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Publisher: John Wiley and Sons   (Total: 1589 journals)

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Showing 1 - 200 of 1589 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: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 48, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 53, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 168, 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: 6, 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: 37, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 5)
Addiction     Hybrid Journal   (Followers: 36, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 14, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, 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: 51, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 295, 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: 7, 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: 21)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 13)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 11)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 16, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 11, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 3, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 32, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 51, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 152, 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: 93, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 29, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 35, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 13, 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: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 290, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 16, 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: 18, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 138, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 9, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 20)
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: 179)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 229, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 41, 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: 7, 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: 48, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 1, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 8, 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: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, 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: 91, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 50, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 8, 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: 70, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 209, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 50, 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: 32, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, 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: 29, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 26, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 13, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 274, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 54, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 15)
Asia & the Pacific Policy Studies     Open Access   (Followers: 16)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 326, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, 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: 4, 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   (Followers: 1, SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 6, 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: 3, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 15, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, 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: 6, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 14, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 47, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 31, 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: 15, 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: 419, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 72, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 23, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 36, 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: 11, 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: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 10, 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: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 5, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 41, 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: 44, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 152, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 38, 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: 7, 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: 247, 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]   [16 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  [1589 journals]
  • Spectrum of bone marrow pathology and hematological abnormalities in
           methylmalonic acidemia
    • Authors: Nasir A. Bakshi; Talal Al-Anzi, Said Y. Mohamed, Zuhair Rahbeeni, Moeen AlSayed, Mohammed Al-Owain, Raashda A. Sulaiman
      Abstract: Patients with isolated methylmalonic acidemia (MMA) may present with a wide range of hematological complications including anemia, leukopenia, thrombocytopenia, and pancytopenia. However, there are very limited data on the development of hemophagocytosis or myelodysplasia in these patients. We report three patients with isolated MUT related MMA who presented with severe refractory pancytopenia during acute illness. Their bone marrow examination revealed a wide spectrum of pathology varying from bone marrow hypoplasia, hemophagocytosis to myelodysplasia with ring sideroblasts. We discuss their management and outcome. This report emphasizes the need for bone marrow examination in these patients with refractory or unexplained severe cytopenia, to confirm bone marrow pathology, and to rule out other diseases with similar clinical presentation for a better clinical outcome.
      PubDate: 2018-01-13T02:00:30.410064-05:
      DOI: 10.1002/ajmg.a.38599
  • A novel pathogenic MYH3 mutation in a child with Sheldon–Hall
           syndrome and vertebral fusions
    • Authors: Marcello Scala; Andrea Accogli, Elisa De Grandis, Anna Allegri, Christoph P. Bagowski, Moneef Shoukier, Mohamad Maghnie, Valeria Capra
      Abstract: Sheldon–Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non‐progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman–Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3‐related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3‐related disorders.
      PubDate: 2018-01-05T02:40:36.905966-05:
      DOI: 10.1002/ajmg.a.38593
  • UBE2A deficiency in two siblings: A novel splicing variant inherited from
           a maternal germline mosaicism
    • Authors: Teresa Giugliano; Claudia Santoro, Annalaura Torella, Francesca Del Vecchio Blanco, Pia Bernardo, Vincenzo Nigro, Giulio Piluso
      Abstract: UBE2A deficiency is a syndromic condition of X-linked intellectual disability (ID) characterized by typical dysmorphic features that include synophrys, prominent supraorbital ridges, almond-shaped, and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, micropenis, and onychodystrophy. To date, only seven familial UBE2A intragenic mutations and nine larger microdeletions encompassing UBE2A have been reported. Here, we describe two siblings with X-linked ID and typical clinical features of UBE2A deficiency caused by a novel hemizygous variant, identified by massively parallel sequencing of X-exome. The synonymous c.330G>A substitution in UBE2A modifies the last nucleotide of exon 5, causing the exon skipping and resulting in an out-of-frame transcript, likely encoding for a truncated form of the ubiquitin-conjugating enzyme E2 A. As confirmed by deep sequencing, the c.330G>A substitution in UBE2A was undetectable in genomic DNA from maternal blood cells, suggesting that the recurrent UBE2A deficiency observed in males of this family is caused by a maternal germline mosaicism.
      PubDate: 2017-12-28T06:26:26.082935-05:
      DOI: 10.1002/ajmg.a.38589
  • Phenotypic heterogeneity of POMT2 gene variants
    • Authors: Josef Finsterer
      PubDate: 2017-12-28T06:26:07.683884-05:
      DOI: 10.1002/ajmg.a.38588
  • Genetic diagnosis of Down syndrome in an underserved community
    • Authors: Andrew K. Sobering; Joshua B. Stevens, Janice L. Smith, Beverly Nelson, Tyhiesia Donald, Sarah H. Elsea
      Abstract: It is a matter of course that in high‐income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low‐ and middle‐income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource‐limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource‐limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.
      PubDate: 2017-12-26T08:45:21.726861-05:
      DOI: 10.1002/ajmg.a.38573
  • Arthrogryposis and pterygia as lethal end manifestations of genetically
           defined congenital myopathies
    • Authors: Atif A. Ahmed; Priya Skaria, Nicole P. Safina, Isabelle Thiffault, Alex Kats, Eugenio Taboada, Sultan Habeebu, Carol Saunders
      Abstract: Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.
      PubDate: 2017-12-23T08:00:28.074253-05:
      DOI: 10.1002/ajmg.a.38577
  • Severe rhizomelic shortening in a child with a complex
           duplication/deletion rearrangement of chromosome X
    • Authors: Ashish R. Deshwar; Lucie Dupuis, Carsten Bergmann, James Stavropoulos, Roberto Mendoza-Londono
      Abstract: Mesomelic and rhizo‐mesomelic dysplasias are a group of disorders characterized by abnormal shortening of the limbs. One of the most common causes of mesomelic shortening is the loss of the transcription factor SHOX. In this clinical report, we present a patient who in addition to mesomelic shortening has severe rhizomelic shortening and developmental delay. Karyotyping revealed a recombinant X chromosome in which the region distal to Xp22.33 (where SHOX is found) was replaced with material from Xq28. Included in the region distal to Xq28 is the gene MECP2 and this patient presents with features of MECP2 duplication syndrome. We find that this patient has skeletal features not typical with the loss of SHOX that are likely explained by the rearrangement of the X chromosome. Further delineation of this rearrangement may allow for the identification of additional genetic mechanisms critical for the development of the limbs.
      PubDate: 2017-12-22T07:50:58.473599-05:
      DOI: 10.1002/ajmg.a.38570
  • Prader–Willi syndrome and early‐onset morbid obesity NIH rare disease
           consortium: A review of natural history study
    • Authors: Merlin G. Butler; Virginia Kimonis, Elisabeth Dykens, June A. Gold, Jennifer Miller, Roy Tamura, Daniel J. Driscoll
      Abstract: We describe the National Institutes of Health rare disease consortium for Prader–Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11‐q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early‐onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11‐q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype–phenotype correlations, and clinical outcomes in PWS.
      PubDate: 2017-12-22T07:50:55.52615-05:0
      DOI: 10.1002/ajmg.a.38582
  • Elsahy–Waters syndrome is caused by biallelic mutations in CDH11
    • Authors: Frederike L. Harms; Sheela Nampoothiri, Shams Anazi, Dhanya Yesodharan, Malik Alawi, Kerstin Kutsche, Fowzan S. Alkuraya
      Abstract: Elsahy–Waters syndrome (EWS), also known as branchial–skeletal–genital syndrome, is a distinct dysmorphology syndrome characterized by facial asymmetry, broad forehead, marked hypertelorism with proptosis, short and broad nose, midface hypoplasia, intellectual disability, and hypospadias. We have recently published a homozygous potential loss of function variant in CDH11 in a boy with a striking resemblance to EWS. More recently, another homozygous truncating variant in CDH11 was reported in two siblings with suspected EWS. Here, we describe in detail the clinical phenotype of the original CDH11‐related patient with EWS as well as a previously unreported EWS‐affected girl who was also found to have a novel homozygous truncating variant in CDH11, which confirms that EWS is caused by biallelic CDH11 loss of function mutations. Clinical features in the four CDH11 mutation‐positive individuals confirm the established core phenotype of EWS. Additionally, we identify upper eyelid coloboma as a new, though infrequent clinical feature. The pathomechanism underlying EWS remains unclear, although the limited phenotypic data on the Cdh11−/− mouse suggest that this is a potentially helpful model to explore the craniofacial and brain development in EWS‐affected individuals.
