden) trisomy 16 mosaicism than by
           upd(16)mat itself
    • Authors: R. Scheuvens; M. Begemann, L. Soellner, D. Meschede, G. Raabe-Meyer, M. Elbracht, R. Schubert, T. Eggermann
      Abstract: Maternal uniparental disomy of chromosome 16 [upd(16)mat] as the result of trisomy 16 is one of the most frequently reported uniparental disomies in humans, but a consistent phenotype is not obvious. Particularly, it is difficult to discriminate between features resulting from upd(16)mat and mosaic trisomy 16. By evaluating literature data (n = 74) and three own cases we aimed to determine whether the clinical features are due to upd(16)mat or to trisomy 16 mosaicism. While in single cases the clinical symptoms were caused by homozygosity of autosomal recessive mutations on chromosome 16, it turned out that clinical features in upd(16)mat are caused by (hidden) trisomy 16 mosaicism and a specific chromosome 16-associated imprinting disorder does not exist. In trisomy 16/upd(16)mat pregnancies, the management should be based on the ultrasound results and on the clinical course of the pregnancy. In fact, mosaic trisomy 16 pregnancies require a close monitoring because of the higher risk for hypertensive disorders. Postnatal testing for upd(16)mat should be considered in case of homozygosity for an autosomal-recessive mutation, in individuals carrying chromosome 16 aberrations and in phenotypes comprising features of the trisomy 16/upd(16)mat spectrum. Finally, upd(16)mat probably represents a bioindicator for a hidden trisomy 16 mosaicism.
      PubDate: 2017-03-08T00:15:56.770441-05:
      DOI: 10.1111/cge.12958
  • Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a
           cohort of 226 Chinese CMT families
    • Authors: L. Liu; X.B. Li, Z.H.M. Hu, X.H. Zi, X. Zhao, Y.Z. Xie, S.H.X. Huang, K. Xia, B.S. Tang, R.X. Zhang
      Abstract: The aim of this study is to explore the phenotypic and genotypic features of X-linked Charcot–Marie-Tooth (CMT) disease in the mainland of China and to study the cellular effects of six novel Gap junction protein beta-1 variants. We identified 25 missense and 1 non-sense mutations of GJB1 in 31 unrelated families out of 226 CMT families. The frequency of GJB1 mutations was 13.7% of the total and 65% of intermediate CMT. Six novel GJB1 variants (c.5A>G, c.8G>A, c.242T>C, c.269T>C, c.317T>C and c.434T>G) were detected in six unrelated intermediate CMT families. Fluorescence revealed that HeLa cells transfected with EGFP-GJB1-V74M, EGFP-GJB1-L81P or EGFP-GJB1-L90P had diffuse endoplasmic reticulum staining, HeLa cells transfected with EGFP-GJB1-L106P had diffuse intracellular staining, and HeLa cells transfected with EGFP-GJB1-N2S had cytoplasmic and nuclear staining. The distribution of Cx32 in HeLa cells transfected with EGFP-GJB1-F145C was similar to that of those transfected with wild-type (WT). These six variants resulted in a higher percentage of apoptosis than did WT as detected by flow cytometry and Hoechst staining. In conclusion, mutation screening should be first performed in intermediate CMT patients, especially those with additional features. The novel GJB1 variants c.5A>G, c.8G>A, c.242T>C and c.269T>C are considered pathogenic, and c.317T>C and c.434T>G are classified as probably pathogenic.
      PubDate: 2017-03-08T00:15:45.18914-05:0
      DOI: 10.1111/cge.12913
  • Genotype and phenotype in 12 additional individuals with SATB2-associated
    • Authors: Y.A. Zarate; L. Kalsner, A. Basinger, J.R. Jones, C. Li, M. Szybowska, Z.L. Xu, S. Vergano, A.R. Caffrey, C.V. Gonzalez, H. Dubbs, E. Zackai, F. Millan, A. Telegrafi, B. Baskin, R. Person, J.L. Fish, D.B. Everman
      Abstract: SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.
      PubDate: 2017-03-07T05:50:40.653865-05:
      DOI: 10.1111/cge.12982
  • Expanding the mutation spectrum in ICF syndrome: Evidence for a gender
           bias in ICF2
    • Authors: M.L. Boogaard; P.E. Thijssen, C. Aytekin, F. Licciardi, A.A. Kıykım, L. Spossito, V.A.S.H. Dalm, G.J. Driessen, R. Kersseboom, F. Vries, M.M. Ostaijen-ten Dam, A. Ikinciogullari, F. Dogu, M. Oleastro, E. Bailardo, L. Daxinger, E. Nain, S. Baris, M.J.D. Tol, C. Weemaes, S.M. Maarel
      Abstract: BackgroundImmunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations).AimTo study the mutation spectrum in ICF syndrome.Materials and methodsGenetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. ResultsWe describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients.DiscussionThe biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort.ConclusionOur study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
      PubDate: 2017-03-07T05:50:35.063728-05:
      DOI: 10.1111/cge.12979
  • TYROSINEMIA TYPE II: Mutation update, eleven novel mutations and
           description of five independent subjects with a novel founder mutation
    • Authors: Luis Peña-Quintana; Gerd Scherer, María Lutgarda Curbelo-Estévez, Francisco Jiménez-Acosta, Britta Hartmann, Fátima La Roche, Silvia Meavilla-Olivas, Celia Pérez-Cerdá, Nuria García Segarra, Yves Giguère, Peter Huppke, Grant A. Mitchell, Eberhard Mönch, Dorothy Trump, Christine Vianey-Saban, Elisabeth R. Trimble, Isidro Vitoria-Miñana, Desiderio Reyes-Suárez, Teresa Ramírez-Lorenzo, Antonio Tugores
      Abstract: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. We report eleven novel genetic variants and have performed an extensive review of all cases described in the literature, identifying a total of 106 families, represented by 143 individuals, carrying a total of 36 genetic variants including 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants resulting in reduced function, truncated or absent TAT polypeptides. We also report five patients from Gran Canaria, representing the largest known group of apparently unrelated families sharing the same P406L mutation, that did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis. All patients improved the oculo-cutaneous lesions after dietary treatment leading to decreased blood tyrosine levels but neurological symptoms prevailed. The discovery of a founder mutation in an isolated population and the benefits of early intervention should increase diagnostic awareness and facilitate genetic screening in newborns.
      PubDate: 2017-03-03T01:55:27.859312-05:
      DOI: 10.1111/cge.13003
  • Further delineation of a rare recessive encephalomyopathy linked to
           mutations in GFER thanks to data sharing of whole exome sequencing data
    • Authors: S. Nambot; D. Gavrilov, J. Thevenon, A.L. Bruel, M. Bainbridge, M. Rio, C. Goizet, A. Rötig, J. Jaeken, N. Niu, F. Xia, A. Vital, N. Houcinat, F. Mochel, P. Kuentz, D. Lehalle, Y. Duffourd, J.B. Rivière, C. Thauvin-Robinet, A.L. Beaudet, L. Faivre
      Abstract: BackgroundAlterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community.Materials and MethodsWhole exome sequencing was performed as part of a “diagnostic odyssey” for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER.ResultsThanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease.ConclusionThis report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra-rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.
      PubDate: 2017-03-01T22:20:46.263847-05:
      DOI: 10.1111/cge.12985
  • A novel missense mutation in NR0B1 causes delayed-onset primary adrenal
           insufficiency in adults
    • Authors: C.-M. Oh; S. Chun, J.-E. Lee, J.S. Lee, S. Park, H.Y. Gee, S.W. Kim
      Abstract: A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late-onset adrenal insufficiency without hypogonadism.
