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Publisher: John Wiley and Sons   (Total: 1577 journals)

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Showing 1 - 200 of 1577 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 61, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 45, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 49, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 144, 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: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, 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: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 3)
Addiction     Hybrid Journal   (Followers: 33, 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: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 250, 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: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
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: 35, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, 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: 30, 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: 34, 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: 133, 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: 92, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 27, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 31, 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 Physical Anthropology     Hybrid Journal   (Followers: 36, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 255, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, 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: 16, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 125, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
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: 159)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 210, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 36, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, 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: 44, 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: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
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: 69, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 140, 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: 14, 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: 25, 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: 225, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 50, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 28, 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: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 14)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 315, 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: 4, 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: 12, 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: 13, 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: 8, 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: 4, 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: 43, 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: 7, 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: 25, 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: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 398, 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: 68, 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: 10, 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: 5, 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: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 23, 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: 15, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, 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: 137, 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: 18, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 35, 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)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 221, SJR: 2.083, h-index: 125)

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Journal Cover American Journal of Medical Genetics Part A
  [SJR: 1.115]   [H-I: 61]   [15 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1552-4825 - ISSN (Online) 1552-4833
   Published by John Wiley and Sons Homepage  [1577 journals]
  • SERPINI1 pathogenic variants: An emerging cause of childhood-onset
           progressive myoclonic epilepsy
    • Authors: Emmanuelle Ranza; Stephanie Garcia-Tarodo, Konstantinos Varvagiannis, Michel Guipponi, Johannes A. Lobrinus, Armand Bottani, Ilse Kern, Mary Kurian, Marie-Pascale Pittet, Stylianos E. Antonarakis, Joel Fluss, Christian M. Korff
      Abstract: Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies.
      PubDate: 2017-06-20T06:49:41.990891-05:
      DOI: 10.1002/ajmg.a.38317
  • Growth hormone excess in children with neurofibromatosis type-1 and optic
    • Authors: Paola Cambiaso; Stefania Galassi, Melania Palmiero, Angela Mastronuzzi, Francesca Del Bufalo, Rossella Capolino, Antonella Cacchione, Paola S. Buonuomo, Michaela V. Gonfiantini, Andrea Bartuli, Marco Cappa, Marina Macchiaiolo
      Abstract: In children with neurofibromatosis type 1 (NF1) and optic pathways glioma (OPG), growth hormone (GH) excess has been rarely reported and mainly associated to central precocious puberty. The aim of our study is to evaluate the prevalence of GH excess, the association with central precocious puberty, the relation with tumor site and the evolution over time in a large cohort of children with NF1 and OPG. Sixty-four NF1 children with OPG were evaluated. Patients with stature and/or height velocity >2 SD for age were studied for GH secretion. Seven out of 64 children (10.9%) with NF1 and optic pathways glioma showed GH excess, isolated in 5 cases and associated to central precocious puberty in 2. All the children with GH excess had a tumor involving the chiasma. Children with GH excess underwent medical treatment with lanreotide and a minimum clinical/biochemical follow up of 2 years is reported. The present study demonstrates that GH excess should be considered as a relative frequent endocrine manifestation in NF1 patients, similarly to central precocious puberty. Therefore, these patients should undergo frequent accurate auxologic evaluations. On the other hand, an increase in height velocity in children with NF1, even despite normal ophthalmological exams, can suggest the presence of OPG and therefore represents an indication to perform brain MRI.
      PubDate: 2017-06-20T06:49:15.475153-05:
      DOI: 10.1002/ajmg.a.38308
  • Expanding the allelic disorders linked to TCTN1 to include Varadi syndrome
           (Orofaciodigital syndrome type VI)
    • Authors: Mohammad M. Al-Qattan; Ranad Shaheen, Fowzan S. Alkuraya
      Abstract: Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel–Gruber syndrome.
      PubDate: 2017-06-20T06:49:12.505951-05:
      DOI: 10.1002/ajmg.a.38336
  • The importance of phase analysis in multiexon copy number variation
           detected by aCGH in autosomal recessive disorder loci
    • Authors: Madelyn A. Gillentine; Christian P. Schaaf, Ankita Patel
      Abstract: Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to the exonic level, however it has its limitations. It cannot detect balanced structural variation nor determine the phase of copy number variants. Heterozygous multi-exonic copy number variation in autosomal recessive genes should be interpreted in the context of a clinical phenotype, and, if warranted, phase analysis should be performed before sequence analysis for that gene is pursued. This patient emphasizes the need of obtaining clinical information and determining the phase in multi-exonic copy number variants for accurate diagnosis and risk counseling.
      PubDate: 2017-06-20T06:49:10.279001-05:
      DOI: 10.1002/ajmg.a.38328
  • Dual molecular diagnosis contributes to atypical Prader–Willi
           phenotype in monozygotic twins
    • Authors: Fernanda S. Jehee; Valdirene T. de Oliveira, Juliana Gurgel-Giannetti, Rafaella X. Pietra, Fernando V. M. Rubatino, Natália V. Carobin, Gabrielle S. Vianna, Mariana L. de Freitas, Karla S. Fernandes, Beatriz S. V. Ribeiro, Hennie T. Brüggenwirth, Roza Ali-Amin, , Janson J. White, Zeynep C. Akdemir, Shalini N. Jhangiani, Richard A. Gibbs, James R. Lupski, Monica C. Varela, Célia Koiffmann, Carla Rosenberg, Cláudia M. B. Carvalho
      Abstract: We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader–Willi syndrome and Pitt–Hopkins syndrome. These girls were diagnosed in early infancy with Prader–Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.
      PubDate: 2017-06-20T06:48:47.407528-05:
      DOI: 10.1002/ajmg.a.38315
  • Psychiatric and cognitive characteristics of individuals with Danon
           disease (LAMP2 gene mutation)
    • Authors: Maya Yardeni; Omri Weisman, Hanna Mandel, Ronnie Weinberger, Giovanni Quarta, Joel Salazar-Mendiguchía, Pablo Garcia-Pavia, Maria José Lobato-Rodríguez, Lourdes Fajardo Simon, Freimark Dov, Michael Arad, Doron Gothelf
      Abstract: Danon disease (DD) is a rare X-linked disorder caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein. It is characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Whereas the molecular and pathophysiological mechanisms underlying this disorder have been previously reported and continue to be explored, the cognitive deficits and psychiatric comorbidities manifested in DD remain an understudied topic. We systematically assessed cognitive abilities and psychiatric comorbidities in 13 males and females. Most of the participants in our cohort (n = 9; 75%) had an IQ score within the normal range, while only one participant had intellectual disability. Participants’ performance on the Cognitive Neuropsychiatric Battery (CNB) showed only mildly impaired cognitive abilities in most modules, except in the executive functioning test, which was low compared to healthy controls. Of note, 69% of the participants met criteria for at least one psychiatric disorder, mainly mood and anxiety disorders, occurring alone or in combination in the same patient. The results of the present study challenge earlier reports suggesting that mental retardation is a core constituent in DD. Of importance, it underscores the need to refer Danon patients to psychiatric assessment.
      PubDate: 2017-06-19T05:21:05.602167-05:
      DOI: 10.1002/ajmg.a.38320
  • The immune deficiency of chromosome 22q11.2 deletion syndrome
    • Authors: Megan Morsheimer; Terri F. Brown Whitehorn, Jennifer Heimall, Kathleen E. Sullivan
      Abstract: The syndrome originally described by Dr. Angelo DiGeorge had immunodeficiency as a central component. When a 22q11.2 deletion was identified as the cause in the majority of patients with DiGeorge syndrome, the clinical features of 22q11.2 deletion syndrome became so expansive that the immunodeficiency became less prominent in our thinking about the syndrome. This review will focus on the immune system and the changes in our understanding over the past 50 years. Initially characterized as a pure defect in T cell development, we now appreciate that many of the clinical features related to the immunodeficiency are well downstream of the limitation imposed by a small thymus. Dysfunctional B cells presumed to be secondary to compromised T cell help, issues related to T cell exhaustion, and high rates of atopy and autoimmunity are aspects of management that require consideration for optimal clinical care and for designing a cogent monitoring approach. New data on atopy are presented to further demonstrate the association.
      PubDate: 2017-06-19T05:20:59.2442-05:00
      DOI: 10.1002/ajmg.a.38319
  • Motor performance in children with Noonan syndrome
    • Authors: Ellen A. Croonen; Marlou Essink, Ineke van der Burgt, Jos M. Draaisma, Cees Noordam, Maria W. G. Nijhuis-van der Sanden
      Abstract: Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen using valid norm-referenced tests. The study assessed motor performance in 19 children with Noonan syndrome (12 females, mean age 9 years 4 months, range 6 years 1 month to 11 years and 11 months, SDS 1 year and 11 months). More than 60% of the parents of the children reported pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. The mean standard scores on the Visual Motor Integration (VMI) test and Movement Assessment Battery for Children 2, Dutch version (MABC-2-NL) items differed significantly from the reference scores. Grip strength, muscle force, and 6 min Walking Test (6 MWT) walking distance were significantly lower, and the presence of generalized hypermobility was significantly higher. All MABC-2-NL scores (except manual dexterity) correlated significantly with almost all muscle strength tests, VMI total score, and VMI visual perception score. The 6 MWT was only significantly correlated to grip strength. This is the first study that confirms that motor performance, strength, and endurance are significantly impaired in children with Noonan syndrome. Decreased functional motor performance seems to be related to decreased visual perception and reduced muscle strength. Research on causal relationships and the effectiveness of interventions is needed. Physical and/or occupational therapy guidance should be considered to enhance participation in daily life.