      PubDate: 2017-12-22T07:50:53.769886-05:
      DOI: 10.1002/ajmg.a.38568
  • Expanding the phenotype associated with biallelic WDR60 mutations:
           Siblings with retinal degeneration and polydactyly lacking other features
           of short rib thoracic dystrophies
    • Authors: Naseebullah Kakar; Denise Horn, Eva Decker, Nadine Sowada, Christian Kubisch, Jamil Ahmad, Guntram Borck, Carsten Bergmann
      Abstract: Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra‐ and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short‐rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high‐throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N‐terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co‐segregated with the disease in the family. Our finding broadens the spectrum of WDR60‐related phenotypes and shows the utility of broad multigene panels during the genetic work‐up of patients with ciliopathies.
      PubDate: 2017-12-22T07:50:47.479873-05:
      DOI: 10.1002/ajmg.a.38562
  • The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of
           the CR3 region in two patients with Noonan syndrome, including one with a
           rare brain tumor
    • Authors: Frederike L. Harms; Malik Alawi, David J. Amor, Tiong Y. Tan, Goran Cuturilo, Christina Lissewski, Julia Brinkmann, Denny Schanze, Kerstin Kutsche, Martin Zenker
      Abstract: Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS‐MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C‐terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial‐like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well‐established association of NS with malignant tumors, especially childhood hemato‐oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.
      PubDate: 2017-12-22T07:50:25.012939-05:
      DOI: 10.1002/ajmg.a.38569
  • A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of
           phenotype, dysmorphology, and natural history
    • Authors: Lauren Jeffries; Hirohito Shima, Weizhen Ji, David Panisello-Manterola, James McGrath, Lynne M. Bird, Monica Konstantino, Satoshi Narumi, Saquib Lakhani
      Abstract: Germline gain‐of‐function variants in SAMD9 have been associated with a high risk of mortality and a newly recognized constellation of symptoms described by the acronym MIRAGE: Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy. Here, we describe two additional patients currently living with the syndrome, including one patient with a novel de novo variant for which we provide functional data supporting its pathogenicity. We discuss features of dysmorphology, contrasting with previously described patients as well as drawing attention to additional clinical features, dysautonomia and hearing loss that have not previously been reported. We detail both patients’ courses following diagnosis, with attention to treatment plans and recommended specialist care. Our patients are the oldest known with arginine‐substituting amino acid variants, and we conclude that early diagnosis and multidisciplinary management may positively impact outcomes for this vulnerable group of patients.
      PubDate: 2017-12-21T08:03:20.858085-05:
      DOI: 10.1002/ajmg.a.38557
  • Manifestation of recessive combined D‐2‐, L‐2‐hydroxyglutaric
           aciduria in combination with 22q11.2 deletion syndrome
    • Authors: Mariko Eguchi; Erina Ozaki, Toshifumi Yamauchi, Masaaki Ohta, Takashi Higaki, Kiyoshi Masuda, Issei Imoto, Eiichi Ishii, Minenori Eguchi-Ishimae
      Abstract: 22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life‐threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D‐2‐ and L‐2‐hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.
      PubDate: 2017-12-19T07:45:36.637501-05:
      DOI: 10.1002/ajmg.a.38578
  • The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood
    • Authors: Laura S. Farach; Mary E. Little, Angela L. Duker, Clare V. Logan, Andrew Jackson, Jaqueline T. Hecht, Michael Bober
      Abstract: RNU4ATAC pathogenic variants to date have been associated with microcephalic osteodysplastic primordial dwarfism, type 1 and Roifman syndrome. Both conditions are clinically distinct skeletal dysplasias with microcephalic osteodysplastic primordial dwarfism, type 1 having a more severe phenotype than Roifman syndrome. Some of the overlapping features of the two conditions include developmental delay, microcephaly, and immune deficiency. The features also overlap with Lowry Wood syndrome, another rare but well‐defined skeletal dysplasia for which the genetic etiology has not been identified. Characteristic features include multiple epiphyseal dysplasia and microcephaly. Here, we describe three patients with Lowry Wood syndrome with biallelic RNU4ATAC pathogenic variants. This report expands the phenotypic spectrum for biallelic RNU4ATAC disorder causing variants and is the first to establish the genetic cause for Lowry Wood syndrome.
      PubDate: 2017-12-19T03:20:44.060865-05:
      DOI: 10.1002/ajmg.a.38581
  • Patient perspectives on the use of categories of conditions for decision
           making about genomic carrier screening results
    • Authors: Stephanie A. Kraft; Carmit K. McMullen, Kathryn M. Porter, Tia L. Kauffman, James V. Davis, Jennifer L. Schneider, Katrina A. B. Goddard, Benjamin S. Wilfond
      Abstract: As expanded genome‐scale carrier screening becomes increasingly prevalent, patients will face decisions about whether to receive results about a vast number of genetic conditions. Understanding patient preferences is important to meaningfully demonstrate the ethical goal of respect and support patient autonomy. We explore one possible way to elicit preferences by sorting conditions into categories, which may support patient decision making, but the extent to which categories are helpful is unknown. In the context of a randomized trial of genome sequencing for preconception carrier screening compared to usual care (single disease carrier testing), we interviewed 41 participants who had genome sequencing about their experience using a taxonomy of conditions to select categories of results to receive. We then conducted interviews with an additional 10 participants who were not randomized to genome sequencing, asking them about the taxonomy, their reasons for selecting categories, and alternative ways of presenting information about potential results to receive. Participants in both groups found the categories helpful and valued having a meaningful opportunity to choose which results to receive, regardless of whether they opted to receive all or only certain categories of results. Additionally, participants who received usual care highlighted preparedness as a primary motivation for receiving results, and they indicated that being presented with possible reasons for receiving or declining results for each category could be helpful. Our findings can be used to develop approaches, including the use of categories, to support patient choices in expanded carrier screening. Further research should evaluate and optimize these approaches.
      PubDate: 2017-12-18T04:28:04.927675-05:
      DOI: 10.1002/ajmg.a.38583
  • VACTERL phenotype with mosaic trisomy 5 and uniparental disomy 5
    • Authors: Samuel Hwang; Mary Katharine Rudd, Lisa Finch, Suzanne E. Peterson, Raj P. Kapur
      PubDate: 2017-12-18T04:24:04.223315-05:
      DOI: 10.1002/ajmg.a.38579
  • Allometric considerations when assessing aortic aneurysms in Turner
           syndrome: Implications for activity recommendations and medical
    • Authors: Holly Corbitt; Cheryl Maslen, Siddharth Prakash, Shaine A. Morris, Michael Silberbach
      Abstract: In Turner syndrome, the potential to form thoracic aortic aneurysms requires routine patient monitoring. However, the short stature that typically occurs complicates the assessment of severity and risk because the relationship of body size to aortic dimensions is different in Turner syndrome compared to the general population. Three allometric formula have been proposed to adjust aortic dimensions, all employing body surface area: aortic size index, Turner syndrome‐specific Z‐scores, and Z‐scores based on a general pediatric and young adult population. In order to understand the differences between these formula we evaluated the relationship between age and aortic size index and compared Turner syndrome‐specific Z‐scores and pediatric/young adult based Z‐scores in a group of girls and women with Turner syndrome. Our results suggest that the aortic size index is highly age‐dependent for those under 15 years; and that Turner‐specific Z‐scores are significantly lower than Z‐scores referenced to the general population. Higher Z‐scores derived from the general reference population could result in stigmatization, inappropriate restriction from sports, and increasing the risk of unneeded medical or operative treatments. We propose that when estimating aortic dissection risk clinicians use Turner syndrome‐specific Z‐score for those under fifteen years of age.
      PubDate: 2017-12-15T08:20:42.013275-05:
      DOI: 10.1002/ajmg.a.38584
  • Cover Image, Volume 176A, Number 1, January 2018
    • Authors: Satoru Ikenoue; Kei Miyakoshi, Tomohiro Ishii, Yu Sato, Toshimitsu Otani, Yohei Akiba, Yoshifumi Kasuga, Daigo Ochiai, Tadashi Matsumoto, Yosuke Ichihashi, Yohei Matsuzaki, Kanako Tachikawa, Toshimi Michigami, Gen Nishimura, Kazushige Ikeda, Tomonobu Hasegawa, Mamoru Tanaka
      Abstract: The cover image, by Satoru Ikenoue et al., is based on the Clinical Report Discordant fetal phenotype of hypophosphatasia in two siblings,
      DOI : 10.1002/ajmg.a.38531.