      PubDate: 2017-03-01T22:20:38.011649-05:
      DOI: 10.1111/cge.12966
  • Unraveling molecular pathways shared by Kabuki and Kabuki-like syndromes
    • Authors: C. Lintas; A.M. Persico
      Abstract: Kabuki syndrome (KS) is a rare genetic syndrome characterized by a typical facial gestalt, variable degrees of intellectual disability, organ malformations, postnatal growth retardation and skeletal abnormalities. So far, KMT2D or KDM6A mutation has been identified as the main cause of KS, accounting for 56%-75% and 3%-8% of cases, respectively. Patients without mutations in 1 of the 2 causative KS genes are often referred to as affected by Kabuki-like syndrome. Overall, they represent approximately 30% of KS cases, pointing toward substantial genetic heterogeneity for this condition. Here, we review all currently available literature describing KS-like phenotypes (or phenocopies) associated with genetic variants located in loci different from KMT2D and KDM6A. We also report on a new KS phenocopy harboring a 5 Mb de novo deletion in chr10p11.22-11.21. An enrichment analysis aimed at identifying functional Gene Ontology classes shared by the 2 known KS causative genes and by new candidate genes currently associated with KS-like phenotypes primarily converges upon abnormal chromatin remodeling and transcriptional dysregulation as pivotal to the pathophysiology of KS phenotypic hallmarks. The identification of mutations in genes belonging to the same functional pathways of KMT2D and KDM6A can help design molecular screenings targeted to KS-like phenotypes.
      PubDate: 2017-03-01T22:20:30.779454-05:
      DOI: 10.1111/cge.12983
  • Reconstruction of a Palaeosurface and Archaeological Site Location in an
           Anthropogenic Drift Sand Area
    • Authors: Anna Schneider; Florian Hirsch, Klaus-Peter Wechler, Alexandra Raab, Thomas Raab
      Abstract: Knowledge of the position of archaeological remains in the surface relief provides important basic information for archaeological survey design and interpretation. Geomorphological processes in (pre)history may have resulted in a modification of the local relief around archaeological sites, especially in areas that are prone to sediment erosion and relocation, such as sheet sand and dune landscapes. In this study, we reconstructed and analysed the palaeorelief of an archaeological excavation site in an inland dune area in southern Brandenburg, Germany. The remains of two Mesolithic sites were documented in the archaeological excavations and found to be associated with a buried soil horizon. To gather information on the relief of the buried soil surface, we used a combination of sedimentological and pedological profile descriptions along archaeological survey trenches and geophysical prospection with ground penetrating radar supplemented with microdrone photography and photogrammetry, global positioning system (GPS) surveys, and analysis of LiDAR-based elevation models. A digital elevation model of the buried surface was generated and analysed using a geographical information system (GIS). A comparison of the palaeosurface model with the recent surface elevation model shows that sand remobilization resulted in a considerable reshaping of the relief. Further, an analysis of the buried surface model shows that the relief position of the two archaeological sites in the study area was considerably more prominent in relation to the corresponding buried soil surface than in relation to the recent surface morphology. The results affirm the significance of Holocene sediment relocation for the local surface morphology and the importance of considering such relief modifications in archaeological surveys. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-28T03:00:40.646207-05:
      DOI: 10.1002/arp.1571
  • Chondrodysplasia with multiple dislocations: comprehensive study of a
           series of 30 cases
    • Authors: E. Ranza; C. Huber, N. Levin, G. Baujat, C. Bole-Feysot, P. Nitschke, C. Masson, Y. Alanay, L. Al-Gazali, P. Bitoun, O. Boute, P. Campeau, C. Coubes, M. McEntagart, N. Elcioglu, L. Faivre, A. Gezdirici, D. Johnson, E. Mihci, B.G. Nur, L. Perrin, C. Quelin, P. Terhal, B. Tuysuz, V. Cormier-Daire
      Abstract: The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
      PubDate: 2017-02-23T02:41:19.622916-05:
      DOI: 10.1111/cge.12885
  • Broadening the phenotypic spectrum of POP1-skeletal dysplasias:
           identification of POP1 mutations in a mild and severe skeletal dysplasia
    • Authors: J. Barraza-García; C.I. Rivera-Pedroza, A. Hisado-Oliva, A. Belinchón-Martínez, L. Sentchordi-Montané, E.L. Duncan, G.R. Clark, A. Pozo, K. Ibáñez-Garikano, A. Offiah, P. Prieto-Matos, V. Cormier-Daire, K.E. Heath
      Abstract: Processing of Precursor 1 (POP1) is a large protein common to the ribonuclease-mitochondrial RNA processing (RNase-MRP) and RNase-P (RMRP) endoribonucleoprotein complexes. Although its precise function is unknown, it appears to participate in the assembly or stability of both complexes. Numerous RMRP mutations have been reported in individuals with cartilage-hair hypoplasia (CHH) but, to date, only three POP1 mutations have been described in two families with features similar to anauxetic dysplasia (AD). We present two further individuals, one with severe short stature and a relatively mild skeletal dysplasia and another in whom AD was suspected. Biallelic POP1 mutations were identified in both. A missense mutation and a novel single base deletion were detected in proband 1, p.[Pro582Ser]:[Glu870fs*5]. Markedly reduced abundance of RMRP and elevated levels of pre5.8s rRNA was observed. In proband 2, a homozygous novel POP1 mutation was identified, p.[(Asp511Tyr)];[(Asp511Tyr)]. These two individuals show the phenotypic extremes in the clinical presentation of POP1-dysplasias. Although CHH and other skeletal dysplasias caused by mutations in RMRP or POP1 are commonly cited as ribosomal biogenesis disorders, recent studies question this assumption. We discuss the past and present knowledge about the function of the RMRP complex in skeletal development.
      PubDate: 2017-02-22T03:16:36.37931-05:0
      DOI: 10.1111/cge.12964
  • SF1 and spleen development: new heterozygous mutation, literature review
           and consequences for NR5A1-mutated patient's management
    • Authors: C. Colson; E. Aubry, M. Cartigny, A.-A. Rémy, H. Franquet, X. Leroy, G. Kéchid, C. Lefèvre, R. Besson, M. Cools, A.F. Spinoit, C. Sultan, S. Manouvrier, P. Philibert, J. Ghoumid
      Abstract: Steroidogenic factor 1 (encoded by SF1/NR5A1) is a transcription factor with multiple target genes involved in the development and function of multiple steroidogenic and non-steroidogenic tissues. NR5A1 mutations lead to several phenotypes, including sex reversal, spermatogenesis failure, premature ovarian failure and adrenocortical insufficiency. The implication of NR5A1 mutations in spleen development anomalies was recently highlighted. We provide new evidence of this involvement, describing a novel heterozygous non-sense NR5A1 mutation in a 46,XY-DSD with polysplenia female proband and her father, who had hypospadias and asplenia.
      PubDate: 2017-02-22T03:16:11.595022-05:
      DOI: 10.1111/cge.12957
  • Multilocus analysis reveals three candidate genes for Chinese migraine
    • Authors: X.-K. An; J. Fang, Z.-Z. Yu, Q. Lin, C.-X. Lu, H.-L. Qu, Q.-L. Ma
      Abstract: Several genome-wide association studies (GWASs) in Caucasian populations have identified 12 loci that are significantly associated with migraine. More evidence suggests that serotonin receptors are also involved in migraine pathophysiology. In the present study, a case–control study was conducted in a cohort of 581 migraine cases and 533 ethnically matched controls among a Chinese population. Eighteen polymorphisms from serotonin receptors and GWASs were selected, and genotyping was performed using a Sequenom MALDI-TOF mass spectrometry iPLEX platform. The genotypic and allelic distributions of MEF2D rs2274316 and ASTN2 rs6478241 were significantly different between migraine patients and controls. Univariate and multivariate analysis revealed significant associations of polymorphisms in the MEF2D and ASTN2 genes with migraine susceptibility. MEF2D, PRDM16 and ASTN2 were also found to be associated with migraine without aura (MO) and migraine with family history. And, MEF2D and ASTN2 also served as genetic risk factors for the migraine without family history. The generalized multifactor dimensionality reduction analysis identified that MEF2D and HTR2E constituted the two-factor interaction model. Our study suggests that the MEF2D, PRDM16 and ASTN2 genes from GWAS are associated with migraine susceptibility, especially MO, among Chinese patients. It appears that there is no association with serotonin receptor related genes.