      PubDate: 2017-06-19T05:20:57.383101-05:
      DOI: 10.1002/ajmg.a.38322
  • Development of emotional and behavioral problems in neurofibromatosis type
           1 during young childhood
    • Authors: André B. Rietman; Rianne Oostenbrink, Kimberley van Noort, Marie-Christine J. P. Franken, Coriene E. Catsman-Berrevoets, Femke K. Aarsen, Jos G. Hendriksen, Pieter F. A. de Nijs
      Abstract: This retrospective longitudinal study in young children with neurofibromatosis type 1 (NF1) aimed to identify if, and how early problems in behavior, intelligence, and language development are associated with later behavioral problems. At the first assessment at preschool age, we evaluated language skills, intelligence, and emotional and behavioral problems as reported by parents. The second assessment at school-age we evaluated intelligence, and emotional and behavioral problems as reported by parents and teachers. Association of baseline assessments with secondary assessment was evaluated using multivariable linear regression analysis. Of the 61 patients (25 males, 36 females; mean age 4;5 years [SD 1;1 years]) with NF1 who had a first assessment, 38 children (21 males, 17 females; mean age 7;11 years [SD 2;1 years]) had a second assessment after a mean period of 3;5 years. Longitudinal data on behavioral problems were collected for 23 of these children. Intelligence and language development were not associated with internalizing problems. Parent-rated internalizing behavioral problems significantly increased with age in this subgroup. Baseline internalizing problems predicted later internalizing problems (adjusted R2 = 0.33, p = 0.003). The presence of these problems at pre-school age may be predictive of internalizing problems at a later age.
      PubDate: 2017-06-19T05:20:47.61315-05:0
      DOI: 10.1002/ajmg.a.38323
  • Characterization of thrombosis in patients with Proteus syndrome
    • Authors: Kim M. Keppler-Noreuil; Jay N. Lozier, Julie C. Sapp, Leslie G. Biesecker
      Abstract: Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic, progressive overgrowth disorder involving vasculature, skin, and skeleton, and caused by a somatic activating mutation in AKT1. We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. We found that six of ten patients, who were deceased, died secondary to deep venous thrombosis and/or pulmonary embolism. Of the remaining 47 living patients, six had thromboembolic events that all occurred postoperatively and in an affected limb. Eleven of 21 patients had an abnormal hypercoagulable panel including Factor V Leiden heterozygotes, antithrombin III deficiency, positive lupus anticoagulant, or Protein C or S deficiencies. We observed that eight of 17 patients had an abnormal D-dimer level>0.5 mcg/dl, but deep venous thromboses occurred in only four of those with D-dimer>1.0 mcg/dl. We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation on platelet function or the vascular endothelium. The D-dimer test is useful as a screen for thromboembolism, although the screening threshold may need to be adjusted for patients with this disorder. We propose developing a registry to collect D-dimer and outcome data to facilitate adjustment of the D-dimer threshold for Proteus syndrome and related disorders, including PIK3CA-Related Overgrowth Spectrum.
      PubDate: 2017-06-19T00:30:35.350523-05:
      DOI: 10.1002/ajmg.a.38311
  • Variable expressivity of a likely pathogenic variant in KCNQ2 in a
           three-generation pedigree presenting with intellectual disability with
           childhood onset seizures
    • Authors: Stacy Hewson; Klajdi Puka, Saadet Mercimek-Mahmutoglu
      Abstract: KCNQ2 has been reported as a frequent cause of autosomal dominant benign familial neonatal seizures. De novo likely pathogenic variants in KCNQ2 have been described in neonatal or early infantile onset epileptic encephalopathy patients. Here, we report a three-generation family with six affected patients with a novel likely pathogenic variant (c.628C>T; p.Arg210Cys) in KCNQ2. Four family members, three adults and a child, presented with a childhood seizure onset with variability in the severity of seizures and response to treatment, intellectual disability (ID) as well as behavioral problems. The two youngest affected patients had a variable degree of global developmental delay with no seizures at their current age. This three-generation family with six affected members expands the phenotypic spectrum of KCNQ2 associated encephalopathy to KCNQ2 associated ID and or childhood onset epileptic encephalopathy. We think that KCNQ2 associated epileptic encephalopathy should be included in the differential diagnosis of childhood onset epilepsy and early onset global developmental delay, cognitive dysfunction, or ID. Furthermore, whole exome sequencing in families with ID and history of autosomal dominant inheritance pattern with or without seizures, may further broaden the phenotypic spectrum of KCNQ2 associated epileptic encephalopathy or encephalopathy.
      PubDate: 2017-06-11T10:10:22.77733-05:0
      DOI: 10.1002/ajmg.a.38281
  • Growth charts for Australian children with achondroplasia
    • Authors: Louise Tofts; Sandeep Das, Felicity Collins, Karen L. O. Burton
      Abstract: Achondroplasia is an autosomal dominant disorder, the most common genetic cause of short stature in humans. Reference curves for head circumference, weight, height, and BMI are needed in clinical practice but none exist for the Australian population. This study aimed to produce head circumference, height, weight, and BMI reference percentile curves for Australian children and adolescents with achondroplasia. Measurements of head circumference, height and weight taken at clinical visits were retrospectively extracted from the electronic medical record. Age was corrected for prematurity. Patients were excluded from head circumference analysis if they had significant neurosurgical complications and from the weight and BMI analysis when they had a clinical diagnosis of overweight. Measurements were available on 138 individuals (69 males and 69 females) taken between 1970 and 2015, with over 50% collected since 2005. A total of 3,352 data points were available. The LMS method was used to produce growth charts with estimated centiles (10, 25, 50, 75, and 90th) separately for males and females. For females birth weight was 3 kg (2.5–3.5 kg), birth length 48 cm (44–50 cm) and head circumference 37.5 cm (36–39 cm), adult height was 125 cm (116–132 cm), weight 42 kg (34–54 kg), and head circumference 58 cm (55.5–60.5 cm) all 50th centile (10–90th). For males birth weight was 3.5 kg (3–4 kg), length 49 cm (46–52 cm) and head circumference 38.5 cm (36–41 cm), adult height was 134 cm (125–141 cm), weight 41 kg (24.5–57 kg) and head circumference 61 cm (58–64 cm). The curves are similar to previously published reference data from the USA and have expected population wide variation from curves from an Argentinian population. Despite limitations of our curves for adolescents (12 years and older) due to data paucity, these Australian growth charts for children and adolescents with achondroplasia will be a useful reference in clinical practice.
      PubDate: 2017-06-09T11:05:42.977561-05:
      DOI: 10.1002/ajmg.a.38312
  • Clinical and molecular genetic characterization of two siblings with
           trisomy 2p24.3-pter and monosomy 5p14.3-pter
    • Authors: Daisuke Fukushi; Kenji Kurosawa, Yasuyo Suzuki, Kaoru Suzuki, Kenichiro Yamada, Seiji Watanabe, Kenji Yokochi, Nobuaki Wakamatsu
      Abstract: Partial trisomy 2p syndrome is occasionally associated with neural tube defects (NTDs), such as anencephaly, encephalocele, and spina bifida, in addition to common features of intellectual disability, developmental delay, and characteristic facial appearance. The 2p24 region has been reported to be associated with NTDs. Here, we report the cases of 2 siblings with trisomy 2p24.3-pter and monosomy 5p14.3-pter caused by the paternal translocation t(2;5)(p24.3;p14.3). Of the two siblings, the elder sister had spina bifida. We determined the nucleotide sequences of the chromosomal breakpoints and found that the sizes of trisomy 2p and monosomy 5p segments were 18.77 and 17.89 Mb, respectively. NTDs were present in four of seven previously reported patients with trisomy 2p and monosomy 5p as well as in one of the two patients examined in the present study. Although the monosomy 5p of the nine patients were similar in size, the two patients reported here had the smallest size of trisomy 2p. When the clinical features of the nine patients were compared to the present two patients, the elder sister had postaxial polydactyly of the left foot in addition to the characteristic facial appearance and spina bifida, indicating that these features were associated with trisomy 2p24.3-pter. To our knowledge, this is the first study on spina bifida to determine the nucleotide sequences of breakpoints for trisomy 2p24.3-pter and monosomy 5p14.3-pter. Increased gene dosages of dosage-sensitive genes or genes at the trisomy segment (2p24.3) of the presented patients could be associated with NTDs of patients with trisomy 2p.
      PubDate: 2017-06-09T11:05:38.779273-05:
      DOI: 10.1002/ajmg.a.38313
  • Clinical and molecular cytogenetic characterization of four unrelated
           patients carrying 2p14 microdeletions
    • Authors: Marie-Laure Mathieu; Caroline Demily, Sandra Chantot-Bastaraud, Alexandra Afenjar, Cyril Mignot, Joris Andrieux, Marion Gerard, Jaume Catala-Mora, Pierre Simon Jouk, Audrey Labalme, Patrick Edery, Damien Sanlaville, Massimiliano Rossi
      Abstract: We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1. Here, we report three further patients carrying proximal 2p14 microdeletions not including OTX1 and one patient carrying a more distal 2p14p15 microdeletion including this gene, providing new insights into the associated phenotypic spectrum. First, our study and a review of the literature showed that 3/4 patients carrying proximal 2p14 microdeletions had sensorineural hearing loss, suggesting the presence of a previously unreported deafness-causing gene in this chromosomal region. Second, one patient developed a progressive cardiomyopathy, suggesting that a cardiac follow-up should be systematically warranted even in the absence of congenital heart disease. We speculate that ACTR2 and MEIS1 might respectively play a role in the pathogenesis of the observed deafness and cardiomyopathy. Third, we observed other previously unreported features such as glaucoma, retinopathy, and mild midline abnormalities including short corpus callosum, hypospadias and anteriorly placed anus. Finally, the patient carrying a 2p14p15 deletion including OTX1 had normal kidneys and genitalia, thus confirming that OTX1 haploinsufficiency is not invariably associated with genitourinary defects. In conclusion, our study contributes significantly to delineate the phenotypic spectrum of 2p14 microdeletions.
      PubDate: 2017-06-09T11:05:32.550792-05:
      DOI: 10.1002/ajmg.a.38307
  • On the significance of craniosynostosis in a case of Kabuki syndrome with
           a concomitant KMT2D mutation and 3.2 Mbp de novo 10q22.3q23.1 deletion
    • Authors: Alexandra Topa; Lena Samuelsson, Lovisa Lovmar, Göran Stenman, Lars Kölby
      Abstract: Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disorders, such as Kabuki syndrome, should be considered among the differential diagnoses of syndromic forms of craniosynostosis.