      PubDate: 2017-12-12T10:01:56.77579-05:0
  • Associations between laterality of orofacial clefts and medical and
           academic outcomes
    • Authors: Emily R. Gallagher; Babette Siebold, Brent R. Collett, Timothy C. Cox, Verena Aziz, Michael L. Cunningham
      Abstract: Patients with oral clefts have an increased risk of other malformations, syndromes, and lower academic performance in school. Few studies have investigated if laterality of clefts is associated with medical and academic outcomes. Oral clefts have nonrandom laterality, with left‐sided clefts occurring approximately twice as often as right‐sided clefts. Using a retrospective study design, we examined potential associations of cleft attributes and outcomes in patients with cleft lip with or without cleft palate (CL/P) born in 2003–2010 who were treated at the Seattle Children's Craniofacial Center. The following variables were extracted from medical records: cleft type, medical history, maternal hyperglycemia, other malformations, and the need for academic support at school. We used logistic regression to examine risk of associations with outcomes of interest. Relative to patients with left‐sided clefts, patients with bilateral CL/P were more likely to have a syndrome. Patients with nonsyndromic right‐sided CL/P had a higher risk (OR and 95%CI: 3.5, 1.3–9.5, and 5.5, 1.9–16.0, respectively) of having other malformations and requiring academic support at school, when compared to patients with left‐sided CL/P. Understanding the etiology of oral clefts is complicated, in part because both genetic and environmental factors contribute to the risk of developing a cleft. However, the different outcomes associated with cleft laterality suggest that right‐sided clefts may have a distinct etiology. Using laterality to study cleft subgroups may advance our understanding of the etiology of this common birth defect.
      PubDate: 2017-12-12T09:57:08.205359-05:
      DOI: 10.1002/ajmg.a.38567
  • A child with Myhre syndrome presenting with corectopia and tetralogy of
    • Authors: Marianna Alagia; Gerarda Cappuccio, Michele Pinelli, Annalaura Torella, Raffaella Brunetti-Pierri, Francesca Simonelli, Giuseppe Limongelli, Guido Oppido, Vincenzo Nigro, Nicola Brunetti-Pierri,
      Abstract: Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2‐year‐old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.
      PubDate: 2017-12-12T03:07:34.544702-05:
      DOI: 10.1002/ajmg.a.38560
  • Autopsy findings in EPG5‐related Vici syndrome with antenatal onset:
           Additional report of Focal cortical microdysgenesis in a second trimester
    • Authors: Shagun Aggarwal; Ashwani Tandon, Aneek Das Bhowmik, Ashwin Dalal
      PubDate: 2017-12-11T08:00:49.304201-05:
      DOI: 10.1002/ajmg.a.38575
  • “Lowe syndrome: A particularly severe phenotype without clinical
           kidney involvement”
    • Authors: Etesam Abdalla; Ahmed El-Beheiry, Klaus Dieterich, Julien Thevenon, Julien Fauré, John Rendu
      Abstract: Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23‐year‐old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.
      PubDate: 2017-12-11T00:38:01.622729-05:
      DOI: 10.1002/ajmg.a.38572
  • Small supernumerary marker chromosome 15 and a ring chromosome 15
           associated with a 15q26.3 deletion excluding the IGF1R gene
    • Authors: András Szabó; Márta Czakó, Kinga Hadzsiev, Balázs Duga, Zsolt Bánfai, Katalin Komlósi, Béla Melegh
      Abstract: Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.
      PubDate: 2017-12-11T00:37:39.088596-05:
      DOI: 10.1002/ajmg.a.38566
  • A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V:
           Possible phenotypic expansion
    • Authors: Idan Cohen; Orna Staretz-Chacham, Ohad Wormser, Yonatan Perez, Ann Saada, Rotem Kadir, Ohad S. Birk
      Abstract: SLC25A1 mutations are associated with combined D,L‐2‐hydroxyglutaric aciduria (DL‐ 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal‐onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2‐OH‐glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V‐associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.
      PubDate: 2017-12-11T00:36:58.643931-05:
      DOI: 10.1002/ajmg.a.38574
  • Mixoploidy combined with aneuploidy in a 13 year‐old patient with severe
           multiple congenital abnormalities and intellectual disability
    • Authors: Laura J. C. M. van Zutven; Grazia M. S. Mancini, Karen G. C. B. Bindels −de Heus, Erica L. T. van den Akker, Lorette O. M. Hulsman, Marjan Smit, H. Berna Beverloo
      PubDate: 2017-12-11T00:36:54.528155-05:
      DOI: 10.1002/ajmg.a.38553
  • A novel truncating variant within exon 7 of KAT6B associated with features
           of both Say–Barber–Bieseker–Young–Simpson syndrome and
           genitopatellar syndrome: Further evidence of a continuum in the clinical
           spectrum of KAT6B‐related disorders
    • Authors: Giuseppe Marangi; Marilena C. Di Giacomo, Serena Lattante, Daniela Orteschi, Sara Patrizi, Paolo N. Doronzio, Francesco N. Riviello, Alessandro Vaisfeld, Silvia Frangella, Marcella Zollino
      Abstract: KAT6B sequence variants have been identified in both patients with the Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16–18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant‐negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B‐related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8‐year‐old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear‐cut genotype‐phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B‐associated disorders.
      PubDate: 2017-12-11T00:36:29.670213-05:
      DOI: 10.1002/ajmg.a.38571
  • Novel compound heterozygous mutations in GPT2 linked to microcephaly, and
           intellectual developmental disability with or without spastic paraplegia
    • Authors: Hande Kaymakcalan; Yanki Yarman, Nukte Goc, Fatih Toy, Cihan Meral, A. Gulhan Ercan-Sencicek, Murat Gunel
      Abstract: We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic‐pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate‐dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease‐causing by meta‐SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole‐exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.
      PubDate: 2017-12-11T00:35:50.599137-05:
      DOI: 10.1002/ajmg.a.38558
  • Spontaneous intramural duodenal hematoma as the manifestation of Noonan
    • Authors: Kazuki Yamazawa; Yohei Yamada, Tatsuo Kuroda, Hideki Mutai, Tatsuo Matsunaga, Osamu Komiyama, Takao Takahashi
      PubDate: 2017-12-11T00:35:28.791186-05:
      DOI: 10.1002/ajmg.a.38556
  • Spontaneously regressing brain lesions in Smith–Lemli–Opitz
    • Authors: An N. Dang Do; Eva H. Baker, Katherine E. Warren, Simona E. Bianconi, Forbes D. Porter
      Abstract: Smith–Lemli–Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals’ clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.
      PubDate: 2017-12-11T00:35:25.964824-05:
      DOI: 10.1002/ajmg.a.38563
  • Therapy development in Huntington disease: From current strategies to
           emerging opportunities
    • Authors: Audrey S. Dickey; Albert R. La Spada
      Abstract: Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has highlighted a role for bioenergetics abnormalities stemming from mitochondrial dysfunction, and for synaptic defects, including impaired neurotransmission and excitotoxicity. Interference with transcription regulation may underlie the mitochondrial dysfunction. Current therapies for HD are directed at treating symptoms, as there are no disease‐modifying therapies. Commonly prescribed drugs for involuntary movement control include tetrabenazine, a potent and selective inhibitor of vesicular monoamine transporter 2 that depletes synaptic monoamines, and olanzapine, an atypical neuroleptic that blocks the dopamine D2 receptor. Various drugs are used to treat non‐motor features. The HD therapeutic pipeline is robust, as numerous efforts are underway to identify disease‐modifying treatments, with some small compounds and biological agents moving into clinical trials. Especially encouraging are dosage reduction strategies, including antisense oligonucleotides, and molecules directed at transcription dysregulation. Given the depth and breadth of current HD drug development efforts, there is reason to believe that disease‐modifying therapies for HD will emerge, and this achievement will have profound implications for the entire neurotherapeutics field.
      PubDate: 2017-12-08T00:56:36.061418-05:
      DOI: 10.1002/ajmg.a.38494
  • Intrafamilial variability in the clinical manifestations of
           mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS)
    • Authors: Can Ficicioglu; Roberto Giugliani, Paul Harmatz, Nancy J. Mendelsohn, Virginie Jego, Rossella Parini
      Abstract: Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ≥5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members.
      PubDate: 2017-12-06T06:36:46.449479-05:
      DOI: 10.1002/ajmg.a.38551
  • Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with
           neurologic symptoms
    • Authors: Rika Kosaki; Reiko Horikawa, Eriko Fujii, Kenjiro Kosaki
      Abstract: Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we report female siblings with biallelic mutations in LARS2, p.Glu294Lys, and p.Thr519Met, who were classified as type 2. The proposita developed progressive sensorineural hearing loss at 18 months and pervasive developmental disorder at 8 years, with repetitive behavior, insistence on sameness, attention deficit, tic, irritability, and an ataxic gait. At age 15 years, she was diagnosed as having primary amenorrhea with elevated FSH and LH and a decreased estradiol; ultrasound and magnetic resonance imaging examinations revealed a small uterus and no detectable ovaries. The proposita's younger sister presented with neonatal sensorineural hearing loss and a mild delay in motor and speech development. She was diagnosed as having primary amenorrhea with endocrinologic and radiographic findings that were comparable to those of her sister. She had difficulty with reading comprehension, and had trouble with open-ended test questions at 12 years of age. We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise.