      PubDate: 2017-02-22T03:16:04.505957-05:
      DOI: 10.1111/cge.12962
  • Drones in Archaeology. State-of-the-art and Future Perspectives
    • Authors: Stefano Campana
      Abstract: In addition to traditional platforms for low-level remote sensing (balloons, kites, etc.) new and more complex automated systems [unmanned aerial vehicles (UAVs) or drones] have become available in the last decade. The success and market expansion of these platforms has been a driving force in the development of active and passive sensors specifically designed for UAVs. In the last few years archaeologists have started testing both platforms and sensors, particularly for the following applications: three-dimensional (3D) documentation of archaeological excavations; 3D survey of monuments and historic buildings; survey of archaeological sites and landscapes; exploratory aerial survey; and the archaeological survey of woodland areas. The scale of these applications has ranged from site-based to landscapes-based (approximately up to about 10 km2 in extent). The role of such platforms in the archaeological survey of excavations and landscapes, and in diagnostics more generally, is of great interest and is inexorably growing. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-17T00:11:29.941166-05:
      DOI: 10.1002/arp.1569
  • Reconstructing Palaeogeography and Inter-island Visibility in the
           Wallacean Archipelago During the Likely Period of Sahul Colonization,
           65–45 000 Years Ago
    • Authors: Shimona Kealy; Julien Louys, Sue O'Connor
      Abstract: The palaeogeography of the Wallacea Archipelago is a significant factor in understanding early modern human colonization of Sahul (Australia and New Guinea), and models of colonization patterns, as well as archaeological survey and site interpretation, are all heavily dependent on the specific palaeogeographic reconstruction employed. Here we present five reconstructions for the periods 65, 60, 55, 50, and 45 000 years ago, using the latest bathometric chart and a sea-level model that is adjusted to account for the average uplift rate known from Wallacea. Using this data we also reconstructed island areal extent as well as topography for each time period. These reconstructions were then used to estimate visibility for each island in the archipelago, and finally to model how intervisible each island was during the period of likely human colonization. Our models provide the first evidence for intervisibility between Timor and Australia at ca. 65–62 ka and 47–12 ka, the second of which is notable for its overlap with the oldest radiocarbon dates from Timor-Leste and Australia. Based on intervisibility alone, however, our study suggests that the northern route into Papua New Guinea was the most parsimonious route for first modern human entry into Sahul. Our study provides archaeologists with an important baseline from which to conduct physical surveys, interpret archaeological data, and theorize the colonization of Wallacea and Sahul. © 2017 The
      Authors . Archaeological Prospection Published by John Wiley & Sons Ltd.
      PubDate: 2017-02-16T22:31:11.905921-05:
      DOI: 10.1002/arp.1570
  • Digital Terrain Analysis Reveals New Insights into the Topographic Context
           of Australian Aboriginal Stone Arrangements
    • Authors: W. Boone Law; Michael J. Slack, Bertram Ostendorf, Megan M. Lewis
      Abstract: Satellite-derived surface elevation models are an important resource for landscape archaeological studies. Digital elevation data is useful for classifying land features, characterizing terrain morphology, and discriminating the geomorphic context of archaeological phenomena. This paper shows how remotely sensed elevation data obtained from the Japan Aerospace Exploration Agency's Advanced Land Observing Satellite was integrated with local land system spatial data to digitally classify the topographic slope position of seven broad land classes. The motivation of our research was to employ an objective method that would allow researchers to geomorphometrically discriminate the topographic context of Aboriginal stone arrangements, an important archaeological site type in the Pilbara region of northwest Australia. The resulting digital terrain model demonstrates that stone arrangement sites are strongly correlated with upper topographic land features, a finding that contradicts previous site recordings and fundamentally changes our understanding of where stone arrangement sites are likely to have been constructed. The outcome of this research provides investigators with a stronger foundation for testing hypotheses and developing archaeological models. To some degree, our results also hint at the possible functions of stone arrangements, which have largely remained enigmatic to researchers. © 2017 The
      Authors . Archaeological Prospection Published by John Wiley & Sons Ltd.
      PubDate: 2017-02-16T04:20:53.940818-05:
      DOI: 10.1002/arp.1567
  • Mutations of MYH14 Are Associated to Anorectal Malformations with
           Recto-perineal Fistulas in a Small Subset of Chinese Population
    • Authors: Zhongxian Zhu; Lei Peng, Guanglin Chen, Weiwei Jiang, Ziyang Shen, Chunxia Du, Rujin Zang, Yang Su, Hua Xie, Hongxing Li, Yankai Xia, Weibing Tang
      Abstract: Anorectal malformations (ARMs) are among the most commonly congenital abnormalities of distal hindgut development, ranging from anal stenosis to anal atresia with or without fistulas and persistent cloaca. The etiology remains elusive for most ARM cases and the majority of genetic studies on ARMs were based on a candidate gene approach. Here, we first performed whole-exome sequencing in a non-consanguineous Chinese family and the result revealed a homozygous mutation (GenBank: NM_001077186; c.5393C>A[p.Ala1806Asp]) in MYH14, which encodes one of the NM II heavy chain (NMHC II) proteins playing vital roles in cell adhesion and migration. Subsequently, exome sequencing of MYH14 in 72 unrelated probands with ARMs revealed one Chinese subject with compound heterozygous MYH14 changes (c.6003delC[p.Gln2003Serfs*33] and c.488G>A[p.Arg163Gln]). Immunohistochemical analysis suggest stronger MYH14 protein NMHC IIC localization in the epithelium of the murine embryonic cloaca, urorectal septum and hindgut during the anorectal development compared with another two NMHC II isoforms., which might compensate for the loss of NMHC IIC. This is the first identification of mutations in MYH14 as a cause of perineal fistulas in ARMs, at least in these two families. The stronger localization of NMHC IIC in E11.5-13.5 mouse cloacal regions further indirectly supports the role of MYH14 in anorectal development.