      PubDate: 2017-06-07T05:10:22.922611-05:
      DOI: 10.1002/ajmg.a.38296
  • Clinical report: A patient with a late diagnosis of cerebrotendinous
           xanthomatosis and a response to treatment
    • Authors: Ahmad Alhariri; Katherine Hamilton, Vikash Oza, Kelly Cordoro, Nara L. Sobreira, Mary Malloy, Anne Slavotinek
      Abstract: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.
      PubDate: 2017-06-07T05:10:21.221885-05:
      DOI: 10.1002/ajmg.a.38314
  • Co-occurrence of Jalili syndrome and muscular overgrowth
    • Authors: Anna Wawrocka; Joanna Walczak-Sztulpa, Magdalena Badura-Stronka, Michal Owecki, Przemysław Kopczynski, Ewa Mrukwa-Kominek, Anna Skorczyk-Werner, Piotr Gasperowicz, Rafal Ploski, Maciej R. Krawczynski
      Abstract: Jalili syndrome is a rare disorder inherited in an autosomal recessive pattern manifesting as a combination of cone-rod dystrophy including progressive loss of visual acuity, color blindness, photophobia, and amelogenesis imperfecta with hypoplastic, immature, or hypocalcified dental enamel. It is caused by mutations in CNNM4, which encodes the ancient conserved domain protein 4. Here we report three brothers with Jalili syndrome and muscle overgrowth of the legs. Myopathic changes were found in needle electromyography. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant. In order to exclude other causative variants that could modify the patients’ phenotype we performed exome sequencing and MLPA analysis of the DMD gene in Patient 1. These analyses did not identify any additional variants. Our results expand the mutational spectrum associated with Jalili syndrome and suggest that mild myopathy with muscle overgrowth of the legs could be a newly identified manifestation of the disorder.
      PubDate: 2017-06-06T10:15:31.827271-05:
      DOI: 10.1002/ajmg.a.38318
  • A heterozygous microdeletion of 20p12.2–3 encompassing PROKR2 and BMP2
           in a patient with congenital hypopituitarism and growth hormone deficiency
    • Authors: Samuel J. H. Parsons; Neville B. Wright, Emma Burkitt-Wright, Mars S. Skae, Phillip G. Murray
      Abstract: Congenital growth hormone deficiency is a rare disorder with an incidence of approximately 1 in 4,000 live births. Pituitary development is under the control of a multitude of spatiotemporally regulated signaling molecules and transcription factors. Mutations in the genes encoding these molecules can result in hypopituitarism but for the majority of children with congenital hypopituitarism, the aetiology of their disease remains unknown. The proband is a 5-year-old girl who presented with neonatal hypoglycaemia and prolonged jaundice. No definitive endocrine cause of hypoglycaemia was identified in the neonatal period. She was born of normal size at 42 weeks but demonstrated growth failure with a progressive reduction in height to −3.2 SD by age 4.5 years and failed a growth hormone stimulation test with a peak growth hormone of 4.2 mcg/L. MRI of the pituitary gland demonstrated a hypoplastic anterior lobe and ectopic posterior lobe. Array CGH demonstrated an inherited 0.2 Mb gain at 1q21.1 and a de novo 4.8 Mb heterozygous deletion at 20p12.2–3. The deletion contained 17 protein coding genes including PROKR2 and BMP2, both of which are expressed during embryological development of the pituitary gland. PROKR2 mutations have been associated with hypopituitarism but a heterozygous deletion of this gene with hypopituitarism is a novel observation. In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies.
      PubDate: 2017-06-06T10:15:30.545219-05:
      DOI: 10.1002/ajmg.a.38306
  • Associated anomalies in cases with esophageal atresia
    • Authors: Claude Stoll; Yves Alembik, Beatrice Dott, Marie-Paule Roth
      Abstract: Esophageal atresia (EA) is a common type of congenital anomaly. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. Infants with esophageal atresia often have other non-EA associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with EA were collected in all livebirths, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 116 cases with esophageal atresia, representing a prevalence of 2.99 per 10,000, 54 (46.6%) had associated anomalies. There were 9 (7.8%) cases with chromosomal abnormalities including 6 trisomies 18, and 20 (17.2%) nonchromosomal recognized dysmorphic conditions including 12 cases with VACTERL association and 2 cases with CHARGE syndrome. Twenty five (21.6%) of the cases had multiple congenital anomalies (MCA). Anomalies in the cardiovascular, the digestive, the urogenital, the musculoskeletal, and the central nervous systems were the most common other anomalies. The anomalies associated with esophageal atresia could be classified into a recognizable malformation syndrome or pattern in 29 out of 54 cases (53.7%). This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA.
      PubDate: 2017-06-03T08:15:26.780356-05:
      DOI: 10.1002/ajmg.a.38303
  • Neuroradiographic findings in 22q11.2 deletion syndrome
    • Authors: Lauren A. Bohm; Tom C. Zhou, Tyler J. Mingo, Sarah L. Dugan, Richard J. Patterson, James D. Sidman, Brianne B. Roby
      Abstract: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.
      PubDate: 2017-06-03T08:15:23.427074-05:
      DOI: 10.1002/ajmg.a.38304
  • Anthropometric charts and congenital anomalies in newborns with Down
    • Authors: Clotilde Mircher; Jeanne Toulas, Cécile Cieuta-Walti, Isabelle Marey, Martine Conte, Laura González Briceño, Marie-Laure Tanguy, Marie-Odile Rethore, Aime Ravel
      Abstract: The objectives of this study were to obtain updated neonatal measurements in French newborns with Down Syndrome (DS) according to their gestational age, and to assess the frequency and distribution of congenital anomalies. Data on congenital malformations, birth weight, birth length and birth occipito-frontal circumference (OFC) according to the gestational age was gathered from 1,030 babies, born between 1980 and 2010. The mean gestational age was 38 weeks from the date of the last menstrual period (LMP) (range: 29–42 weeks). Repartition of complications was found to be similar to previous studies, with no difference according to the date of birth. For girls born after 37 weeks, the mean birth weight was 3,012 ± 430 g, the mean birth length was 47.7 ± 2 cm, and the mean birth OFC was 33 ± 1.4 cm. For boys born after 37 weeks, the mean birth weight was 3,103 ± 459, the mean birth length was 48.4 ± 2.2 cm, and the mean birth OFC was 33.2 ± 1.4 cm. We did not find any difference in these measurements when we compared children born before 1997 and after 2007. When compared to the general population (French data and WHO charts), newborns with DS have a more pronounced difference in their birth length and their birth OFC (15–25th) than in their birth weight (25–50th). The shape of the growth curves shows that growth velocity decreases during the last weeks of gestation in all measurements, which suggests that the modal age for delivery could be earlier in DS newborns than in the general population.
      PubDate: 2017-06-02T09:30:28.864234-05:
      DOI: 10.1002/ajmg.a.38305
  • A new diagnosis of Williams–Beuren syndrome in a 49-year-old man
           with severe bullous emphysema
    • Authors: Monica H. Wojcik; Nikkola Carmichael, Frederick R. Bieber, Daniel C. Wiener, Rachna Madan, Barbara R. Pober, Benjamin A. Raby
      Abstract: Williams–Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema where the diagnosis of WBS was established subsequent to the discovery of severe bullous emphysema. Haploinsufficiency of ELN likely contributed to this pulmonary manifestation of WBS. This case emphasizes the contribution of rare genetic variation in cases of severe emphysema and provides further evidence that emphysema should be considered in patients with WBS who have respiratory symptoms, as it may be under-recognized in this patient population.
      PubDate: 2017-06-02T07:05:53.563902-05:
      DOI: 10.1002/ajmg.a.38289
  • A heritable microduplication encompassing TBL1XR1 causes a genomic
           sister-disorder for the 3q26.32 microdeletion syndrome
    • Authors: Vera Riehmer; Florian Erger, Peter Herkenrath, Saskia Seland, Miriam Jackels, Alfred Wiater, Raoul Heller, Bodo B. Beck, Christian Netzer
      Abstract: Recently, a new syndrome with intellectual disability (ID) and dysmorphic features due to deletions or point mutations within the TBL1XR1 gene located in the chromosomal band 3q26.32 has been described (MRD41, OMIM 616944). One recurrent point mutation in the TBL1XR1 gene has been identified as the cause of Pierpont syndrome (OMIM 602342), a distinct intellectual disability syndrome with plantar lipomatosis. In addition, different de novo point mutations in the TBL1XR1 gene have been found in patients with autism spectrum disorders (ASD) and intellectual disability. Here, we report four patients from two unrelated families in whom array-CGH analysis and real-time quantitative PCR of genomic DNA revealed a TBL1XR1-microduplication. Adjacent genes were not affected. The microduplication occurred as a de novo event in one patient, whereas the other three cases occurred in two generations of a second, unrelated family. We compare and contrast the clinical findings in TBL1XR1 microdeletion, point mutation, and microduplication cases and expand the TBL1XR1-associated phenotypic spectrum. ID, hearing loss, and ASD are common features of TBL1XR1-associated diseases. Our clinical observations add to the increasing evidence of the role of TBL1XR1 in brain development, and they simultaneously demonstrate that different genetic disease mechanisms affecting TBL1XR1 can lead to similar ID phenotypes. The TBL1XR1-microduplication syndrome is an intellectual disability/learning disability syndrome with associated incomplete penetrance ASD, hearing loss, and delay of puberty. Its phenotypic overlap indicates that it is a genomic sister-disorder to the 3q26.32 microdeletion syndrome.
      PubDate: 2017-06-02T07:05:48.682743-05:
      DOI: 10.1002/ajmg.a.38285
  • A novel mutation in GMPPA in siblings with apparent intellectual
           disability, epilepsy, dysmorphism, and autonomic dysfunction
    • Authors: Wendy A. Gold; Nara Sobreira, Elsa Wiame, Alexandre Marbaix, Emile Van Schaftingen, Patricia Franzka, Lisa G. Riley, Lisa Worgan, Christian A. Hübner, John Christodoulou, Lesley C. Adès
      Abstract: GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5′-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.