      PubDate: 2017-12-03T10:45:26.509059-05:
      DOI: 10.1002/ajmg.a.38552
  • Incomplete penetrance, variable expressivity, or dosage insensitivity in
           four families with directly transmitted unbalanced chromosome
    • Authors: Mark S. Bateman; Morag N. Collinson, David J. Bunyan, Amanda L. Collins, Philippa Duncan, Rachel Firth, Victoria Harrison, Tessa Homfray, Shuwen Huang, Beth Kirk, Katherine L. Lachlan, Viv K. Maloney, John C. K. Barber
      Abstract: The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.
      PubDate: 2017-12-01T07:10:37.65582-05:0
      DOI: 10.1002/ajmg.a.38564
  • Riboflavin transporter deficiency mimicking mitochondrial myopathy caused
           by complex II deficiency
    • Authors: Graeme A. M. Nimmo; Resham Ejaz, Dawn Cordeiro, Peter Kannu, Saadet Mercimek-Andrews
      Abstract: Biallelic likely pathogenic variants in SLC52A2 and SLC52A3 cause riboflavin transporter deficiency. It is characterized by muscle weakness, ataxia, progressive ponto-bulbar palsy, amyotrophy, and sensorineural hearing loss. Oral riboflavin halts disease progression and may reverse symptoms. We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8-year-old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss. His muscle biopsy showed complex II deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing revealed a homozygous likely pathogenic variant in SLC52A2 (c.917G>A; p.Gly306Glu). Patient 2 is a 14-month-old boy with global developmental delay, respiratory insufficiency requiring ventilator support within the first year of life. His muscle biopsy revealed combined complex II + III deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing identified a homozygous likely pathogenic variant in SCL52A3 (c.1223G>A; p.Gly408Asp). We report two new patients with riboflavin transporter deficiency, caused by mutations in two different riboflavin transporter genes. Both patients presented with complex II deficiency. This treatable neurometabolic disorder can mimic mitochondrial myopathy. In patients with complex II deficiency, riboflavin transporter deficiency should be included in the differential diagnosis to allow early treatment and improve neurodevelopmental outcome.
      PubDate: 2017-11-30T01:10:44.967197-05:
      DOI: 10.1002/ajmg.a.38530
  • Clinical and molecular characterization of an emerging chromosome 22q13.31
           microdeletion syndrome
    • Authors: Pietro Palumbo; Maria Accadia, Maria P. Leone, Teresa Palladino, Raffaella Stallone, Massimo Carella, Orazio Palumbo
      Abstract: Microdeletion of chromosome 22q13.31 is a very rare condition. Fourteen patients have been annotated in public databases but, to date, a clinical comparison has not been done and, consequently, a specific phenotype has not been delineated yet. We describe a patient showing neurodevelopmental disorders, dysmorphic features, and multiple congenital anomalies in which SNP array analysis revealed an interstitial 3.15 Mb de novo microdeletion in the 22q13.31 region encompassing 21 RefSeq genes and seven non-coding microRNAs. To perform an accurate phenotype characterization, clinical features observed in previously reported cases of 22q13.31 microdeletions were reviewed and compared to those observed in our patient. To the best of our knowledge, this is the first time that a comparison between patients carrying overlapping 22q13.31 deletions has been done. This comparison allowed us to identify a distinct spectrum of clinical manifestations suggesting that patients with a de novo interstitial microdeletion involving 22q13.31 have an emerging syndrome characterized by developmental delay/intellectual disability, speech delay/language disorders, behavioral problems, hypotonia, urogenital, and hands/feet anomalies. The microdeletion identified in our patient is the smallest reported so far and, for this reason, useful to perform a detailed genotype-phenotype correlation. In particular, we propose the CELSR1, ATXN10, FBLN1, and UPK3A as candidate genes in the onset of the main clinical features of this contiguous gene syndrome. Thus, the patient reported here broadens our knowledge of the phenotypic consequences of 22q13.31 microdeletions facilitating genotype-phenotype correlations. Additional cases are needed to corroborate our hypothesis and confirm genotype–phenotype correlations of this emerging syndrome.
      PubDate: 2017-11-28T10:48:15.414785-05:
      DOI: 10.1002/ajmg.a.38559
  • Clinical and genetic characterization of AP4B1-associated SPG47
    • Authors: Darius Ebrahimi-Fakhari; Chi Cheng, Kira Dies, Amelia Diplock, Danielle B. Pier, Conor S. Ryan, Brendan C. Lanpher, Jennifer Hirst, Wendy K. Chung, Mustafa Sahin, Elisabeth Rosser, Basil Darras, James T. Bennett,
      Abstract: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.
      PubDate: 2017-11-28T10:48:08.060778-05:
      DOI: 10.1002/ajmg.a.38561
  • Oligonephronia and Wolf-Hirschhorn syndrome: A further observation
    • Authors: Antonio Gatto; Pietro Ferrara, Chiara Leoni, Roberta Onesimo, Marcella Zollino, Francesco Emma, Giuseppe Zampino
      Abstract: Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by a partial deletion of chromosome 4 (4p16.3p16.2). We describe a case of a male 9 years old children with WHS proteinuria and hypertension. Laboratory data showed creatinine 1.05 mg/dl, GFR 65.9 ml/min/1.73 m2, cholesterol 280 mg/dl, triglyceride 125 mg/dl with electrolytes in the normal range. Urine collection showed protein 2.72 g/L with a urine protein/creatinine ratio (UP/UCr ratio) of 4.2 and diuresis of 1,100 ml. Renal ultrasound showed reduced kidney dimensions with diffusely hyperechogenic cortex and poorly visualized pyramids. Renal biopsy showed oligonephronia with focal segmental glomerulosclerosis associated with initial tubulointerstitial sclerotic atrophy. The child began therapy with Angiotensin-converting enzyme inhibitors (ACE-inhibitors) to reduce proteinuria and progression of chronic kidney disease. In the literature the anomalies of number of glomeruli oligonephronia and oligomeganephronia (OMN) are described in two forms, one without any associated anomalies, sporadic, and solitary and the other with one or more anomalies. Our review of the literature shows that the pathogenesis of this anomaly is unknown but the role of chromosome 4 is very relevant. Many cases of OMN are associated with anomalies on this chromosome, in the literature cases series we observed this association in 14/48 cases (29.2%) and in 7 of these 14 cases with WHS. Our case and the review of literature demonstrate how periodic urinalysis and renal ultrasound monitoring is recommended in patients affected by WHS and the renal biopsy must be performed when there is the onset of proteinuria.
      PubDate: 2017-11-28T10:46:05.125472-05:
      DOI: 10.1002/ajmg.a.38554
  • Cognitive and behavioral phenotype of children with
           pseudohypoparathyroidism type 1A
    • Authors: Katia M. Perez; Evon B. Lee, Sachini Kahanda, Jessica Duis, Monica Reyes, Harald Jüppner, Ashley H. Shoemaker
      Abstract: Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and 15 controls. Results are presented as mean (SD). The PHP1A group had a composite IQ of 85.9 (17.2); 25% had a composite IQ 
      PubDate: 2017-11-28T10:46:00.594573-05:
      DOI: 10.1002/ajmg.a.38534
  • Rare FMR1 gene mutations causing fragile X syndrome: A review
    • Authors: Adam F. Sitzmann; Robert T. Hagelstrom, Flora Tassone, Randi J. Hagerman, Merlin G. Butler
      Abstract: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG-repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG-repeat expansion. He had more features of FXS than the previously reported patient with the same mutation. Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual disability. Four of the 20 individuals had a mutation within exon 15, three within exon 5, and two within exon 2. The FMR1 missense mutation (c.413G>A) is the same as in a previously reported male where it was shown that there was preservation of the post-synaptic function of the fragile X mental retardation protein (FMRP), the encoded protein of the FMR1 gene was preserved. Both patients with this missense mutation had physical, cognitive, and behavioral features similarly seen in FXS.