      PubDate: 2017-02-13T10:50:25.630355-05:
      DOI: 10.1111/cge.12993
  • The Passive Seismic Technique ‘HVSR’ as a Reconnaissance Tool for
           Mapping Paleo-soils: The Case of the Pilastri Archaeological Site,
           Northern Italy
    • Authors: Nasser Abu Zeid; Erica Corradini, Samuel Bignardi, Valentino Nizzo, Giovanni Santarato
      Abstract: Horizontal-to-vertical spectral ratio (HVSR) is a widely used geophysical technique in seismic microzonation studies. It is based on a specific analysis of seismic ambient noise. The method allows to obtain the frequency and amplitude of the resonance peaks of a layered earth with increasing acoustic impedance contrasts. The peaks can be interpreted to obtain an estimation of depth(s) of the impedance contrast horizon(s).Based on the assumption that long-term human trampling results in sediment's stiffening, which increased both density and velocity of seismic shear waves, the HVSR method was applied to investigate the shallow subsurface of an important, Middle Bronze Age, archaeological site called ‘Pilastri Terramara’ discovered at the end of the last century.Following recent excavations, archaeologists supposed that the settlement could extend outside the initially hypothesized borders, and decided to involve geophysicists to verify the truthiness of this new hypothesis and consequently to map the possible spatial extent of the paleo-surfaces frequented by ancient occupants. The purpose of the geophysical investigation was then to detect and possibly to map one or more anthropogenic paleo-surfaces over a relatively large area (about 12000 m2).Unfortunately, direct evidences showed that the paleo-surfaces were embedded in clayey sediments and laying at depths ranging between 50 and 170 cm below ground level. Furthermore, the area to be investigated is occupied by a farm with glasshouses and other buildings. These obstacles constituted a real challenge that hindered the utilization of the most commonly used geophysical methods in archaeology, i.e. ground penetration radar (GPR), magnetometry and electrical resistivity tomography. For these reasons, we decided to use the HVSR method as a reconnaissance exploration tool, to confirm or rule out the presence of such paleo-surfaces.Spectral peaks related to acoustic horizons provided evidences about their presence and allowed to estimate their depths as was later confirmed by a new excavation. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-10T02:05:51.911673-05:
      DOI: 10.1002/arp.1568
  • Geochemical Survey and Evaluation Excavations at Alderley Edge:
           Recognizing Anthropogenic Signatures within a Mining Site-scape
    • Authors: Christopher J. Carey; Norman R. Moles
      Abstract: Archaeological science and field investigations are making greater use of multi-element geochemical survey as a tool for site prospection and intra-excavation analysis. This increasing use of geochemical survey is allowing a new field of geoprospection to develop, a technique that has specific relevance to the investigation of sites containing archaeometallurgical evidence, due to the high geochemical loadings within archaeological contexts produced from past metalworking activities. Correspondingly, there have been relatively few published examples that compare the results of geochemical surveys against excavation data. This study reports the use of geochemical data to investigate a multi-period mining site-scape at Alderley Edge, Cheshire, UK. The geochemical data is analysed using principle component analysis, which facilitates the identification of a number of geochemical anomalies. The site taphonomy and stratigraphic evolution of this mining site-scape is complex, with naturally occurring areas of lead and copper mineralization and a history of exploitation since the early Bronze Age. The geochemical anomalies were compared to the results of excavation within the survey area and this combination of excavation and prospection data allowed the reasons for the different geochemical anomalies to be explained. The article highlights the potential of using multi-element geochemical survey to investigate sites containing archaeometallurgical remains and provides a discussion of why context specificity is essential to correctly interpret multi-element geochemical data. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-02T05:40:42.606026-05:
      DOI: 10.1002/arp.1566
  • Erythropoietic Protoporphyria (EPP), a Clinical and Molecular Study from
    • Authors: Humam Kadara; Georges Nemer, Remi Safi, Nelly Rebeiz, Laetitia Daou, Diana Delbani, Waed Btadini, Ossama Abbas, Mona Tofaili, Fadi Bitar, Abdul Ghani Kibbi, Yutaka Shimomura, Mazen Kurban
      Abstract: Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in six large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed two novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun exposed fibroblasts, relative to sun protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy.
      PubDate: 2017-01-11T05:31:31.948357-05:
      DOI: 10.1111/cge.12968
  • Issue Information
    • Pages: 1 - 2
      Abstract: No abstract is available for this article.
      PubDate: 2017-03-02T03:34:15.866571-05:
      DOI: 10.1002/arp.1554
  • Issue Information - Editorial Board
    • Pages: 651 - 651
      PubDate: 2017-04-12T03:33:14.191877-05:
      DOI: 10.1111/cge.12938
  • Catastrophic cellular events leading to complex chromosomal rearrangements
           in the germline
    • Authors: M. Fukami; H. Shima, E. Suzuki, T. Ogata, K. Matsubara, T. Kamimaki
      Pages: 653 - 660
      Abstract: Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from ‘all-at-once’ catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.
      PubDate: 2017-02-22T03:15:47.097523-05:
      DOI: 10.1111/cge.12928
  • Evaluation of a population-based approach to familial colorectal cancer
    • Authors: P.S. Parfrey; E. Dicks, O. Parfrey, P.J. McNicholas, H. Noseworthy, M.O. Woods, C. Negriin, J. Green
      Pages: 672 - 682
      Abstract: As Newfoundland has the highest rate of familial colorectal cancer (CRC) in the world, we started a population-based clinic to provide colonoscopic and Lynch syndrome (LS) screening recommendations to families of CRC patients based on family risk. Of 1091 incident patients 51% provided a family history. Seventy-two percent of families were at low or intermediate–low risk of CRC and colonoscopic screening recommendations were provided by letter. Twenty-eight percent were at high and intermediate–high risk and were referred to the genetic counsellor, but only 30% (N = 48) were interviewed by study end. Colonoscopy was recommended more frequently than every 5 years in 35% of families. Lower family risk was associated with older age of proband but the frequency of screening colonoscopy recommendations varied across all age groups, driven by variability in family history. Twenty-four percent had a high MMR predict score for a Lynch syndrome mutation, and 23% fulfilled the Provincial Program criteria for LS screening. A population-based approach in the provision of colonoscopic screening recommendations to families at risk of CRC was limited by the relatively low response rate. A family history first approach to the identification of LS families was inefficient.Flow chart for patients provided colonoscopic screening recommendations in the familial colorectal cancer clinic.
      PubDate: 2017-03-08T00:16:04.714234-05:
      DOI: 10.1111/cge.12877
  • Gene mutation analysis of 175 Chinese patients with early-onset epileptic
    • Authors: Q. Zhang; J. Li, Y. Zhao, X. Bao, L. Wei, J. Wang
      Pages: 717 - 724
      Abstract: The aim of the study is to investigate the genetic characteristics and clinical features of a cohort of Chinese patients with early-onset epileptic encephalopathies (EOEEs). Targeted next-generation sequencing (NGS), focusing on 17 genes, was performed on 175 Chinese patients with EOEEs to screen gene mutations. The mutation rate was 32% (56/175). All mutations were de novo and heterozygous, including 41 novel and 15 reported mutations. Patients with cyclin-dependent kinase-like 5 (CDKL5) gene mutation accounted for the largest proportion, 13.1% (23/175). All patients with CDKL5 mutation presented severe psychomotor developmental delay and refractory seizures. The female patients presented obvious Rett-like features, which were not observed in male patients. Potassium channel, voltage-gated KQT-like subfamily Q, member 2(KCNQ2) gene mutations were detected in 13 patients. Patients with this mutation presented with early seizure onset within the first week after birth. Valproate (VPA), levetiracetam (LEV) and topiramate (TPM) were effective in most patients. Patients with specific gene mutations presented some unique clinical features, but not always. Many genes are involved in EOEEs. Targeted NGS showed a high diagnostic yield in patients with EOEEs. These findings provide useful insights for recommending treatment of gene-associated EOEEs using antiepileptic drugs.
      PubDate: 2017-02-16T05:25:51.61501-05:0
      DOI: 10.1111/cge.12901
  • Phenotypic and genotypic characterization of Chinese children diagnosed
           with tuberous sclerosis complex
    • Authors: G. Yang; Z.N. Shi, Y. Meng, X.Y. Shi, L.Y. Pang, S.F. Ma, M.N. Zhang, Y.Y. Wang, L.P. Zou
      Pages: 764 - 768
      Abstract: We investigated the clinical phenotypes and genetic mutations in Chinese children diagnosed with tuberous sclerosis complex (TSC). Sequencing of TSC1 and TSC2 genes was performed in 117 children with TSC and their parents. Association of TSC gene mutations with clinical manifestations was investigated. All gene mutations were heterozygous including in 16 patients (13.7%) with mutations in TSC1 gene and 101 patients (86.3%) with mutations in TSC2 gene. Among the 16 patients with TSC1 gene mutations, 15 different types of mutations were found, which included 5 novel mutations; all patients had skin manifestations and epilepsy. Among the 101 patients with TSC2 mutations, 85 different types of mutations were found, which included 25 novel mutations; 97 patients (96.0%) had skin manifestations; 97 (96.0%) had epilepsy; 74 (73.3%) had intellectual disability and 25 patients (24.8%) were autistic. The clinical phenotype of the 14 children with familial TSC was more severe than that of their parents.