      PubDate: 2017-06-02T07:05:43.052341-05:
      DOI: 10.1002/ajmg.a.38292
  • Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome
    • Authors: Jonathan Lévy; Aurélie Coussement, Céline Dupont, Fabien Guimiot, Clarisse Baumann, Géraldine Viot, Sandrine Passemard, Yline Capri, Séverine Drunat, Alain Verloes, Eva Pipiras, Brigitte Benzacken, Jean-Michel Dupont, Anne-Claude Tabet
      Abstract: Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype–phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype–genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.
      PubDate: 2017-06-01T22:16:21.418073-05:
      DOI: 10.1002/ajmg.a.38302
  • Auditory and otologic profile of Alström syndrome: Comprehensive single
           center data on 38 patients
    • Authors: Spencer Lindsey; Carmen Brewer, Olga Stakhovskaya, Hung Jeffrey Kim, Chris Zalewski, Joy Bryant, Kelly A. King, Jürgen K. Naggert, William A. Gahl, Jan D. Marshall, Meral Gunay-Aygun
      Abstract: Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7–37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5–15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10–15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation.
      PubDate: 2017-06-01T22:16:15.078227-05:
      DOI: 10.1002/ajmg.a.38316
  • Phenotypes and genotypes in individuals with SMC1A variants
    • Authors: Sylvia Huisman; Paul A. Mulder, Egbert Redeker, Ingrid Bader, Anne-Marie Bisgaard, Alice Brooks, Anna Cereda, Constanza Cinca, Dinah Clark, Valerie Cormier-Daire, Matthew A. Deardorff, Karin Diderich, Mariet Elting, Anthonie van Essen, David FitzPatrick, Cristina Gervasini, Gabriele Gillessen-Kaesbach, Katta M. Girisha, Yvonne Hilhorst-Hofstee, Saskia Hopman, Denise Horn, Mala Isrie, Sandra Jansen, Cathrine Jespersgaard, Frank J. Kaiser, Maninder Kaur, Tjitske Kleefstra, Ian D. Krantz, Phillis Lakeman, Annemiek Landlust, Davor Lessel, Caroline Michot, Jo Moss, Sarah E. Noon, Chris Oliver, Ilaria Parenti, Juan Pie, Feliciano J. Ramos, Claudine Rieubland, Silvia Russo, Angelo Selicorni, Zeynep Tümer, Rieneke Vorstenbosch, Tara L. Wenger, Ingrid van Balkom, Sigrid Piening, Jolanta Wierzba, Raoul C. Hennekam
      Abstract: SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.
      PubDate: 2017-05-26T07:40:43.373953-05:
      DOI: 10.1002/ajmg.a.38279
  • Presynaptic congenital myasthenic syndrome with a homozygous sequence
           variant in LAMA5 combines myopia, facial tics, and failure of
           neuromuscular transmission
    • Authors: Ricardo A. Maselli; Juan Arredondo, Jessica Vázquez, Jessica X. Chong, , Michael J. Bamshad, Deborah A. Nickerson, Marian Lara, Fiona Ng, Victoria L. Lo, Peter Pytel, Craig M. McDonald
      Abstract: Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
      PubDate: 2017-05-25T07:25:45.163113-05:
      DOI: 10.1002/ajmg.a.38291
  • A tumor profile in Patau syndrome (trisomy 13)
    • Authors: Daniel Satgé; Motoi Nishi, Nicolas Sirvent, Michel Vekemans, Marie-Pierre Chenard, Ann Barnes
      Abstract: Individuals with trisomic conditions like Down syndrome and Edwards syndrome are prone to certain types of malignancy. However, for Patau syndrome (constitutional trisomy 13), which occurs in 1/10,000–1/20,000 live births, the tumor profile has not been well characterized. An awareness of susceptibility to malignancies can improve care of affected individuals, as well as further our understanding of the contribution of trisomy to carcinogenesis. Therefore, we conducted an extensive review of the literature; we found 17 malignancies reported in individuals with Patau syndrome. These comprised eight embryonic tumors, three leukemias, two malignant germ cell tumors, two carcinomas, a malignant brain tumor, and a sarcoma. Benign tumors were mainly extragonadal teratomas. The small number of reported malignant tumors suggests that there is not an increased risk of cancer in the context of trisomy 13. The tumor profile in Patau syndrome differs from that observed in Edwards syndrome (trisomy 18) and Down syndrome (trisomy 21), suggesting that the supernumerary chromosome 13 could promote particular tumor formations as it does particular malformations. No general and direct relationships of tumor occurrence with organ weight, congenital malformations, histological changes, or presence of tumor suppressor genes on chromosome 13 were observed. However, some tumors were found in tissues whose growth and development are controlled by genes mapping to chromosome 13. Recent reports of successful outcomes following surgical treatment and adapted chemotherapy indicate that treatment of cancer is possible in Patau syndrome.
      PubDate: 2017-05-25T07:25:42.687639-05:
      DOI: 10.1002/ajmg.a.38294
  • 4.7 Mb deletion encompassing TGFB2 associated with features of
           Loeys–Dietz syndrome and osteoporosis in adulthood
    • Authors: Harald Gaspar; Bernd Lutz, Kerstin Reicherter, Simon Lühl, Rita Taurman, Heinz Gabriel, Rolf E. Brenner, Guntram Borck
      PubDate: 2017-05-25T07:25:30.331532-05:
      DOI: 10.1002/ajmg.a.38286
  • Correspondence to Gripp et al. nephroblastomatosis or Wilms tumor in a
           fourth patient with a somatic PIK3CA mutation
    • Authors: Floor A. M. Postema; Saskia M. J. Hopman, Matthew A. Deardorff, Johannes H. M. Merks, Raoul C. Hennekam
      PubDate: 2017-05-24T09:15:23.146703-05:
      DOI: 10.1002/ajmg.a.38290
  • A mutation in GABRB3 associated with Dravet syndrome
    • Authors: Sy Vinh Le; Phan Hoang Truc Le, Thi Khanh Van Le, Thi Thuy Kieu Huynh, Thi Thu Hang Do
      Abstract: Dravet syndrome is a rare and severe type of epilepsy in infants. Approximately, 70–80% of patients with Dravet syndrome have mutations in SCN1A, the gene encoding the alpha-1 subunit of the sodium channel, while some simplex patients have variants in one of several other genes, including but not limited to GABRA1, SCN2A, STXBP1, GABRG2, and SCN1B. In this study, we performed exome sequencing in six patients with SCN1A-negative Dravet syndrome to identify other genes related to this disorder. In one affected individual, we detected a novel de novo heterozygous missense variant, c.695G>A, p.(Arg232Gln), in GABRB3, the gene encoding the β3-subunit of the gamma-aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signaling within the central nervous system. In summary, the data in this study identify GABRB3 as a candidate gene for Dravet syndrome.
      PubDate: 2017-05-24T00:49:04.156321-05:
      DOI: 10.1002/ajmg.a.38282
  • 37th Annual David W. Smith Workshop on Malformations and Morphogenesis:
           Abstracts of the 2016 Annual Meeting
    • Authors: Kim M. Keppler-Noreuil; Julian A. Martinez-Agosto, Louanne Hudgins, John C. Carey
      Abstract: The 37th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on September 9th–14th, 2016 at the University of California—Los Angeles Conference Center in Lake Arrowhead, CA. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted five themes besides mechanisms of morphogenesis and New Syndromes: Neural Crestopathies, Mosaicism, Disorders of Skin Pigmentation, Therapies, and Ear Malformations and Hearing Loss. This Conference Report includes the abstracts presented at the 2016 Workshop.
      PubDate: 2017-05-24T00:49:00.747551-05:
      DOI: 10.1002/ajmg.a.38229
  • Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions
           including the SH2B1 gene
    • Authors: Lin Li; Linhuan Huang, Shaobin Lin, Yanmin Luo, Qun Fang
      Abstract: A 200∼240 kb SH2B1-containing deletion region on 16p11.2 is associated with early-onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microdeletion on 16p11.2 including 9 Refseq genes, including SH2B1, was identified in the twins. The novel findings in monozygotic twins may expand the phenotypic spectrum of 16p11.2 microdeletion. Further studies are needed to strengthen the correlation between genotypes and abnormal clinical features.
      PubDate: 2017-05-24T00:48:57.060141-05:
      DOI: 10.1002/ajmg.a.38284
  • Obstructive sleep apnea in Down syndrome: Benefits of surgery and
           noninvasive respiratory support
    • Authors: Benjamin Dudoignon; Alessandro Amaddeo, Annick Frapin, Briac Thierry, Livio de Sanctis, Jorge Olmo Arroyo, Sonia Khirani, Brigitte Fauroux
      Abstract: Children with Down syndrome are at increased risk of obstructive sleep apnea (OSA). The aim of the study was to describe the management of OSA in a large cohort of children with Down syndrome. A retrospective analysis of sleep studies and consequent management was performed for all consecutive Down syndrome patients evaluated between September 2013 and April 2016. The data of 57 patients were analyzed: 51/53 had an interpretable overnight polygraphy and 4 the recording of nocturnal gas exchange. Mean age at baseline sleep study was 6.2 ± 5.9 years. Eighteen patients (32%) had prior upper airway surgery. Mean apnea-hypopnea index (AHI) was 14 ± 16 events/hr with 41 of the 51 (80%) patients having OSA with an AHI >1 event/hr and 20 patients (39%) having an AHI ≥10 events/hr. Consequently, eight patients (14%) had upper airway surgery. OSA improved in all patients except two who needed noninvasive respiratory support. Nineteen (33%) patients required noninvasive respiratory support. Mean age at noninvasive respiratory support initiation was 7 ± 7 years. On 11 patients with objective adherence data available, mean compliance at 2 ± 1 years of treatment was excellent with an average use per night of 8 hr46 ± 3 hr59 and 9 patients using the noninvasive respiratory support >4 hr/night. Noninvasive respiratory support was associated with an improvement of nocturnal gas exchange. The prevalence of OSA is high in Down syndrome. Upper airway surgery is not always able to correct OSA. Noninvasive respiratory support represents then an effective treatment for OSA and good compliance may be achieved in a majority of patients.