      PubDate: 2017-11-27T04:50:49.720325-05:
      DOI: 10.1002/ajmg.a.38504
  • Higher adaptive functioning and lower rate of psychotic comorbidity in
           married versus unmarried individuals with 22q11.2 deletion syndrome
    • Authors: Mariela Mosheva; Stav Eyal, Omri Weisman, Reut Gilad, Yael Fishman, Ronnie Weinberger, Abraham Weizman, Doron Gothelf
      Abstract: 22q11.2 deletion syndrome (22q11.2DS) is a relatively common genetic disorder. Due to improvement in pediatric care, affected individuals live into adulthood, some of whom marry or have committed relationships, and reproduce. The current study aimed to identify the factors that discriminate between married and unmarried adults with 22q11.2DS. In the presents study, 90 adults with 22q11.2DS (48 men/42 women), aged 29.8 ± 10.3 years, were included in the analysis. Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold‐standard diagnostic tools. Demographic factors, marital status, and reproductive status were evaluated by self‐reports. Of the sample 25 adults (27.7%) were married and 14 (56%) of those had children. Married, as compared to unmarried individuals, were older, had less psychotic comorbidities, showed higher adaptive functioning in all domains of the Vineland Adaptive Behavior Scale, and had higher rates of independent living and sustained employment. Unexpectedly, married individuals showed higher rates of mood disorders and full scale IQ scores did not discriminate between the groups. We propose that multiple factors are associated with marital status among individuals with 22q11.2DS. Identification of key personal, functional, and social characteristics of those who married and reproduced may help counseling health professionals and clinicians in advising affected individuals and their families.
      PubDate: 2017-11-24T06:15:30.722798-05:
      DOI: 10.1002/ajmg.a.38555
  • Biallelic mutations in NALCN: Expanding the genotypic and phenotypic
           spectra of IHPRF1
    • Authors: Toshiki Takenouchi; Mie Inaba, Tomoko Uehara, Takao Takahashi, Kenjiro Kosaki, Seiji Mizuno
      Abstract: Loss‐of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi‐allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi‐allelic splice site mutations, that is c.1267‐2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next‐generation sequencing.
      PubDate: 2017-11-23T00:32:23.830889-05:
      DOI: 10.1002/ajmg.a.38543
  • Single suture craniosynostosis: Identification of rare variants in genes
           associated with syndromic forms
    • Authors: Christine M. Clarke; Vincent T. Fok, Jennifer A. Gustafson, Matthew D. Smyth, Andrew E. Timms, Chris D. Frazar, Joshua D. Smith, Craig B. Birgfeld, Amy Lee, Richard G. Ellenbogen, Joseph S. Gruss, Richard A. Hopper, Michael L. Cunningham
      Abstract: We report RNA‐Sequencing results on a cohort of patients with single suture craniosynostosis and demonstrate significant enrichment of heterozygous, rare, and damaging variants among key craniosynostosis‐related genes. Genetic burden analysis identified a significant increase in damaging variants in ATR, EFNA4, ERF, MEGF8, SCARF2, and TGFBR2. Of 391 participants, 15% were found to have damaging and potentially causal variants in 29 genes. We observed transmission in 96% of the affected individuals, and thus penetrance, epigenetics, and oligogenic factors need to be considered when recommending genetic testing in patients with nonsyndromic craniosynostosis.
      PubDate: 2017-11-23T00:32:10.356217-05:
      DOI: 10.1002/ajmg.a.38540
  • Less common underlying genetic diagnoses found in a cohort of 139
           individuals surgically corrected for craniosynostosis
    • Authors: Benjamin R. Ittleman; Jasmine Mckissick, Katherine A. Bosanko, Eylem Ocal, Michael Golinko, Yuri A. Zarate
      PubDate: 2017-11-21T00:35:57.112271-05:
      DOI: 10.1002/ajmg.a.38532
  • Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A
           systematic review
    • Authors: Jelle F. Homans; Isabel N. Tromp, Dino Colo, Tom P. C. Schlösser, Moyo C. Kruyt, Vincent F. X. Deeney, Terrence B. Crowley, Donna M. McDonald-McGinn, René M. Castelein
      Abstract: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk‐of‐bias tool, a best‐evidence synthesis was performed and the prevalence data was extracted. Sixty‐nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5–100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6–60%. Two studies demonstrated that 5–6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1–13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10–20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0–3.7%), syndactyly (11–11.8%), butterfly vertebrae (11.1%) and 13 ribs (2–19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients.
      PubDate: 2017-11-21T00:35:49.262993-05:
      DOI: 10.1002/ajmg.a.38545
  • Longitudinal perspectives on the psychosis spectrum in 22q11.2 deletion
    • Authors: Sunny X. Tang; Raquel E. Gur
      Abstract: The prevalence of psychotic disorders in individuals with 22q11.2 Deletion Syndrome (22q11DS) reaches 25–35% in young adulthood and may provide a neurogenetic model for clinical risk of psychotic disorders in the general population. This review focuses on prospective longitudinal studies in 22q11DS, which capture fluctuations in psychosis symptoms over time and may provide insights into potential demographic, clinical, cognitive, and neuroimaging predictors of psychosis‐spectrum outcomes in the general population. Findings are compared and contrasted with those from idiopathic psychosis‐spectrum populations. Onset of psychotic disorders in 22q11DS can occur over a wide range of ages, peaking in late adolescence. Symptoms may be gradually progressive or episodic in nature, highlighting the importance and challenge of risk and resilience prediction models. Converging results suggest that psychosis‐spectrum outcomes in 22q11DS are predicted by lower baseline functioning, higher baseline psychosis‐spectrum symptoms, presence of mood disturbance or anxiety, and lower baseline and subsequent decline in global measures of cognition. Predictors of transition to threshold psychotic disorders and ages of onset are similar in idiopathic clinical risk. They also share similarly global cognitive deficits, but not to the same extent as in 22q11DS. While neuroimaging studies in idiopathic clinical risk suggest loss of prefrontal gray matter, there is no consistent evidence yet emerging in the limited literature in 22q11DS. Interventional efforts in 22q11DS aimed at halting progression to psychosis or mitigating outcomes in early psychosis may be best implemented during the adolescent age range. Collaborative longitudinal efforts may help to address existing gaps in our understanding.
      PubDate: 2017-10-19T07:15:53.318484-05:
      DOI: 10.1002/ajmg.a.38500
  • A randomized controlled trial of levodopa in patients with Angelman
    • Authors: Wen-Hann Tan; Lynne M. Bird, Anjali Sadhwani, Rene L. Barbieri-Welge, Steven A. Skinner, Lucia T. Horowitz, Carlos A. Bacino, Lisa M. Noll, Cary Fu, Rachel J. Hundley, Logan K. Wink, Craig A. Erickson, Gregory N. Barnes, Anne Slavotinek, Rita Jeremy, Alexander Rotenberg, Sanjeev V. Kothare, Heather E. Olson, Annapurna Poduri, Mark P. Nespeca, Hillary C. Chu, Jennifer M. Willen, Kevin F. Haas, Edwin J. Weeber, Paul A. Rufo
      Abstract: Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin‐dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long‐term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin‐dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi‐center double‐blind randomized placebo‐controlled 1‐year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1‐year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1‐year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well‐tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.
      PubDate: 2017-09-25T01:10:20.269998-05:
      DOI: 10.1002/ajmg.a.38457
  • The 22q11.2 deletion syndrome: Cancer predisposition, platelet
           abnormalities and cytopenias
    • Authors: Michele P. Lambert; Abinaya Arulselvan, Amanda Schott, Stephen J. Markham, Terrance B. Crowley, Elaine H. Zackai, Donna M. McDonald-McGinn
      Abstract: The 22q11.2 deletion syndrome (DS) is associated with variable phenotypic expression as findings range from severely affected individuals with the classical triad of DiGeorge and velocardiofacial syndromes, including congenital heart disease, immunodeficiency, hypocalcemia, and palatal abnormalities, to subtly affected adults who only come to attention following the diagnosis of a more severely affected child. The multiple manifestations can affect all organ systems, including the hematologic system resulting in baseline lower platelet counts for individuals with 22q11.2DS and increased platelet size. In addition, there may be an associated increased risk of bleeding. Individuals with 22q11.2DS are also at increased risk of autoimmune cytopenias that can complicate the evaluation or management of other manifestations. Finally, there may be an increased risk of malignancy, although the mechanism for this risk is not fully understood. This review summarizes the currently available data on hematologic/oncologic manifestations of 22q11.2DS and reports on our findings within a large cohort of individuals with the deletion.
      PubDate: 2017-09-22T07:47:49.102713-05:
      DOI: 10.1002/ajmg.a.38474
  • From clinical observations and molecular dissection to novel therapeutic
           strategies for primary immunodeficiency disorders
    • Authors: Hans D. Ochs; Daniel Petroni
      Abstract: The field of primary immunodeficiency diseases (PID) is rapidly expanding with more than 300 genetically defined disorders that have been clinically described and molecularly analyzed. The molecular dissection of these entities has led to the discovery of new immunologic pathways and to novel and effective disease‐specific therapies. This review provides a summary of these primary immune defects categorized by clinical phenotype and molecular similarity as defined by the International Union of Immunologic Societies (IUIS) Expert Committee for PID. In this synopsis, we discuss the molecular basis of various categories of PIDs including, but not limited to, severe combined immunodeficiencies, primary antibody deficiencies, immune dysregulation syndromes, as well as defects of the innate immune system such as phagocytic abnormalities, autoinflammatory fever syndromes, and complement deficiencies. We have attempted to focus on current strategies to prevent complications, ameliorate symptoms, or cure these disorders by promptly using antimicrobial therapies, immunoglobulin replacement, and hematopoietic stem cell transplantation. In addition, we will explore novel therapies such as molecularly targeted immunosuppression with monoclonal antibodies and specific immunomodulatory agents. Finally, we address experimental therapies targeting specific molecular defects, including gene therapy and gene editing.