      PubDate: 2017-02-22T03:16:16.287153-05:
      DOI: 10.1111/cge.12920
  • Genotype–phenotype correlation in 44 Czech, Slovak, Croatian and Serbian
           patients with mucopolysaccharidosis type II
    • Authors: L. Dvorakova; H. Vlaskova, A. Sarajlija, D. P. Ramadza, H. Poupetova, E. Hruba, A. Hlavata, V. Bzduch, K. Peskova, G. Storkanova, B. Kecman, M. Djordjevic, I. Baric, K. Fumic, I. Barisic, M. Reboun, J. Kulhanek, J. Zeman, M. Magner
      Pages: 787 - 796
      Abstract: Mucopolysaccharidosis type II (Hunter syndrome, MPS II, OMIM 309900) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS). We analyzed clinical and laboratory data from 44 Slavic patients with this disease. In total, 21 Czech, 7 Slovak, 9 Croatian and 7 Serbian patients (43 M/1 F) were included in the study (median age 11.0 years, range 1.2–43 years). Birth prevalence ranged from 1:69,223 (Serbia) to 1:192,626 (Czech Rep.). In the majority of patients (71%), the disease manifested in infancy. Cognitive functions were normal in 10 patients. Four, six and 24 patients had mild, moderate, and severe developmental delay, respectively, typically subsequent to developmental regression (59%). Residual enzyme activity showed no predictive value, and estimation of glycosaminoglycans (GAGs) had only limited importance for prognosis. Mutation analysis performed in 36 families led to the identification of 12 novel mutations, eight of which were small deletions/insertions. Large deletions/rearrangements and all but one small deletion/insertion led to a severe phenotype. This genotype–phenotype correlation was also identified in six cases with recurrent missense mutations. Based on patient genotype, the severity of the disease may be predicted with high probability in approximately half of MPS II patients.
      PubDate: 2017-03-17T00:05:33.158442-05:
      DOI: 10.1111/cge.12927
  • BRDF and its Impact on Aerial Archaeological Photography
    • Authors: Geert Verhoeven
      Abstract: Despite the arguments in favour of oblique photographs acquired during observer-directed reconnaissance sorties, many aerial archaeologists have extracted much valuable information from verticals generated during total coverage mapping surveys. This paper looks at one of these arguments: the issue of anisotropic surface reflectance, which is responsible for the allegedly superior rendering of (mainly) vegetation and shadow marks when observed from certain oblique viewpoints. However, after a theoretical and practical assessment of the Bidirectional Reflectance Distribution Function (BRDF) of vegetation, it becomes clear that nadir views provide a more than satisfying alternative to the extremes of an oblique approach. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-28T05:25:28.94053-05:0
      DOI: 10.1002/arp.1559
  • Object-based Shell Craters Classification from LiDAR-derived Sky-view
    • Authors: Luigi Magnini; Cinzia Bettineschi, Armando De Guio
      Abstract: This paper presents the results of the first attempt to assess, identify and quantify the residual number of shell craters of World War I currently present in the Vezzena/Luserna/Lavarone Plateau, areas of Millegrobbe, Bisele and Cima Campo (Province of Trento, Italy). Historical sources report the existence of several thousand artillery explosions: therefore, a field survey or a classic photo-interpretation would be labour-intensive and highly time-consuming. For this reason, a digital terrain model (DTM) of the test-site was processed using the Sky-view Factor algorithm and was analysed with an object-based approach, which implied: (1) multiresolution segmentation; (2) classification (main features considered size, shape and colour).The automatically classified shell craters were thus verified during an in situ survey that determined the accuracy of the method in the order of 84% of the total occurrences. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-23T00:46:35.734456-05:
      DOI: 10.1002/arp.1565
  • Simulating Trial Trenches for Archaeological Prospection: Assessing the
           Variability in Intersection Rates
    • Authors: Kristof Haneca; Sofie Debruyne, Sofie Vanhoutte, Anton Ervynck, Maarten Vermeyen, Philip Verhagen
      Abstract: In this study we draw attention to the inherent variability in the results of trial trenching, when taking into account the countless variations in orientation and positioning of trenches. Grids of trial trenches were simulated time and again on the excavation plans of 16 archaeological sites from Flanders, Belgium. Orientation and positioning of the grid layout was shifted randomly, whilst the area coverage varied from 2.5% to 80%. The intersection rates of the archaeological features allow to gain more insight in trends and variability that are inherent to the chosen design of trial trenches. It is assessed how robust a chosen grid layout performs on (multi-period) archaeological sites and how variable these results might be. The most effective layout appears to be a grid with short, parallel and discontinuous trenches or a standard grid, closely followed by 2 m wide continuous trenches. Implementing 4 m wide trenches reduces the effectiveness of the latter method substantially. When the area coverage of the trenches is below 10%, the results of the archaeological prospection become unreliable and can potentially lead to a substantial over-or underestimation of the actual feature density on the site. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T21:15:37.281306-05:
      DOI: 10.1002/arp.1564
  • GPR versus Geoarchaeological Findings in a Complex Archaeological Site
           (Badia Pozzeveri, Italy)
    • Authors: Adriano Ribolini; Monica Bini, Ilaria Isola, Francesco Coschino, Carlo Baroni, Maria Cristina Salvatore, Giovanni Zanchetta, Antonio Fornaciari
      Abstract: The results of a Ground-penetrating radar (GPR) survey were compared with the archaeological excavation outcomes of a twelfth century abbey site (Badia Pozzeveri). The goal was to associate the types of reflections recorded in GPR profiles and high-amplitude features visible in amplitude maps with unearthed archaeological features. GPR profiles crossing the walls evidenced axes of hyperbolic point source reflections and short planar reflections respectively generated by the stones forming the lateral sides/upper corners and the top of the structure. Moreover, the stones in the core of the wall caused small hyperbolic point source reflections with interfering axes, which produced a chaotic reflection profile. The resampling and gridding of these reflections collectively generated high-amplitude linear features in the amplitude maps. The presence in the graves of bones generates small hyperbolic point source reflections with interfering axes in the GPR profile, with a consequently chaotic reflection profile. Moreover, the existence of lythic slabs topping and/or siding the graves generates short planar reflections and axes of hyperbolic point source reflections. The resampling and gridding of these types of reflections generates in the amplitude map features that cannot be locally distinguished from those caused by the local aggregation of sediments with no archaeological relevance. The GPR profiles crossing trenches and pit-kiln showed dipping reflectors unconformably resting on a basal planar reflector. Disconformity marks the onset of trench and pit-kiln decommissioning with the infilling of clayey silty layers and anthropogenic remains. These features in the amplitude maps correspond to medium to high-amplitude areas.The results show that types of reflection can be associated to specific elements of archaeological structure for a detailed interpretation of a complex subsurface setting. Furthermore, it is evidenced that the interpretation of GPR profiles must be considered an indispensable pre-requisite for a full comprehension of amplitude maps. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T20:51:05.94948-05:0
      DOI: 10.1002/arp.1561
  • 2D-ERT Survey for the Identification of Archaeological and Historical
           Structures beneath the Plaza of Santo Domingo, Mexico City, Mexico
    • Authors: Pedro Paz-Arellano; Andrés Tejero-Andrade, Denisse Argote-Espino
      Abstract: Santo Domingo public square (Plaza of Santo Domingo) is located in Mexico City's downtown area. The history of its transformations began in pre-Hispanic times and is still being written. The objectives of this investigation were to establish the position of the northwest corner of the ancient Mexica wall and to determine whether the Plaza became a public square during pre-Hispanic or colonial times, taking into account the contradictions of the historical sources. For this purpose, we implemented three 80-m-long electrical resistivity tomography (ERT) profiles in the Plaza and one on the eastern side of the Church of Santo Domingo de Guzmán. A Wenner–Schulmberger array was designed for the data acquisition. The results could support the hypothesis that the Plaza of Santo Domingo was designed and constructed as an open public area in colonial times, since the observations in the electric profiles beneath the square could reveal the presence of a pre-Hispanic structure. This structure could be part of the wall that surrounded the Mexica ceremonial compound. At the eastern side of the Dominican church, the foundations of the first Spanish chapel were identified, as well as portions of modern concrete deposits injected into the subsoil to stabilize the constant subsidence of the building. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-19T02:20:16.329216-05:
      DOI: 10.1002/arp.1560
  • Geophysical and Geochemical Studies on Historical Layers in the Area of
           Old Krakow, Poland
    • Authors: Mikołaj Łyskowski; Bernadetta Pasierb, Marta Wardas-Lasoń, Wioleta Antonik, Ewelina Mazurkiewicz
      Abstract: In the present study, application of complementary to each other non-invasive geophysical methods and geochemical slim hole drilling allowed to locate a small fragment of the historical water system, and to determine the type and stratigraphy of the sediments filling it. The most universal, and frequently used geophysical methods are electrical resistivity tomography (ERT) and ground penetrating radar (GPR). These methods are characterized by high precision mapping of the investigated medium, and the possibility of implementation even in small areas. They play an important role in defining the location of archaeological excavations sites. The applied geophysical methods enabled precise and comprehensive analyses of near-surface zones in the area of Planty Park in Krakow (Poland), such as engineering/geological recognition, and detection of anthropogenic structures. As an important metropolis of Central Europe in the medieval period, Krakow due to rapid development of craft and trade had a high demand for water both for the general population and craftsmen. As a result, the city continuously developed and used a complex watercourse and sewage collection system. The layout of the system has not yet been accurately mapped. The authors decided that the ERT method was suitable for this case study. The study was conducted in the eastern part of Planty Park, near Dominikańska Street, measurements were taken using a two-dimensional (2D) parallel layout of ERT profiles. The authors also carried out a three-dimensional (3D) image interpretation process. Even though the ERT method is limited by the requirement of a minimal implementation area, it makes the detection of former watercourses possible. In order to verify the ERT results, three small-diameter mechanical holes drillings were carried for purpose of macroscopic analysis of the ground type with determination of its lithology and layer layout. On gathered samples laboratory measurements of pH, oxidation–reduction potential Eh, and conductivity EC were done. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-19T01:11:02.136129-05:
      DOI: 10.1002/arp.1563
  • Reassessing Surface Artefact Scatters. The Integration of
           Artefact-Accurate Fieldwalking with Geophysical Data at Medieval Harbour
           Sites Near Bruges (Belgium)
    • Authors: Jan Trachet; Samuël Delefortrie, Marc Van Meirvenne, Bieke Hillewaert, Wim De Clercq
      Abstract: Archaeological fieldwalking is particularly used to detect sites within a landscape, rather than to assess the internal structure of a site itself. Contributory to this trend is that surface artefact patterns collected by pedestrian field survey are rarely seen as valuable archaeological data for intra-site research. In recent decades, they have been overtaken by other non-invasive prospection methods, which seem to be more efficient and time-effective. This paper aims to reassess fieldwalking as a valuable intra-site prospection method and explores its added value when used in a multidisciplinary framework. The medieval lost harbour site of Monnikerede near Bruges (Belgium) is used as a first test-case. The site was subjected to a grid survey in 1985 and recently acted as the location for an intensive artefact-accurate fieldwalking survey as well as an extensive geophysical survey. Comparing the recent global navigation satellite system (GNSS)-underpinned fieldwalking survey results with a 10 m × 10 m grid survey from 1985, demonstrates the gain in knowledge and detail using the former method. The combination of both fieldwalking and geophysics showed both significant positive and negative relations between surface artefact scatters and subsurface anomalies, hence pointing to the complementary nature and added value of the methods being jointly applied. In addition, the combination of both techniques was tested on a second lost harbour site near Hoeke, to further evaluate the potential of the applied methodology. The results demonstrate that, although the sites have been heavily ploughed for decades, the lateral displacement of artefacts is limited and confined to the original medieval allotment. Finally the integration of surface artefacts with geophysical anomalies enabled to enhance the spatio-temporal interpretation of both sites. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-27T21:05:52.965221-05:
      DOI: 10.1002/arp.1552
  • Geophysical Research at the Prepoštská Cave and Čertova Pec Cave
           Neanderthal Sites (Western Slovakia)
    • Authors: René Putiška; Martin Sabol, Dávid Kušnirák, Ivan Dostál
      Abstract: The sedimentary filling of two Slovak Neanderthal sites – the Prepoštská Cave near Prievidza (Micoquian) and the Čertova Pec Cave near Radošina (Szeletian, Mousterian) was investigated, while archaeological and palaeontological studies have shown these caves are very important sites from the viewpoint of the ancient man settlements. No geophysical research had previously been conducted here, therefore ground penetrating radar (GPR) and electrical resistivity tomography (ERT) geophysical methods were applied in order to expose its depths for future archaeological and palaeontological field campaigns. The GPR survey at the Prepoštská Cave revealed a disrupted zone in the southwest (SW) corner of the investigate area, encapsulated in travertine surrounding the bedrock layer identified at a depth between 0.4 to 2.4 m. This discovered zone is assumed to be an undocumented recent excavation zone. The combined ERT and GPR survey also identified at the Čertova Pec Cave, aside from some main structures (large limestone blocks, loamy-clayey sediment in the central part and debris), intact cave sediments, deposited under the debris filling and large limestone block, located at approximately 2 m depth in the back part of the cave, close to its northeast (NE) entrance. These unconsolidated intact deposits represent the lower part of the Mousterian horizon. Thus, the geophysical survey supported previous hypotheses on the assumed existence of deeper layers with potential archaeological and/or palaeontological content, which have since been spatially defined. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-25T02:55:44.93409-05:0
      DOI: 10.1002/arp.1558
  • Advances in Reconstructing Archaeological Magnetic Signals; an Algorithm
           for Filtering Noise due to the Ploughing Effect
    • Authors: Mariangela Noviello; Marcello Ciminale, Vincenzo Del Gaudio, Leonardo Amoruso
      Abstract: Archaeological remains are very often buried under uneven soil of agricultural fields crossed by rather parallel furrows and ridges. Consequently, ploughing in a magnetic survey might produce a repetitive, quite regular, linear noise in the data, which could impede optimal recovery of the archaeological magnetic anomalies; depending on the acquisition line orientation, this noise may show as an oblique, vertical or horizontal pattern in the magnetic maps.Several studies have tested and verified methods for oblique ploughing minimization, but, to our knowledge, no procedures regarding the vertical and horizontal types of noise have been published.The present research proposes a procedure to filter each type of ploughing effect through an algorithm working in the wavenumber domain. The procedure produces images with a considerable reduction of the noise in any direction, resulting in enhanced visibility and readability of the archaeological anomalies. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-23T14:05:42.902232-05:
      DOI: 10.1002/arp.1550
  • Searching for the Antigonea Theatre: A Magnetic Survey in an Ancient
           Epirus City
    • Authors: Antonio Schettino; Dhimiter Çondi, Roberto Perna, Pietro Paolo Pierantoni, Annalisa Ghezzi
      Pages: 3 - 15
      Abstract: We report on two magnetic surveys performed in July and September 2015 at the ancient Hellenistic city of Antigonea, located in southern Albania. The main objective of the two surveys was to find the city theatre and determine possible sites of future excavations. We suggest a new technique for dense collecting of magnetic data along difficult terrains, with minimization of the topographic effect. Evidence of a possible location of the theatre was found along the southern slope of the Jermë hill, just outside the city walls. Other interesting structures indicate the presence of many other buildings in this part of the Antigonea settlement. Copyright © 2016 John Wiley & Sons, Ltd. StartCopTextStartCopTextCopyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-08-06T07:16:39.304637-05:
      DOI: 10.1002/arp.1549
  • Under the Park. Recent Geophysical Surveys at Verulamium (St Albans,
           Hertfordshire, UK)
    • Authors: Kris Lockyear; Ellen Shlasko
      Pages: 17 - 36
      Abstract: This paper presents the first results of the geophysical surveys – principally a large scale gradiometer survey – of Verulamium Park, St Albans, Hertfordshire, UK, under which lies approximately half of the Roman city. Verulamium was the third largest Roman city in the province of Britannia – covering some 81 ha – and the largest which is currently available for survey. Approximately 65 ha lies under parkland or pasture. The 30 ha available under the Park was the subject of a magnetometry survey in 2013–2014, along with smaller areas of ground penetrating radar (GPR), earth resistance and magnetic susceptibility. These surveys were undertaken as part of a community archaeology project funded by the Arts and Humanities Research Council (AHRC). The surveys have detected a wide variety of features including stone buildings of varying size and complexity, pottery kilns, roads, pits and ditches. The results so far suggest the town can be divided into an area of largely elite housing, an area characterised by smaller structures and industrial features, and a somewhat enigmatic magnetically quiet area. Challenges in the interpretation of the results are discussed, as are potential solutions and planned future work. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-30T08:13:53.469994-05:
      DOI: 10.1002/arp.1548
  • Archaeological Applications of Low-Cost Integrated Sidescan
           Sonar/Single-Beam Echosounder Systems in Irish Inland Waterways
    • Authors: Kieran Westley; Rory Mcneary
      Pages: 37 - 57
      Abstract: Inland waterways, such as rivers and lakes have been foci of human settlement and use for millennia. However, underwater archaeological prospection or survey in these environments is often hindered by poor or no-visibility conditions. While this can be overcome using a range of well-established geophysical techniques, their application in inland waterways seems comparatively less common than in offshore environments. Possible reasons include the logistical challenges of surveying shallow confined, often inaccessible and uncharted waters coupled with a wider lack of awareness of the submerged archaeological potential of inland waterways. This paper demonstrates one method by which the logistical challenge can be circumvented, specifically the use of low-cost acoustic systems which combine a single-beam echo sounder and sidescan sonar. These systems have appeared within the last decade and are smaller and cheaper than their survey-grade counterparts. Although developed for the sport fishing community, as shown here, they can also be used for archaeological purposes. Their effectiveness for archaeological prospection is illustrated via three case studies from lacustrine and riverine settings in Northern Ireland and by reference to object detection and bathymetric mapping. The data presented indicate that the low-cost systems are capable of collecting data that is sufficient for archaeological purposes but they are best suited to shallow confined waters where their disadvantages (limited range and depth of operation, reduced image quality) are minimized. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-09-30T03:26:55.347153-05:
      DOI: 10.1002/arp.1551
  • On the Use of Fluxgate 3-Axis Magnetometers in Archaeology: Application
           with a Multi-sensor Device on the Site of Qasr ‘Allam in the Western
           Desert of Egypt
    • Authors: Bruno Gavazzi; Rozan Alkhatib-Alkontar, Marc Munschy, Frédéric Colin, Catherine Duvette
      Pages: 59 - 73
      Abstract: Fluxgate 3-axis magnetometers are seldom used on archaeological sites due to their lack of precision. Nonetheless, they offer light weight, low power consumption and the ability of compensation of the magnetization of the prospecting device. This study proposes to use calibration and compensation processes developed for space research and aerial measurement to build a multi-sensor and georeferenced device to assess deep and shallow objects for large-scale archaeological investigations in Qasr 'Allam, in a context of heavy sedimentary coverage and uneven surface. The use of the device on the site in combination with potential field transformations of the signal such as the double reduction to the pole and the vertical derivative reveal a vast irrigation system as well as a large religious facility. A comparison with gradiometric measurements shows a resolution as good at least for shallow sources. The precise positioning allows targeted excavations that validate the geophysical interpretations and offer new archaeological information. These discoveries give enough proof to the local authorities to define the area to be protected from the threatening progression of agricultural fields. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-27T21:55:46.212227-05:
      DOI: 10.1002/arp.1553
  • The Value of Complementarity. Integrating the Evidence from Air Survey and
           ALS in Bohemia
    • Authors: Martin Gojda
      Pages: 75 - 83
      Abstract: This paper offers a contribution to discussion of the value of integrating different airborne perspectives for landscape prospection. A case study in Bohemia, Czech Republic, illustrates how the integration of the results of a long-term programme of aerial reconnaissance and recently acquired airborne laser scanning (ALS) (LiDAR) data has significantly improved the methodology and knowledge dividend for the study of past landscapes and settlements. Three types of features – barrows/ring ditches, a hillfort, and a nineteenth century artillery redoubts – have been surveyed repeatedly in order to detect the degree to which sites known from differential cropmarking in arable crops are also evident in ALS-derived digital terrain models (DTMs), and vice versa. It is noted that components of the hillfort and redoubts are clearly evident in the DTMs despite lying in fields that have been intensively cultivated for many decades at least, and are not easily recognized from the ground because their outline is so smoothed. This study illustrates the complementarities of cropmark aerial survey and ALS even in heavily ploughed environments, where there is often an assumption that features recorded as cropmarks have no surface expression, when in fact this often depends on the scale of the features. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-15T20:50:44.667631-05:
      DOI: 10.1002/arp.1562
  • Comprehensive review of the duplication 3q syndrome and report of a
           patient with Currarino syndrome and de novo duplication 3q26.32-q27.2
    • Authors: G.C. Dworschak; C. Crétolle, A. Hilger, H. Engels, E. Korsch, H. Reutter, M. Ludwig
      Pages: 661 - 671
      Abstract: Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well-described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32-q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3-q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.
      PubDate: 2016-10-10T03:30:49.921714-05:
      DOI: 10.1111/cge.12848
  • Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role
           of loss-of-function vs missense variants
    • Authors: C.P. Savastano; L.A. Brito, Á.C. Faria, N. Setó-Salvia, E. Peskett, C.M. Musso, L. Alvizi, S.A.M. Ezquina, C. James, GOSgene, P. Beales, M. Lees, G.E. Moore, P. Stanier, M.R. Passos-Bueno
      Pages: 683 - 689
      Abstract: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent, complex congenital malformation. Genome-wide association studies (GWAS) on NSCL/P have consistently identified association for the 1p22 region, in which ARHGAP29 has emerged as the main candidate gene. ARHGAP29 re-sequencing studies in NSCL/P patients have identified rare variants; however, their clinical impact is still unclear. In this study we identified 10 rare variants in ARHGAP29, including five missense, one in-frame deletion, and four loss-of-function (LoF) variants, in a cohort of 188 familial NSCL/P cases. A significant mutational burden was found for LoF (Sequence Kernel Association Test, p = 0.0005) but not for missense variants in ARHGAP29, suggesting that only LoF variants contribute to the etiology of NSCL/P. Penetrance was estimated as 59%, indicating that heterozygous LoF variants in ARHGAP29 confer a moderate risk to NSCL/P. The GWAS hits in IRF6 (rs642961) and 1p22 (rs560426 and rs4147811) do not seem to contribute to the penetrance of the phenotype, based on co-segregation analysis. Our data show that rare variants leading to haploinsufficiency of ARHGAP29 represent an important etiological clefting mechanism, and genetic testing for this gene might be taken into consideration in genetic counseling of familial cases.