      PubDate: 2017-05-24T00:48:43.294465-05:
      DOI: 10.1002/ajmg.a.38283
  • Haploinsufficiency of NR4A2 is associated with a neurodevelopmental
           phenotype with prominent language impairment
    • Authors: Miriam S. Reuter; Mandy Krumbiegel, Gregor Schlüter, Arif B. Ekici, André Reis, Christiane Zweier
      Abstract: Non-recurrent deletions in 2q24.1, minimally overlapping two genes, NR4A2 and GPD2, were recently described in individuals with language impairment and behavioral and cognitive symptoms. We herewith report on a female patient with a similar phenotype of severe language and mild cognitive impairment, in whom we identified a de novo deletion covering only NR4A2. NR4A2 encodes a transcription factor highly expressed in brain regions critical for speech and language and implicated in dopaminergic neuronal development. Our findings of a de novo deletion of NR4A2 in an individual with mild intellectual disability and prominent speech and language impairment provides further evidence for NR4A2 haploinsufficiency being causative for neurodevelopmental and particularly language phenotypes.
      PubDate: 2017-05-24T00:48:40.849187-05:
      DOI: 10.1002/ajmg.a.38288
  • A novel variant in MED12 gene: Further delineation of phenotype
    • Authors: Dhanya L. Narayanan; Shubha R. Phadke
      Abstract: MED12 is a multiprotein mediator complex, which has a role in cell growth and differentiation and has been implicated in three distinct X-linked intellectual disability syndromes with distinctive clinical features. These include Opitz–Kaveggia syndrome (FG syndrome), Lujan syndrome, and X-linked Ohdo syndrome. Recently MED12 variants have been implicated in isolated X-linked intellectual disability. We describe a 5-year-old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype–phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12-related disorders.
      PubDate: 2017-05-23T06:40:33.116977-05:
      DOI: 10.1002/ajmg.a.38295
  • Renal anomalies and lymphedema distichiasis syndrome. A rare
    • Authors: Gabriela E. Jones; Anna K. Richmond, Osric Navti, Hatem A. Mousa, Stephen Abbs, Edward Thompson, Sahar Mansour, Pradeep C. Vasudevan
      Abstract: Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.
      PubDate: 2017-05-23T06:40:23.722668-05:
      DOI: 10.1002/ajmg.a.38293
  • Identification of STAC3 variants in non-Native American families with
           overlapping features of Carey–Fineman–Ziter syndrome and Moebius
    • Abstract: Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey–Fineman–Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.
  • Skewed X-inactivation in a family with DLG3-associated X-linked
           intellectual disability
    • Abstract: Mutations in DLG3 are a rare cause of non-syndromic X-linked intellectual disability (XLID) (MRX90, OMIM *300189). Only ten DLG3 mutations have been reported to date. The majority of female heterozygous mutation carriers was healthy and had random X-inactivation patterns. We report on an XLID family with a novel DLG3 mutation. The 12-year-old male index patient had moderate intellectual disability (ID) and dysmorphic features. The mutation was also present in four female relatives. A maternal aunt had moderate ID and significantly skewed X-inactivation favorably inactivating the normal DLG3 allele. The proband's healthy mother also had skewed X-inactivation but in the opposite direction (i.e., inactivation of the mutated allele). Two other female relatives had intermediate cognitive phenotypes and random X-inactivation. This family broadens the mutational and phenotypical spectrum of DLG3-associated XLID and demonstrates that heterozygous female mutation carriers can be as severely affected as males. Reports of additional families will be needed to elucidate the causes of unfavorable skewing in female XLID patients.
  • A human case of SLC35A3-related skeletal dysplasia
    • Abstract: Researchers have identified a subset of Holstein having a range of skeletal deformities, including vertebral anomalies, referred to as complex vertebral malformation due to mutations in the SLC35A3 gene. Here, we report the first case in humans of SLC35A3-related vertebral anomalies. Our patient had prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus flammeus, and a cupped left ear. Clinical exome sequencing revealed a novel missense homozygous mutation in SLC35A3. Follow-up biochemical analysis confirmed abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter, validating the mutations. Congenital disorders of glycosylation, including SLC35A3-CDG, can present as a wide phenotypic spectrum, including skeletal dysplasia. Previously reported patients with SLC35A3-CDG have been described with syndromic autism, epilepsy, and arthrogryposis.
  • A novel genetic syndrome with STARD9 mutation and abnormal spindle
    • Abstract: Intellectual disability (ID) is one of neurodevelopmental disorders characterized by serious defects in both intelligence and adaptive behavior. Although it has been suggested that genetic aberrations associated with the process of cell division underlie ID, the cytological evidence for mitotic defects in actual patient's cells is rarely reported. Here, we report a novel mutation in the STARD9 (also known as KIF16A) gene found in a patient with severe ID, characteristic features, epilepsy, acquired microcephaly, and blindness. Using whole-exome sequence analysis, we sequenced potential candidate genes in the patient. We identified a homozygous single-nucleotide deletion creating a premature stop codon in the STARD9 gene. STARD9 encodes a 4,700 amino acid protein belonging to the kinesin superfamily. Depletion of STARD9 or overexpression of C-terminally truncated STARD9 mutants were known to induce spindle assembly defects in human culture cells. To determine cytological features in the patient cells, we isolated lymphoblast cells from the patient, and performed immunofluorescence analysis. Remarkably, mitotic defects, including multipolar spindle formation, fragmentation of pericentriolar materials and centrosome amplification, were observed in the cells. Taken together, our findings raise the possibility that controlled expression of full-length STARD9 is necessary for proper spindle assembly in cell division during human development. We propose that mutations in STARD9 result in abnormal spindle morphology and cause a novel genetic syndrome with ID.
  • ALG13-CDG in a male with seizures, normal cognitive development, and
           normal transferrin isoelectric focusing
    • Abstract: ALG13-CDG has been recently discovered as a disorder of severe developmental, intellectual and speech disability, microcephaly, visual abnormalities, seizures, hepatomegaly, coagulation abnormalities, and abnormal serumtransferrin isoelectric focusing in serum. A male with seizures, delayed motor, and speech development, but normal cognition carried a hemizygous, predicted pathogenic ALG13 variant (p.E463G). N-glycosylation studies in plasma were normal. ICAM-1 expression was decreased in patient fibroblasts, supporting the variant's pathogenicity. Adding D-galactose to the patient's fibroblast culture increased ICAM-1 expression in vitro, offering a potential treatment option in ALG13-CDG. The present report is a new example for an N-glycosylation disorder, that may present with normal transferrin isoform analysis, and also demonstrates, that CDG type I patients can have normal cognitive development.
  • Expanding the phenotype of DST-related disorder: A case report suggesting
           a genotype/phenotype correlation
    • Abstract: The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue-enriched isoforms in brain, muscle, and skin. The few patients described so far with bi-allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we report a 17-year-old female individual presenting with a more complex phenotype consisting of both skin and neuronal involvement, in addition to several previously unreported findings, such as iris heterochromia, cataract, hearing impairment, syringomyelia, behavioral, and gastrointestinal issues, osteoporosis, and growth hormone deficiency. Family-trio whole exome sequencing revealed that she was a compound heterozygous for two variants in the DST gene with highly-predicted functional impact, c.3886A>G (p.R1296X) in exon 29 and c.806C>T (p.H269R) in exon 7. Interestingly, exon 7 is included in the neuronal isoform whereas exon 29 is expressed in both skin and neuronal isoforms. The patient we described is the first case with a mutation affecting an exon expressed in both the neuronal and skin isoforms that can explain the more complex phenotype compared to previously reported cases.
  • Two unrelated children with overlapping 6q25.3 deletions, motor speech
           disorders, and language delays
    • Abstract: Interstitial and terminal 6q25 deletions are associated with developmental delays, hypotonia, eye pathologies, craniofacial dysmorphologies, and structural brain anomalies. In most cases, speech and language deficits are not described in detail. We report on a case (Patient 1, age 7 years) with a de novo 6q25.3-qter deletion, 11.1 Mb long and encompassing 108 genes, and a case (Patient 2, age 5 years) with an inherited interstitial 6q25.3 deletion, located within Patient 1's deletion region and 403 kb long, the smallest 6q25 deletion reported to date. Both children have hypotonia, motor speech disorders, and expressive language delays. Patient 1's speech was characterized by childhood apraxia of speech (CAS) and dysarthria. Other findings include developmental delay, ataxic cerebral palsy, optic nerve dysplagia, and atypical brain morphologies regarding the corpus callosum and gyration patterns, a clinical profile that closely matches a previously reported case with a nearly identical deletion. Patient 2 had speech characterized by CAS and typical nonverbal processing abilities. His father, a carrier, had typical speech and language but showed difficulties with complex motor speech and hand motor tasks, similar to other adults with residual signs of CAS. The small deletion in this family contains the IGF2R-AIRN-SLC22A2-SLC22A3 gene cluster, which is associated with imprinting and maternal-specific expression of Igf2R, Slc22a2, and Slc22a3 in mice, whereas imprinting in humans is a polymorphic trait. The shared phenotypes in the two patients might be associated with the deletion of the gene cluster.
  • Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with
           hypochondroplasia and hypophosphatasia
    • Abstract: Skeletal dysplasias are a complex group of more than 350 disorders with phenotypic and genotypic heterogeneity affecting bone and cartilage growth. We studied a 2-year-old girl and her 21-year-old mother with disproportionate short stature. In addition to typical features of hypochondroplasia found in both patients, the child had deformities of the extremity bones, metaphyseal flares, and bilateral transverse (Bowdler) fibular spurs with overlying skin dimples detected at birth. Intravenous pamidronate was started in the child since the age of 17 days, and then every two months. Exome sequencing revealed that the girl was heterozygous for a missense mutation (c.1651A>G, p.Ile538Val) in exon 13 of FGFR3, a known mutation for hypochondroplasia, inherited from her mother. Interestingly, the child also harbored compound heterozygous missense mutations in exon 12 of ALPL, c.1460C>T (p.Ala487Val) inherited from her mother and c.1479C>A (p.Asn493Lys) inherited from her healthy father. The former mutation was previously reported in perinatal hypophosphatasia while the latter was novel. Constantly reduced serum alkaline phosphatase levels including the one before the pamidronate administration and a substantially elevated level of plasma pyridoxal 5′-phosphate detected at age 28 months supported the diagnosis of hypophosphatasia. After a definite diagnosis was achieved, pamidronate was withdrawn at the age of 28 months. No adverse events were observed during pamidronate therapy. In conclusion, we describe a unique case with monoallelic FGFR3 and biallelic ALPL mutations leading to features of both hypochondroplasia and hypophosphatasia.
  • Best practices in peri-operative management of patients with skeletal
    • Abstract: Patients with skeletal dysplasia frequently require surgery. This patient population has an increased risk for peri-operative complications related to the anatomy of their upper airway, abnormalities of tracheal-bronchial morphology and function; deformity of their chest wall; abnormal mobility of their upper cervical spine; and associated issues with general health and body habitus. Utilizing evidence analysis and expert opinion, this study aims to describe best practices regarding the peri-operative management of patients with skeletal dysplasia. A panel of 13 multidisciplinary international experts participated in a Delphi process that included a thorough literature review; a list of 22 possible care recommendations; two rounds of anonymous voting; and a face to face meeting. Those recommendations with more than 80% agreement were considered as consensual. Consensus was reached to support 19 recommendations for best pre-operative management of patients with skeletal dysplasia. These recommendations include pre-operative pulmonary, polysomnography; cardiac, and neurological evaluations; imaging of the cervical spine; and anesthetic management of patients with a difficult airway for intubation and extubation. The goals of this consensus based best practice guideline are to provide a minimum of standardized care, reduce perioperative complications, and improve clinical outcomes for patients with skeletal dysplasia.
  • Three cases of multi-generational Pompe disease: Are current practices
           missing diagnostic and treatment opportunities'
    • Abstract: Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive metabolic myopathy with a broad clinical spectrum, ranging from infantile to late-onset presentations. In 2015, Pompe disease was added as a core condition to the Recommended Uniform Screening Panel for state newborn screening (NBS). The clinical importance of Pompe disease is evolving with the use of NBS, increasing awareness of the disease, and higher than previously reported disease prevalence; however, current practices miss additional diagnostic and potential treatment opportunities in close relatives of the family proband. In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late-onset clinical presentations of Pompe disease. The presence of multi-generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a proband's family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at-risk family members. Given that the initial symptoms of the slowly progressive late-onset presentation of Pompe disease may be mild or non-specific, enzymatic testing of all parents of affected infants should be considered.
  • Co-occurring Down syndrome and SUCLA2-related mitochondrial depletion
    • Abstract: Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2-related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who has a normal female chromosome complement, is significantly less affected compared to her brother. While the clinical and molecular findings have been reported in about 50 patients affected with a deficiency of succinate-CoA ligase caused by pathogenic variants in SUCLA2, this report describes the first known individual affected with both a mitochondrial depletion syndrome and trisomy 21.
  • Noonan syndrome in diverse populations
    • Abstract: Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low-set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.
  • Autopsy findings in EPG5-related Vici syndrome with antenatal onset
    • Abstract: Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome–lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.
  • Biallelic COL3A1 mutations result in a clinical spectrum of specific
           structural brain anomalies and connective tissue abnormalities
    • Abstract: Vascular Ehlers–Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3-year-old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C
  • MED resulting from recessively inherited mutations in the gene encoding
           calcium-activated nucleotidase CANT1
    • Abstract: Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80–85% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.
  • Whole exome sequencing identified genetic variations in Chinese
           hemangioblastoma patients
    • Abstract: Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include PCDH9, KLHL12, DCAF4L1, and VHL in sporadic HBs, and ZNF814, DLG2, RIMS1, PNN, and MUC7 in familial HBs. The frequency of CNV varied considerably within sporadic HBs but was relatively similar within familial HBs. Five genes, including OTOGL, PLCB4, SCEL, THSD4, and WWOX, have CNVs in the six patients with sporadic HBs, and three genes, including ABCA6, CWC27, and LAMA2, have CNVs in the five patients with familial HBs. We found new genetic mutations and CNVs that might be involved in HBs; these findings highlight the complexity of the tumorigenesis of HBs and pinpoint potential therapeutic targets for the treatment of HBs.
  • Agenesis of the corpus callosum, developmental delay, autism spectrum
           disorder, facial dysmorphism, and posterior polymorphous corneal dystrophy
           associated with ZEB1 gene deletion
    • Abstract: We report on a girl diagnosed prenatally with agenesis of the corpus callosum (ACC) on fetal ultrasound and MRI. On postnatal follow-up she was noted to have developmental delay, facial dysmorphism, autism spectrum disorder, and posterior polymorphous corneal dystrophy (PPD). Array-comparative genomic hybridization analysis (Array-CGH) showed a 2.05 Mb de novo interstitial deletion at 10p11.23p11.22. The deleted region overlaps 1 OMIM Morbid Map gene, ZEB1 (the zinc finger E-box binding homeobox transcription factor 1), previously associated with posterior polymorphous corneal dystrophy type 3 (PPCD3). To our best knowledge this is the first reported case with a deletion of the ZEB1 gene in an individual with ACC and PPD, showing that the haploinsufficiency of the ZEB1 is likely the cause of our patient's phenotype.
  • Novel PRPS1 gain-of-function mutation in a patient with congenital
           hyperuricemia and facial anomalies
    • Abstract: Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.
  • Additional report on Moreno-Nishimura-Schmidt overgrowth syndrome
  • Variable expressivity and incomplete penetrance in a large family with
           non-classical Diamond-Blackfan anemia associated with ribosomal protein
           L11 splicing variant
    • Abstract: Diamond-Blackfan anemia (DBA) is a group of clinically and genetically heterogeneous bone marrow failure disorders with or without congenital anomalies. Variable expressivity and incomplete penetrance have been observed within affected families. Diamond-Blackfan anemia-7 (DBA7), caused by heterozygous mutations in ribosomal protein L11 (RPL11), accounts for approximately 5% of DBA. DBA7 is usually characterized by early-onset bone marrow failure often accompanied by congenital malformations, especially thumb defects. Here, we present the case of a 2-year-old boy with chronic mild normocytic anemia, short stature, bilateral underdevelopment of the thumbs, atrial septal defect, and hypospadias. Hematological testing revealed slightly decreased hematocrit and hemoglobin, normal HbF, and elevated eADA. Family history included maternal relatives with thumb defects, but the mother's thumbs were normal. Clinical exome sequencing detected a maternally-inherited RPL11 variant, c.396+3A>G, that is predicted to affect splicing. A family correlation study of the identified variant demonstrates segregation with thumb anomalies in the mother's family. RNA studies suggest that the variant produces an alternative transcript that is likely susceptible to nonsense-mediated decay. This report summarizes the prevalence of non-anemia findings in DBA7 and describes a non-classical familial presentation of DBA7 more associated with thumb anomalies than with anemia.
  • Congenital disorders of glycosylation: The Saudi experience
    • Abstract: We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.
  • Drug discovery and development for rare genetic disorders
    • Abstract: Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.
  • The phenotype of EZH2 haploinsufficiency—1.2-Mb deletion at 7q36.1 in a
           child with tall stature and intellectual disability
    • Abstract: Weaver syndrome is a rare overgrowth syndrome with distinct facial features in young children and variable learning disability. Heterozygous missense mutations in EZH2 are present in over 90% of patients with Weaver syndrome but the exact mechanism by which EZH2 mutations cause Weaver syndrome is unknown. We report an 11-year-old boy with a de novo 1.2-Mb deletion at 7q36.1 including EZH2 who has tall stature, significant intellectual disability, and some physical features of Weaver syndrome. Emerging evidence in the literature indicates that Weaver syndrome EZH2 mutations may result in loss of function of the gene and our report suggests that haploinsufficiency of EZH2 may replicate the clinical phenotype of Weaver syndrome.
  • Cervical artery dissection expands the cardiovascular phenotype in
           FBN1-related Weill–Marchesani syndrome
    • Abstract: Weill–Marchesani syndrome (WMS) is a rare form of acromelic dysplasia that is characterized by distinctive skeletal, ocular, and cardiovascular abnormalities. Previously described cardiac manifestations of WMS include aortic and pulmonary valve stenosis, mitral valve prolapse, mitral stenosis, and QTc prolongation. Autosomal dominant forms of WMS result from heterozygous pathogenic variants in FBN1, a gene with a well characterized role in the pathogenesis of thoracic aortic aneurysm (TAA) in the context of Marfan syndrome. In contrast, only one patient has been reported with aortic disease in WMS. Although the risk of aortic dissection from preceding TAA remains the leading cause of morbidity for individuals with Marfan syndrome, rare reports of arterial dissection in the peripheral vasculature have been described. Peripheral artery dissection has not been previously reported in other FBN1-related diseases. We describe a three generation family with FBN1-related WMS whose cardiovascular manifestations include TAA and cervical artery dissection, thus expanding the cardiovascular phenotype of WMS. Further research is required to quantify these risks and establish appropriate recommendations for cardiovascular imaging, medical management, and prophylactic surgical intervention in individuals with FBN1­-related acromelic dysplasia.