      PubDate: 2017-09-21T07:16:06.990704-05:
      DOI: 10.1002/ajmg.a.38480
  • Treating pediatric neuromuscular disorders: The future is now
    • Authors: James J. Dowling; Hernan D. Gonorazky, Ronald D. Cohn, Craig Campbell
      Abstract: Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot–Marie–Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been considered to be without treatment possibilities and to have dire prognoses. This perception has gradually changed, starting in part with the discovery and widespread application of corticosteroids for Duchenne muscular dystrophy. At present, several exciting therapeutic avenues are under investigation for a range of conditions, offering the potential for significant improvements in patient morbidities and mortality and, in some cases, curative intervention. In this review, we will present the current state of treatment for the most common pediatric neuromuscular conditions, and detail the treatment strategies with the greatest potential for helping with these devastating diseases.
      PubDate: 2017-09-10T04:45:45.586824-05:
      DOI: 10.1002/ajmg.a.38418
  • Challenges of developing and conducting clinical trials in rare disorders
    • Authors: Lucas Kempf; Jonathan C. Goldsmith, Robert Temple
      Abstract: Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N-of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non-profit patient advocacy groups, drug developers, and regulatory authorities.
      PubDate: 2017-08-16T08:22:05.380491-05:
      DOI: 10.1002/ajmg.a.38413
  • Table of Contents, Volume 176A, Number 1, January 2018
    • First page: 1
      PubDate: 2017-12-12T10:02:00.657468-05:
      DOI: 10.1002/ajmg.a.38421
  • Publication schedule for 2017
    • First page: 6
      PubDate: 2017-12-12T10:01:59.772466-05:
      DOI: 10.1002/ajmg.a.38422
  • Testing scenario for intellectual disability, developmental delay, and
           autism challenged
    • First page: 7
      PubDate: 2017-12-12T10:01:55.013014-05:
      DOI: 10.1002/ajmg.a.38587
  • Exome sequencing helps diagnose infants in the ICU
    • First page: 8
      PubDate: 2017-12-12T10:02:06.314917-05:
      DOI: 10.1002/ajmg.a.38586
  • In this issue
    • First page: 9
      PubDate: 2017-12-12T10:02:04.532959-05:
      DOI: 10.1002/ajmg.a.38423
  • Congenital limb deficiencies and major associated anomalies in Alberta for
           the years 1980–2012
    • Authors: Tanya Bedard; R. Brian Lowry, Barbara Sibbald, Susan Crawford, Gerhard N. Kiefer
      First page: 19
      Abstract: There is a wide range of the proportion of congenital anomalies associated with limb deficiencies reported in the literature. This variation is primarily attributed to methodology and classification differences. The distribution of associated anomalies among cases with congenital limb deficiencies in Alberta born between January 1, 1980 and December 31, 2012 is described. Of the 170 cases identified, most were live born (75.3%), male (61.8%), had longitudinal limb deficiencies (78.8%), and had associated anomalies outside the musculoskeletal system (77.6%). Significant associations between the preaxial longitudinal group and the central nervous, gastrointestinal, and cardiovascular systems are reported as well as between the postaxial longitudinal group and congenital hip and foot anomalies. Probable and possible syndrome diagnoses are described for cases with recognized malformation patterns.
      PubDate: 2017-11-23T00:32:07.922522-05:
      DOI: 10.1002/ajmg.a.38513
  • Parental education accounts for variability in the IQs of probands with
           Down syndrome: A longitudinal study
    • Authors: David W. Evans; Mirko Uljarević
      First page: 29
      Abstract: Recent work has demonstrated that variability in probands’ phenotypes, including physical features, cognitive abilities, social functioning, and other developmental domains, is influenced by parental traits. Here we examine the role of parental education as a factor contributing to the variability of intelligence quotient (IQ) of offspring with trisomy 21. Participants were 43 probands with trisomy 21, aged 4–21 years of age, and their parents. Data were collected on parental education, and a bi‐parental mean education score (BMES) was calculated. Probands' cognitive abilities were assessed by the Stanford‐Binet 4th edition at baseline (T1), and again 24 months later (T2). Probands were placed into one of two age groups: 4–12 years and 13–21 years. Results indicated higher parent‐proband correlations in Age Group 2 (mean r = .47) relative to Age Group 1 (mean r = .33) and increasing parent‐proband correlations across time, with mean correlations of Age Group 1, T1: r = .26, T2: 39; Age Group 2 T1: r = .49, T2: r = 46. Despite the expected IQ deficits observed in trisomy 21 probands, parental education may still contribute to the variability of probands' cognitive abilities. These findings are consistent with the literature noting increasing heritability of IQ with development.
      PubDate: 2017-11-21T00:35:53.616593-05:
      DOI: 10.1002/ajmg.a.38519
  • Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental
           retardation, ptosis, and polydactyly
    • Authors: Anjana Kar; Shubha R. Phadke, Aneek Das Bhowmik, Ashwin Dalal
      First page: 34
      Abstract: Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.
      PubDate: 2017-11-21T00:36:45.198397-05:
      DOI: 10.1002/ajmg.a.38537
  • A model to characterize psychopathological features in adults with
           Prader‐Willi syndrome
    • Authors: Denise Thuilleaux; Virginie Laurier, Pierre Copet, Julie Tricot, Geneviève Demeer, Fabien Mourre, Maithé Tauber, Joseba Jauregi
      First page: 41
      Abstract: High prevalence of behavioral and psychiatric disorders in adults with Prader‐Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non‐parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional and behavioural issues. This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and Psychotic. The Basic profile is defined by traits and symptoms that are present in varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to 55% of the patients. The rest show, in addition to these characteristics, salient features of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or psychosis (Psychotic profile, 19%). The analysis of factors associated with different profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70% Basic, 9% Psychotic; Non‐deletion: 23% Basic, 43% Psychotic) and a positive correlation between male sex and impulsivity, unmediated by sex hormone treatment. This is a clinical study, based on observation proposing an original model to understand the psychiatric and behavioural disorders in adults with PWS. Further studies are needed in order to test the validity of this model.
      PubDate: 2017-11-17T21:25:28.22042-05:0
      DOI: 10.1002/ajmg.a.38525
  • Structural malformations of the brain, eye, and pituitary gland in PHACE
    • Authors: Jack E. Steiner; Garrett N. McCoy, Christopher P. Hess, William B. Dobyns, Denise W. Metry, Beth A. Drolet, Mohit Maheshwari, Dawn H. Siegel
      First page: 48
      Abstract: PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41–52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndrome who had MRI scans of satisfactory quality were included. Of 55 patients, 34 (62%) demonstrated ≥1 non‐vascular intracranial anomaly; structural brain malformations were present in 19 (35%). There was no difference in the prevalence of brain anomalies between genders. Brain anomalies were more likely in patients with S1 and/or S2 distribution of facial hemangioma. The most common structural brain defects were cerebellar hypoplasia (25%) and fourth ventricle abnormalities (13%). Dandy–Walker complex and malformations of cortical development were present in 9% and 7%, respectively. Extra‐axial findings such as pituitary anomalies (18%) and intracranial hemangiomas (18%) were also observed. Six patients (11%) had anomalies of the globes or optic nerve/chiasm detectable on MRI. Brain malformations comprise a diverse group of structural developmental anomalies that are common in patients with PHACE syndrome. Along with brain malformations, numerous abnormalities of the pituitary, meninges, and globes were observed, highlighting the need for careful radiologic assessment of these structures in the neuroimaging workup for PHACE syndrome.
      PubDate: 2017-11-24T02:00:46.346468-05:
      DOI: 10.1002/ajmg.a.38523
  • Expanding the neurodevelopmental phenotype of PURA syndrome
    • Authors: Bo Hoon Lee; Margot R. F. Reijnders, Oluwatobi Abubakare, Emily Tuttle, Brynn Lape, Kelly Q. Minks, Christopher Stodgell, Loisa Bennetto, Jennifer Kwon, Chin-To Fong, Karen W. Gripp, Eric D. Marsh, Wendy E. Smith, Ahm M. Huq, Stephanie A. Coury, Wen-Hann Tan, Orestes Solis, Rupal I. Mehta, Richard J. Leventer, Diana Baralle, David Hunt, Alex R. Paciorkowski
      First page: 56
      Abstract: PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox–Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype–phenotype associations.