      PubDate: 2016-07-26T03:15:51.693115-05:
      DOI: 10.1111/cge.12823
  • Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and
           variable complex V deficiency associated with TIMM50 mutations
    • Authors: M.A. Shahrour; O. Staretz-Chacham, D. Dayan, J. Stephen, A. Weech, N. Damseh, H. Pri Chen, S. Edvardson, S. Mazaheri, A. Saada, , E. Hershkovitz, A. Shaag, M. Huizing, B. Abu-Libdeh, W.A Gahl, A. Azem, Y. Anikster, T. Vilboux, O. Elpeleg, M.C. Malicdan
      Pages: 690 - 696
      Abstract: Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria.We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.
      PubDate: 2016-10-12T01:55:35.928332-05:
      DOI: 10.1111/cge.12855
  • Further evidence that de novo missense and truncating variants in ZBTB18
           cause intellectual disability with variable features
    • Authors: J.S. Cohen; S. Srivastava, K.D. Farwell Hagman, D.N. Shinde, R. Huether, D. Darcy, R. Wallerstein, G. Houge, S. Berland, K.G. Monaghan, A. Poretti, A.L. Wilson, W.K. Chung, A. Fatemi
      Pages: 697 - 707
      Abstract: Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.
      PubDate: 2016-10-10T03:35:49.675062-05:
      DOI: 10.1111/cge.12861
  • Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual
           disability with microcephaly and brachydactyly
    • Authors: K.D. Kernohan; A. McBride, Y. Xi, N. Martin, J. Schwartzentruber, D.A. Dyment, J. Majewski, S. Blaser, , K.M. Boycott, D. Chitayat
      Pages: 708 - 716
      Abstract: Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.
      PubDate: 2016-11-30T23:06:11.031439-05:
      DOI: 10.1111/cge.12884
  • Microcephaly, intractable seizures and developmental delay caused by
           biallelic variants in TBCD: further delineation of a new
           chaperone-mediated tubulinopathy
    • Authors: B. Pode-Shakked; H. Barash, L. Ziv, K.W. Gripp, E. Flex, O. Barel, K.S. Carvalho, M. Scavina, G. Chillemi, M. Niceta, E. Eyal, N. Kol, B. Ben-Zeev, O. Bar-Yosef, D. Marek-Yagel, E. Bertini, A.L. Duker, Y. Anikster, M. Tartaglia, A. Raas-Rothschild
      Pages: 725 - 738
      Abstract: Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.
      PubDate: 2016-12-16T05:16:00.108098-05:
      DOI: 10.1111/cge.12914
  • BRF1 mutations in a family with growth failure, markedly delayed bone age,
           and central nervous system anomalies
    • Authors: Y.H. Jee; N. Sowada, T.C. Markello, I. Rezvani, G. Borck, J. Baron
      Pages: 739 - 747
      Abstract: Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3 cm, −4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C > G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar–facial–dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.Functional study of P292R mutation in yeast lacking Brf1.
      PubDate: 2016-12-12T01:00:30.95448-05:0
      DOI: 10.1111/cge.12887
  • Association of genetic polymorphisms of de novo nucleotide biosynthesis
           with increased CHD susceptibility in the northern Chinese population
    • Authors: Y.-C. Jiang; L.-L. Kuang, S.-N. Sun, W.-Y. Duan, B. Qiao, H.-Y. Wang
      Pages: 748 - 755
      Abstract: Congenital heart disease (CHD) is one of most prevalent birth defects in the world. However, the underlying molecular mechanism(s) have not been fully understood. Here we report that increased CHD susceptibility is associated with genetic polymorphisms for de novo nucleotide biosynthesis in northern Chinese population, which has been reported with lower plasma folate levels. Nine tagSNPs of four genes (GART, ATIC, MTHFD1 and SHMT1) in de novo nucleotide biosynthesis were sequenced in 802 sporadic CHD patients and 1093 controls from two Han Chinese populations, located in north China (Shandong) and South China (Shanghai), respectively. Six SNPs were found to be significantly associated with CHDs or septation defects only in the Shandong population dataset, but none displayed significant association with any CHDs in the Shanghai population dataset as well as in the combined dataset. We also showed that the minor A allele of rs7279549 in GART reduced transcriptional activity and displayed lower affinity for unknown transcription factor(s), demonstrating the allele is a functional risk factor for CHD in Shandong population. Our study indicates that dysregulation of de novo nucleotide biosynthesis pathway may conditionally contribute to CHD pathogenesis in northern Chinese.
      PubDate: 2016-12-12T00:40:29.702553-05:
      DOI: 10.1111/cge.12874
  • De novo loss of function mutations in KIAA2022 are associated with
           epilepsy and neurodevelopmental delay in females
    • Authors: R. Webster; M.T. Cho, K. Retterer, F. Millan, C. Nowak, J. Douglas, A. Ahmad, G.V. Raymond, M.R. Johnson, A. Pujol, A. Begtrup, D. McKnight, O. Devinsky, W.K. Chung
      Pages: 756 - 763
      Abstract: Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X-linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss-of-function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole-exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X-linked dominant ID, and broadens the phenotype for KIAA2022 mutations.
      PubDate: 2016-09-29T21:50:52.123889-05:
      DOI: 10.1111/cge.12854
  • KIF5A de novo mutation associated with myoclonic seizures and neonatal
           onset progressive leukoencephalopathy
    • Authors: M. Rydzanicz; M. Jagła, J. Kosinska, T. Tomasik, A. Sobczak, A. Pollak, I. Herman-Sucharska, A. Walczak, P. Kwinta, R. Płoski
      Pages: 769 - 773
      Abstract: The KIF5A gene (OMIM 602821) encodes a neuron-specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C-terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2. Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 (SPG10, OMIM 604187). Conversely, the role of loss-of-function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c.2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A/SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C-terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C-terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).
      PubDate: 2016-09-16T03:05:33.212405-05:
      DOI: 10.1111/cge.12831
  • Identification of a second HOXA2 nonsense mutation in a family with
           autosomal dominant non-syndromic microtia and distinctive ear morphology
    • Authors: F. Piceci; S. Morlino, M. Castori, E. Buffone, A. De Luca, P. Grammatico, V. Guida
      Pages: 774 - 779
      Abstract: Microtia is a congenital defect affecting external ears, which appear smaller and sometimes malformed. Here we describe a five-generation family with isolated bilateral microtia segregating as an autosomal dominant trait. Similar features have been previously observed in an autosomal dominant family with non-syndromic microtia and hearing loss segregating with a HOXA2 nonsense variant. HOXA2 biallelic mutations were also described in an inbreed family with autosomal recessive microtia, hearing impairment and incomplete cleft palate. In our family, sequence analysis detected a heterozygous protein truncating nonsense variant [c.670G>T, p.(Glu224*)] segregating in all affected individuals and absent in public databases. This study confirms the role of HOXA2 gene in dominant isolated microtia and contribute to further define the dysmorphogenetic effect of this gene on ear development.Schematic representation of the HOXA2 gene and corresponding protein product showing the position of the c.670G > T p.(Glu224*) mutation and recognized protein domains.
      PubDate: 2016-09-13T03:21:05.890765-05:
      DOI: 10.1111/cge.12845
  • A novel gain-of-function mutation in ORAI1 causes late-onset tubular
           aggregate myopathy and congenital miosis
    • Authors: M. Garibaldi; F. Fattori, B. Riva, C. Labasse, G. Brochier, P. Ottaviani, S. Sacconi, E. Vizzaccaro, F. Laschena, N.B. Romero, A. Genazzani, E. Bertini, G. Antonini
      Pages: 780 - 786
      Abstract: We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a ‘gain-of-function’ mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.
      PubDate: 2016-11-23T23:50:30.591084-05:
      DOI: 10.1111/cge.12888
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