  • Lin-Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B
           related disorders
    • Abstract: We report two patients with sagittal craniosynostosis, hypoplastic male genitalia, agenesis of the corpus callosum, thyroid abnormalities, and dysmorphic features which include short palpebral fissures and retrognathia. The clinical presentation of both patients was initially thought to be suggestive of Lin-Gettig syndrome (LGS), a multiple malformation syndrome associated with craniosynostosis that was initially reported in two brothers in 1990, with a third patient reported in 2003. Our first patient was subsequently found through exome sequencing to have a de novo mutation in KAT6B, c.4572dupT, p.(Thr1525Tyrfs*16). The second patient was ascertained as possible LGS, but KAT6B mutation testing was pursued clinically after the identification of the KAT6B mutation in Patient 1, and identified a de novo mutation, c.4205_4206delCT, p.(Ser1402Cysfs*5). The phenotypic spectrum of KAT6B mutations has been expanding since identification of KAT6B mutations in genitopatellar syndrome (GPS) and Say Barber Biesecker Young Simpson (SBBYS) syndrome patients. We show that craniosynostosis, which has not been previously reported in association with KAT6B mutations, may be part of the genitopatellar/Say Barber Biesecker Young Simpson spectrum. These two patients also further demonstrate the overlapping phenotypes of genitopatellar and SBBYS syndromes recently observed by others. Furthermore, we propose that it is possible that one or more of the previous cases of LGS may have also been due to mutation in KAT6B, and that LGS may actually be a variant within the KAT6B spectrum and not a distinct clinical entity.
  • Cover Image, Volume 173A, Number 8, August 2017
    • Abstract: The cover image, by Monica H. Wojcik et al., is based on the Clinical Report A new diagnosis of Williams-Beuren syndrome in a 49-year-old man with severe bullous emphysema,
      DOI : 10.1002/ajmg.a.38289.
  • Table of Contents, Volume 173A, Number 8, August 2017
  • Publication schedule for 2017
  • 23andMe resumes giving consumers genetic health information
  • Greater focus on patient data sharing urged
  • In this issue
  • Normal IQ is possible in Smith-Lemli-Opitz syndrome
    • Abstract: Children with Smith-Lemli-Opitz syndrome (SLOS) are typically reported to have moderate to severe intellectual disability. This study aims to determine whether normal cognitive function is possible in this population and to describe clinical, biochemical and molecular characteristics of children with SLOS and normal intelligent quotient (IQ). The study included children with SLOS who underwent cognitive testing in four centers. All children with at least one IQ composite score above 80 were included in the study. Six girls, three boys with SLOS were found to have normal or low-normal IQ in a cohort of 145 children with SLOS. Major/multiple organ anomalies and low serum cholesterol levels were uncommon. No correlation with IQ and genotype was evident and no specific developmental profile were observed. Thus, normal or low-normal cognitive function is possible in SLOS. Further studies are needed to elucidate factors contributing to normal or low-normal cognitive function in children with SLOS.
  • CMIP haploinsufficiency in two patients with autism spectrum disorder and
           co-occurring gastrointestinal issues
    • Abstract: Autism spectrum disorder (ASD) is a genetically heterogeneous group of disorders characterized by impairments in social communication and restricted interests. Though some patients with ASD have an identifiable genetic cause, the cause of most ASD remains elusive. Many ASD susceptibility loci have been identified through clinical studies. We report two patients with syndromic ASD and persistent gastrointestinal issues who carry de novo deletions involving the CMIP gene detected by genome-wide SNP microarray and fluorescence in situ hybridization (FISH) analysis. Patient 1 has a 517 kb deletion within 16q23.2q23.3 including the entire CMIP gene. Patient 2 has a 1.59 Mb deletion within 16q23.2q23.3 that includes partial deletion of CMIP in addition to 12 other genes, none of which have a known connection to ASD or other clinical phenotypes. The deletion of CMIP is rare in general population and was not found among a reference cohort of approximately 12,000 patients studied in our laboratory who underwent SNP array analysis for various indications. A 280 kb de novo deletion containing the first 3 exons of CMIP was reported in one patient who also demonstrated ASD and developmental delay. CMIP has previously been identified as a susceptibility locus for specific language impairment (SLI). It is notable that both patients in this study had significant gastrointestinal issues requiring enteral feedings, which is unusual for patients with ASD, in addition to unusually elevated birth length, further supporting a shared causative gene. These findings suggest that CMIP haploinsufficiency is the likely cause of syndromic ASD in our patients.
  • Automatic recognition of the XLHED phenotype from facial images
    • Abstract: X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder that affects ectodermal structures and presents with a characteristic facial appearance. The ability of automated facial recognition technology to detect the phenotype from images was assessed . In Phase 1 of this study we examined if the age of male patients affected the technology's recognition. In Phase 2 we investigated how well the technology discriminated affected males cases from female carriers and from individuals with other ectodermal dysplasia syndromes. The system detected XLHED to be the most likely diagnosis in all genetically confirmed affected male patients of all ages, and in 55% of heterozygous females. Interestingly, patients with other ED syndromes were also detected by the XLHED-targeted analysis, consistent with shared developmental features. Thus the automated facial recognition system represents a promising non-invasive technology to screen patients at all ages for a possible diagnosis of ectodermal dysplasia, with greatest sensitivity and specificity for males affected with XLHED.
  • A novel microduplication of ARID1B: Clinical, genetic, and proteomic
    • Abstract: Genetic alterations of ARID1B have been recently recognized as one of the most common mendelian causes of intellectual disability and are associated with both syndromic and non-syndromic phenotypes. The ARID1B protein, a subunit of the chromatin remodeling complex SWI/SNF-A, is involved in the regulation of transcription and multiple downstream cellular processes. We report here the clinical, genetic, and proteomic phenotypes of an individual with a unique apparent de novo mutation of ARID1B due to an intragenic duplication. His neurodevelopmental phenotype includes a severe speech/language disorder with full scale IQ scores 78–98 and scattered academic skill levels, expanding the phenotypic spectrum of ARID1B mutations. Haploinsufficiency of ARID1B was determined both by RNA sequencing and quantitative RT-PCR. Fluorescence in situ hybridization analysis supported an intragenic localization of the ARID1B copy number gain. Principal component analysis revealed marked differentiation of the subject's lymphoblast proteome from that of controls. Of 3426 proteins quantified, 1014 were significantly up- or down-regulated compared to controls (q 
  • Diagnosis of Xeroderma pigmentosum variant in a young patient with two
           novel mutations in the POLH gene
    • Abstract: We describe the characterization of Xeroderma Pigmentosum variant (XPV) in a young Caucasian patient with phototype I, who exhibited a high sensitivity to sunburn and multiple cutaneous tumors at the age of 15 years. Two novel mutations in the POLH gene, which encodes the translesion DNA polymerase η, with loss of function due to two independent exon skippings, are reported to be associated as a compound heterozygous state in the patient. Western blot analysis performed on proteins from dermal fibroblasts derived from the patient and analysis of the mutation spectrum on immunoglobulin genes produced during the somatic hypermutation process in his memory B cells, show the total absence of translesion polymerase η activity in the patient. The total lack of Polη activity, necessary to bypass in an error-free manner UVR-induced pyrimidine dimers following sun exposure, explains the early unusual clinical appearance of this patient.
  • RNF213 variants in a child with PHACE syndrome and moyamoya vasculopathy
    • Abstract: Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.
  • Demographics and co-occurring conditions in a clinic-based cohort with
           Down syndrome in the United Arab Emirates
    • Abstract: The majority of studies describing demographics and co-occurring conditions in cohorts with Down syndrome come from regions outside of the Middle East, mainly from Europe and North America. This paper describes demographics and co-occurring conditions in a hospital-based cohort of individuals with Down syndrome living in the Middle Eastern country of the United Arab Emirates (UAE). The first dedicated Down syndrome clinic in the UAE was established in 2012 at Tawam Hospital in Al Ain. This paper describes a clinic-based cohort of 221 participants over 4 years from the Gulf Down Syndrome Registry, a new Down syndrome database and contact registry created at Tawam Hospital. Key demographic findings include mean maternal age of 37 years, among the highest described in the literature. Sixty-two percent of mothers are >35 years. Over 90% of mothers received post-natal diagnosis of Down syndrome. High sex ratio, parental consanguinity, and large family size also characterize the group. The spectrum of many co-occurring conditions mirrors that of previously described populations, with some notable differences. Cardiovascular malformations are well represented, however, atrioventricular canal is not the most common. Genitourinary conditions are common, as evidenced by 12% of males with hypospadias and 15% with undescended testes. Glucose-6-phosphate dehydrogenase deficiency, alpha thalassemia trait, hypovitaminosis D, and dental caries are common in our cohort. This study describes a large hospital-based group with Down syndrome presenting to a new dedicated Down syndrome clinic in the UAE, highlighting unique demographic and co-occurring conditions found in that population.
  • Juvenile-onset generalized lipodystrophy due to a novel heterozygous
           missense LMNA mutation affecting lamin C
    • Abstract: The LMNA gene contains 12 exons and encodes lamins A and C by alternative splicing within exon 10. While mutations in lamin A specific residues cause several diseases including lipodystrophy, progeria, muscular dystrophy, neuropathy, and cardiomyopathy, only three families with mutations in lamin C-specific residues are reported with cardiomyopathy, neuropathy, and muscular dystrophy so far. We now report two brothers with juvenile-onset generalized lipodystrophy due to a lamin C-specific mutation. The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis, and kidney failure. His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age. Their father also died of end stage renal disease at age 52 years. Exome sequencing of the proband revealed an extremely rare missense heterozygous variant c.1711_1712CG>TC; p.(Arg571Ser) in LMNA which was confirmed by Sanger sequencing in both the patients. Interestingly, the mutation had no effect on mRNA splicing or relative expression of lamin A or C mRNA and protein in the lymphoblasts. Our observations suggest that mutant lamin C disrupts its interaction with other cellular proteins resulting in generalized lipodystrophy due to defective development and maintenance of adipose tissue.
  • Blake's pouch cyst in 13q deletion syndrome: Posterior fossa malformations
           may occur due to disruption of multiple genes
  • Homozygous null variant in CRADD, encoding an adaptor protein that
           mediates apoptosis, is associated with lissencephaly
    • Abstract: Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause “thin” lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling.