      PubDate: 2017-11-17T21:26:03.120043-05:
      DOI: 10.1002/ajmg.a.38521
  • Auditory evoked potentials in children and adolescents with Down syndrome
    • Authors: Letícia Gregory; Rafael F. M. Rosa, Paulo R. G. Zen, Pricila Sleifer
      First page: 68
      Abstract: Down syndrome, or trisomy 21, is the most common genetic alteration in humans. The syndrome presents with several features, including hearing loss and changes in the central nervous system, which may affect language development in children and lead to school difficulties. The present study aimed to investigate group differences in the central auditory system by long‐latency auditory evoked potentials and cognitive potential. An assessment of 23 children and adolescents with Down syndrome was performed, and a control group composed of 43 children and adolescents without genetic and/or neurological changes was used for comparison. All children underwent evaluation with pure tone and vocal audiometry, acoustic immitance measures, long‐latency auditory evoked potentials, and cognitive potential. Longer latencies of the waves were found in the Down syndrome group than the control group, without significant differences in amplitude, suggesting that individuals with Down syndrome have difficulty in discrimination and auditory memory. It is, therefore, important to stimulate and monitor these children in order to enable adequate development and improve their life quality. We also emphasize the importance of the application of auditory evoked potentials in clinical practice, in order to contribute to the early diagnosis of hearing alterations and the development of more research in this area.
      PubDate: 2017-12-06T06:36:52.523792-05:
      DOI: 10.1002/ajmg.a.38520
  • Expanding the phenotypic spectrum of TP63‐related disorders including
           the first set of monozygotic twins
    • Authors: Tara Wenger; Dong Li, Margaret H. Harr, Wen-Hann Tan, Renata Pellegrino, Zornitza Stark, Hakon Hakonarson, Elizabeth J. Bhoj
      First page: 75
      Abstract: Individuals with Tumor Protein P63 (TP63)‐related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp‐Hodgkin, Hay–Wells, and limb‐mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T‐cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63‐related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63‐related disorders, as it was reported in one prior individual and two of the individuals in our case series.
      PubDate: 2017-11-12T07:40:51.784973-05:
      DOI: 10.1002/ajmg.a.38516
  • Family management of childhood chronic conditions: Does it make a
           difference if the child has an intellectual disability'
    • Authors: Marcia Van Riper; George J. Knafl, Cecelia Roscigno, Kathleen A. Knafl
      First page: 82
      Abstract: The purpose of this analysis was to assess the applicability of the Family Management Measure (FaMM) to families in which there was a child with an intellectual disability versus a chronic condition. Drawing on data from 571 parents of children with a chronic physical condition and 539 parents of children with Down syndrome, we compared the two groups across the six FaMM scales. After accounting for the covariate effects of race, ethnicity, family income, and child age, we found significant differences in four of the six FaMM scales, with parents of children with Down syndrome reporting a significantly more positive view on the Condition Management Effort and View of Condition Impact scales and a significantly less positive view on the Child's Daily Life and Condition Management Ability scales than parents of children with a chronic physical condition. There were no significant differences between groups on the Family Life Difficulty and the Parental Mutuality scales. The analysis provided evidence of the applicability of the FaMM for studying families in which there is a child with Down syndrome and its utility in identifying the common and unique challenges of family management between the groups.
      PubDate: 2017-11-15T10:03:14.248537-05:
      DOI: 10.1002/ajmg.a.38508
  • A homozygous deleterious CDK10 mutation in a patient with agenesis of
           corpus callosum, retinopathy, and deafness
    • Authors: Vincent J. Guen; Simon Edvardson, Nitay D. Fraenkel, Aviva Fattal-Valevski, Chaim Jalas, Irene Anteby, Avraham Shaag, Talia Dor, David Gillis, Eitan Kerem, Jacqueline A. Lees, Pierre Colas, Orly Elpeleg
      First page: 92
      Abstract: The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non‐motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11‐year‐old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin‐dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non‐sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated‐tubulin, γ‐tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association.
      PubDate: 2017-11-12T07:40:41.564786-05:
      DOI: 10.1002/ajmg.a.38506
  • Novel recessive PDZD7 biallelic mutations in two Chinese families with
           non‐syndromic hearing loss
    • Authors: Jing Guan; Hongyang Wang, Lan Lan, Li Wang, Ju Yang, Linyi Xie, Zifang Yin, Wenping Xiong, Lidong Zhao, Dayong Wang, Qiuju Wang
      First page: 99
      Abstract: Autosomal recessive non‐syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high‐throughput sequencing to analyze the exonic, splice‐site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL‐associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.
      PubDate: 2017-10-19T07:15:49.129109-05:
      DOI: 10.1002/ajmg.a.38477
  • Marked yield of re‐evaluating phenotype and exome/target sequencing data
           in 33 individuals with intellectual disabilities
    • Authors: Bing Xiao; Wenjuan Qiu, Xing Ji, Xiaoqing Liu, Zhuo Huang, Huili Liu, Yanjie Fan, Yan Xu, Yu Liu, Hui Yie, Wei Wei, Hui Yan, Zhuwen Gong, Lixiao Shen, Yu Sun
      First page: 107
      Abstract: The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re‐evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re‐evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re‐evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next‐generation sequencing (NGS), periodical re‐evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re‐contacting patients.
      PubDate: 2017-11-21T00:35:41.237718-05:
      DOI: 10.1002/ajmg.a.38542
  • Co‐occurring medical conditions in adults with Down syndrome: A
           systematic review toward the development of health care guidelines
    • Authors: George T. Capone; Brian Chicoine, Peter Bulova, Mary Stephens, Sarah Hart, Blythe Crissman, Andrea Videlefsky, Katherine Myers, Nancy Roizen, Anna Esbensen, Moya Peterson, Stephanie Santoro, Jason Woodward, Barry Martin, David Smith,
      First page: 116
      Abstract: Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co‐occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight‐obesity, sleep apnea, congenital heart disease, and osteopenia‐osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision‐making and management of these medically complex individuals. The development of evidence‐based clinical guidance will require an expanded clinical knowledge‐base in order to move forward.
      PubDate: 2017-11-12T07:40:44.387413-05:
      DOI: 10.1002/ajmg.a.38512
  • Novel STRA6 null mutations in the original family described with
           Matthew–Wood syndrome
    • Authors: Francesca Pasutto; Frances Flinter, Anita Rauch, André Reis
      First page: 134
      PubDate: 2017-11-23T00:32:18.518676-05:
      DOI: 10.1002/ajmg.a.38529
  • FGFR1 disruption identified by whole genome sequencing in a male with a
           complex chromosomal rearrangement and hypogonadotropic hypogonadism
    • Authors: Kaori Yamoto; Shingo Okamoto, Yasuko Fujisawa, Maki Fukami, Hirotomo Saitsu, Tsutomu Ogata
      First page: 139
      PubDate: 2017-11-21T00:36:30.162577-05:
      DOI: 10.1002/ajmg.a.38535
  • Phelan‐McDermid syndrome and cancer predisposition: The value of a
    • Authors: Kent D. McKelvey; Carol J. Trana, Jill Kelsay, Jeffrey Sawyer, Jeffrey Clothier
      First page: 144
      PubDate: 2017-12-06T06:36:55.638192-05:
      DOI: 10.1002/ajmg.a.38541
  • Familial choreoathetosis due to novel heterozygous mutation in PDE10A
    • Authors: Dhanya L. Narayanan; Dipti Deshpande, Aneek Das Bhowmik, Dandu R. Varma, Ashwin Dalal
      First page: 146
      Abstract: PDE10A encodes a dual cAMP‐cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing.
      PubDate: 2017-11-12T07:41:55.251012-05:
      DOI: 10.1002/ajmg.a.38507
  • How chromosomal deletions can unmask recessive mutations' Deletions in
           10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital
           myasthenic syndrome
    • Authors: Mathias Schwartz; Damien Sternberg, Sandra Whalen, Alexandra Afenjar, Arnaud Isapof, Brigitte Chabrol, Marie-France Portnoï, Solveig Heide, Boris Keren, Sandra Chantot-Bastaraud, Jean-Pierre Siffroi
      First page: 151
      Abstract: A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.