  • Neural tube defects in Waardenburg syndrome: A case report and review of
           the literature
    • Abstract: Waardenburg syndrome type 1 (WS1) is an autosomal dominant genetic condition characterized by sensorineural deafness and pigment abnormalities, and is caused by variants in the PAX3 homeodomain. PAX3 variants have been associated with severe neural tube defects in mice and humans, but the frequency and clinical manifestations of this symptom remain largely unexplored in humans. Consequently, the role of PAX3 in human neural tube formation remains a study of interest, for clinical as well as research purposes. Though the association between spina bifida and WS1 is now well-documented, no study has attempted to characterize the range of spina bifida phenotypes seen in WS. Spina bifida encompasses several diagnoses with a wide scope of clinical severity, ranging from spina bifida occulta to myelomeningocele. We present a patient with Waardenburg syndrome type 1 caused by a novel missense variant in PAX3, presenting with myelomeningocele, Arnold-Chiari malformation, and hydrocephalus at birth. Additionally, we review 32 total cases of neural tube defects associated with WS. Including this report, there have been 15 published cases of myelomeningocele, 10 cases of unspecified spina bifida, 3 cases of sacral dimples, 0 cases of meningocele, and 4 cases of miscellaneous other neural tube defects. Though the true frequency of each phenotype cannot be determined from this collection of cases, these results demonstrate that Waardenburg syndrome type 1 carries a notable risk of severe neural tube defects, which has implications in prenatal and genetic counseling.
  • Next generation deep sequencing corrects diagnostic pitfalls of
           traditional molecular approach in a patient with prenatal onset of Pompe
    • Abstract: Pompe disease is a rare inherited metabolic disorder of glycogen metabolism caused by mutations in the GAA gene, encoding the acid α-1,4 glucosidase. Successful diagnosis of Pompe disease is achieved by clinical and biochemical evaluation followed by confirmation with DNA testing. Here, we report a male infant with a prenatal onset of cardiac symptoms and enzyme testing consistent with Pompe disease, but DNA testing by Sanger sequencing revealed no pathogenic variants. Due to the strong indication from clinical, enzymatic, and histological studies (despite the absence of molecular confirmation by traditional Sanger sequencing), enzyme replacement therapy (ERT) for Pompe disease was initiated. Reanalysis of the patient's DNA sample using next generation sequencing (NGS) of a panel of target genes causing glycogen storage disorders demonstrated compound heterozygosity for a point mutation and an exonic deletion in the GAA gene. This case illustrates the value of astute clinical judgement in patient management as well as the power of target capture deep NGS in the simultaneous detection of both a point mutation and a heterozygous exonic deletion by correcting pitfalls of the traditional PCR based sequencing, namely; allele dropout and the inability to detect exonic deletions.
  • FOXC1 haploinsufficiency due to 6p25 deletion in a patient with rapidly
           progressing aortic valve disease
    • Abstract: 6p25 deletion is a rare but well-known entity. The main clinical features include an abnormal facial appearance, developmental delay, and ocular anomalies. Cardiac anomalies are frequently seen but remain poorly delineated. We describe a 4-year-old girl with 6p25.3 deletion, which includes the FOXC1 gene, typical dysmorphic features associated with developmental delay and oculo-motor anomalies. Aortic valve dysplasia was diagnosed early in life. The cardiac lesion progressed very rapidly between the age of 3 and 4 years requiring aortic valve replacement. Genomic analysis of blood and excised valve tissue showed down-regulation of FOXC1 but also FOXC2 expression in the diseased aortic valve. This allows us to speculate on the potential role of FOXC1 in aortic valve anomalies.
  • Assessment of large copy number variants in patients with apparently
           isolated congenital left-sided cardiac lesions reveals clinically relevant
           genomic events
    • Abstract: Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.
  • A prenatal diagnosis of mosaic trisomy 5 reveals a postnatal complete
           uniparental disomy of chromosome 5 with multiple congenital anomalies
    • Abstract: Mosaic trisomy 5 is a very rare condition in liveborns, with few cases reported in the last four decades. There are some reports of prenatally diagnosed mosaic trisomy 5 resulting in phenotypically normal offspring, suggesting a low level of mosaicism, but there are also reports associated with multiple congenital anomalies, cardiovascular malformations, and intrauterine growth restriction. We report an infant male diagnosed with mosaic trisomy 5 (5/15 cells) via amniocentesis. The patient was subsequently found to have uniparental disomy 5 (UPD5) by postnatal chromosome microarray, but high-resolution chromosome analysis on peripheral blood did not identify trisomy 5. Dysmorphic features included a tall forehead with low anterior hairline, hypertelorism, low-set ears, and a prominent nose and midface. Other anomalies included bilateral bifid thumbs, hypospadias, a perineal fistula, unilateral multicystic kidney, and decreased subcutaneous fat with loose skin. He had complex congenital heart disease consisting of ventricular and atrial septal defects and polyvalvular defects. The patient died at age one after a prolonged admission. We add this case to the literature with the added benefit of data from a postnatal microarray, which was not available in other cases, to broaden the phenotype of mosaic trisomy 5 and UPD5.With the current available technology, we stress the importance of postnatal genetic testing to confirm prenatal cytogenetic findings in order to further define such phenotypes. This will provide the most accurate information and counseling to affected families.
  • Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase,
           causes severe infantile onset leukoencephalopathy
    • Abstract: Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.
  • von Hippel-Lindau development in children and adolescents
    • Abstract: The autosomal dominant von Hippel-Lindau disease (vHL) is associated with a lifelong risk of tumor development, especially retinal and CNS hemangioblastomas, pheochromocytoma, and renal cell carcinoma. Knowledge of paediatric vHL development is limited, and current surveillance guidelines are based on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started surveillance before 18 years: 37 Danish patients from the national vHL research database and 62 international patients reported in 15 articles. Overall, 70% (69 of 99) developed manifestations before 18 years (median age at first manifestation: 12 years (range: 6–17 years)). Thirty per cent (30 of 99) had developed more than one manifestation type; the most frequent were retinal (34%) and CNS (30%) hemangioblastomas. Among the 37 Danish patients, 85% (97 of 116) of their tumors were asymptomatic. Vision outcome is significantly improved in hemangioblastomas that are treated while still asymptomatic. We agree with current guidelines that retinal surveillance be performed from birth. The patients had their first CNS hemangioblastomas at the median ages of 13–14 years (range: 6–17 years). Further, 11% (4 of 37) of the Danish patients had CNS surgery in their teenage years. Although the cohort is too small to make definite conclusions about specific initiation ages, regular CNS surveillance from vHL patients’ teenage years seems clinically relevant.
  • Craniosynostosis in patients with RASopathies: Accumulating clinical
           evidence for expanding the phenotype
    • Abstract: RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.
  • Two patients with the heterozygous R189H mutation in ACTA2 and Complex
           congenital heart defects expands the cardiac phenotype of multisystemic
           smooth muscle dysfunction syndrome
  • Expansion of the phenotype of Kosaki overgrowth syndrome
    • Abstract: Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.
  • Progressive SCAR14 with unclear speech, developmental delay, tremor, and
           behavioral problems caused by a homozygous deletion of the SPTBN2
           pleckstrin homology domain
    • Abstract: We report on nine members of a consanguineous Pakistani family with primary presentation of intellectual disability, developmental delay, limb and gait ataxia, behavioral and speech problems, and tremor. By linkage mapping and exome sequencing we identified novel homozygous splicing variant c.6375-1G>C in SPTBN2. To date, only two other SPTBN2 mutations with recessive pattern of inheritance causing SCAR14 (spinocerebellar ataxia, autosomal recessive 14) that manifest with developmental ataxia and cognitive impairment, or cerebellar ataxia, mental retardation, and pyramidal signs have been reported. The mutation we identified is predicted to lead to the deletion of just the pleckstrin homology domain; thus, the earlier onset and more progressive nature of the disease in the presented family, as compared to earlier reports, were unexpected. No other mutation that could possibly explain the features that were unusual for SCAR14—arched palate, limb hypotonia, climacophobia, and behavioral problems—was identified. The disease was more severe in males than females. Our findings expand the recessive SPTBN2 mutation phenotype. We also review SPTBN2 mutation phenotypes. The gene encodes beta-III spectrin, which forms tetramers with alpha-II spectrin. The manifestations of this third recessive mutation suggest that for recessive mutations either no mutant protein is synthesized because the transcript is subject to nonsense-mediated decay or the mutant protein does not bind membrane proteins and, thus, does not exert a negative effect in heterozygotes, whereas the dominant mutations causing SCA5 form defective tetramers that compete with the native tetramers in binding membrane proteins, but are unable to anchor them.
  • Variants in KAT6A and pituitary anomalies
  • Marfan syndrome with a homozygous FBN1 splicing mutation
  • Xq26.1-26.3 duplication including MOSPD1 and GPC3 identified in boy with
           short stature and double outlet right ventricle
    • Abstract: Xq25q26 duplication syndrome has been reported in individuals with clinical features such as short stature, intellectual disability, syndromic facial appearance, small hands and feet, and genital abnormalities. The symptoms are related to critical chromosome regions including Xq26.1-26.3. In this particular syndrome, no patient with congenital heart disease was previously reported. Here, we report a 6-year-old boy with typical symptoms of Xq25q26 duplication syndrome and double outlet right ventricle (DORV) with pulmonary atresia (PA). He had the common duplicated region of Xq25q26 duplication syndrome extending to the distal region including the MOSPD1 locus. MOSPD1 regulates transforming growth factor beta (TGFβ) 2,3 and may be responsible for cardiac development including DORV. In the patient's lymphocytes, mRNA expression of TGFβ2 was lower than control, and might cause DORV as it does in TGFβ2-deficient mice. Therefore, MOSPD1 is a possible candidate gene for DORV, probably in combination with GPC3. Further studies of the combined functions of MOSPD1 and GPC3 are needed, and identification of additional patients with MOSPD1 and GPC3 duplication should be pursued.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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