      PubDate: 2017-11-12T07:40:47.872925-05:
      DOI: 10.1002/ajmg.a.38515
  • p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with
           Aicardi–Goutières syndrome
    • Authors: Malavika Hebbar; Anil Kanthi, Aroor Shrikiran, Snehal Patil, Mamta Muranjan, Febi Francis, Vishnu Bhat B, Katta M Girisha, Anju Shukla
      First page: 156
      Abstract: Aicardi–Goutières syndrome is an early‐onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon‐α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified by whole‐exome sequencing and targeted molecular testing of the variant. Review of literature and our data suggest this is likely to be a founder variant in Asians and it would be a good initial variant to screen in patients with Aicardi–Goutières syndrome in Indians.
      PubDate: 2017-11-17T21:25:34.450506-05:
      DOI: 10.1002/ajmg.a.38522
  • Unique association of hypochondroplasia with craniosynostosis and cleft
           palate in a Mexican family
    • Authors: Ariadna González-del Angel; Alan Caro-Contreras, Miguel Angel Alcántara-Ortigoza, Sandra Ramos, Roberto Cruz-Alcívar, Paola Moyers-Pérez
      First page: 161
      Abstract: Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.
      PubDate: 2017-11-17T21:25:49.269496-05:
      DOI: 10.1002/ajmg.a.38526
  • Wieacker–Wolff syndrome with associated cleft palate in a female
    • Authors: Natalie D. Godfrey; Samandar Dowlatshahi, Madelena M. Martin, Douglas M. Rothkopf
      First page: 167
      Abstract: Wieacker–Wolff syndrome is a rare congenital syndrome with few reported cases in the current literature. It is traditionally described in males as an X‐linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations. The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome. Recent reports have demonstrated that females are rarely severely affected and phenotypic expression is difficult to predict [Zanzottera et al. (); American Journal of Medical Genetics Part A 173A: 1358–1363]. This case supports the unpredictability of Wieacker–Wolff syndrome severity and prompts future questions regarding female mutations and phenotypic expression.
      PubDate: 2017-11-17T21:25:53.650826-05:
      DOI: 10.1002/ajmg.a.38527
  • Discordant fetal phenotype of hypophosphatasia in two siblings
    • Authors: Satoru Ikenoue; Kei Miyakoshi, Tomohiro Ishii, Yu Sato, Toshimitsu Otani, Yohei Akiba, Yoshifumi Kasuga, Daigo Ochiai, Tadashi Matsumoto, Yosuke Ichihashi, Yohei Matsuzaki, Kanako Tachikawa, Toshimi Michigami, Gen Nishimura, Kazushige Ikeda, Tomonobu Hasegawa, Mamoru Tanaka
      First page: 171
      Abstract: Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype‐phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31‐year‐old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks’ gestation. Post‐mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks’ gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of
      PubDate: 2017-11-21T00:36:26.327898-05:
      DOI: 10.1002/ajmg.a.38531
  • Temple syndrome as a differential diagnosis to Prader–Willi syndrome:
           Identifying three new patients
    • Authors: Asgeir Lande; Mette Kroken, Kai Rabben, Lars Retterstøl
      First page: 175
      Abstract: The two imprinting syndromes Temple syndrome (TS14) and Prader–Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation‐sensitive MLPA‐kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS.
      PubDate: 2017-11-21T00:40:25.533751-05:
      DOI: 10.1002/ajmg.a.38533
  • MED13L loss‐of‐function variants in two patients with
           syndromic Pierre Robin sequence
    • Authors: Christopher T. Gordon; Maya Chopra, Myriam Oufadem, Olivier Alibeu, Marc Bras, Nathalie Boddaert, Christine Bole-Feysot, Patrick Nitschké, Véronique Abadie, Stanislas Lyonnet, Jeanne Amiel
      First page: 181
      Abstract: We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L–related disorders are a possible differential diagnosis for syndromic PRS.
      PubDate: 2017-11-21T00:36:34.449731-05:
      DOI: 10.1002/ajmg.a.38536
  • Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical
           features in four unrelated patients
    • Authors: Rüstem Yilmaz; Katalin Szakszon, Anna Altmann, Umut Altunoglu, Leyli Senturk, Marianne McGuire, Olga Calabrese, Suneeta Madan-Khetarpal, Lina Basel-Vanagaite, Guntram Borck
      First page: 187
      Abstract: The “blepharophimosis‐mental retardation” syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.
      PubDate: 2017-11-21T00:36:39.081932-05:
      DOI: 10.1002/ajmg.a.38538
  • Maternal inheritance of BDNF deletion, with phenotype of obesity and
           developmental delay in mother and child
    • Authors: Brooke E. Harcourt; Denise V. R. Bullen, Kung-Ting Kao, Daniella Tassoni, Erin J. Alexander, Trent Burgess, Susan M. White, Matthew A. Sabin
      First page: 194
      Abstract: Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain‐derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro‐deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity.
      PubDate: 2017-11-21T00:35:32.994594-05:
      DOI: 10.1002/ajmg.a.38539
  • BCL11A frameshift mutation associated with dyspraxia and hypotonia
           affecting the fine, gross, oral, and speech motor systems
    • Authors: Julie Soblet; Ivan Dimov, Clemens Graf von Kalckreuth, Julie Cano-Chervel, Simon Baijot, Karin Pelc, Martine Sottiaux, Catheline Vilain, Guillaume Smits, Nicolas Deconinck
      First page: 201
      Abstract: We report the case of a 7‐year‐old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.
      PubDate: 2017-09-27T06:20:35.15876-05:0
      DOI: 10.1002/ajmg.a.38479
  • Interstitial microdeletion of 17q11.2 is associated with hypotonia,
           fatigue, intellectual disability, and a subtle facial phenotype in three
           unrelated patients
    • Authors: Deborah Osio; Julia Rankin, Hannele Koillinen, Adele Reynolds, Hilde Van Esch
      First page: 209
      Abstract: Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease‐causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips. Intellectual disabilities range from mild to severe. One female patient and the male patient were investigated in childhood for significant hypotonia thought to be suggestive of a neuromuscular disorder. The two female patients also show excessive fatigue with daytime somnolence. The patients carry overlapping, de novo microdeletions of chromosome 17q11.2, with sizes ranging from 0.97 to 1.18 Mb. The smallest region of overlap (SRO) between the three patients is 863 kb, and contains seven genes, five of which are predicted to exhibit haploinsufficiency (CDK5R1, PSMD11, RHOT1, SUZ12, ZNF207) although none has yet been associated with genetic syndromes. Of these five genes, the brain expressed CDK5R1 gene constitutes a good candidate for the developmental delay, while the RHOT1 gene, involved in mitochondrial trafficking, might underlie the hypotonia and the excessive fatigue.
      PubDate: 2017-11-12T07:40:25.588586-05:
      DOI: 10.1002/ajmg.a.38499
  • A heterozygous mutation in RPGR associated with X‐linked retinitis
           pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX)
    • Authors: Qi Zhou; Fengxia Yao, Feng Wang, Hui Li, Rui Chen, Ruifang Sui
      First page: 214
      Abstract: Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4‐year follow‐up and molecular findings in a 28‐year‐old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X‐linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X‐linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X‐linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR.
      PubDate: 2017-11-14T07:35:31.493523-05:
      DOI: 10.1002/ajmg.a.38501
  • Tarsal‐carpal coalition syndrome: Report of a novel missense mutation in
           NOG gene and phenotypic delineation
    • Authors: Aneek Das Bhowmik; Vijayalakshmi Salem Ramakumaran, Ashwin Dalal
      First page: 219
      Abstract: We report a family of Indian origin presenting with Tarsal‐carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.
      PubDate: 2017-11-21T00:35:52.070468-05:
      DOI: 10.1002/ajmg.a.38544
  • Further delineation of the GDF6 related multiple synostoses syndrome
    • Authors: Paulien A. Terhal; Nienke E. Verbeek, Nine Knoers, Rutger J. A. J. Nievelstein, Ans van den Ouweland, Ralph J. Sakkers, Lucienne Speleman, Gijs van Haaften
      First page: 225
      Abstract: A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6‐related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6‐related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6‐related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP‐inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6‐related multiple synostoses syndrome.
      PubDate: 2017-11-12T07:40:31.368929-05:
      DOI: 10.1002/ajmg.a.38503
  • Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme
    • Authors: Kenneth A. Myers; Mark F. Bennett, Chung W. Chow, Susan M. Carden, Simone A. Mandelstam, Melanie Bahlo, Ingrid E. Scheffer
      First page: 230
      Abstract: Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next‐generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β‐galactosidase deficiency. A 10‐year‐old girl had progressive neurologic deterioration, macular cherry‐red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β‐galactosidase assay was normal. Trio WES identified a paternally‐inherited pathogenic splice‐site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non‐UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.
      PubDate: 2017-11-21T00:40:20.163268-05:
      DOI: 10.1002/ajmg.a.38549
  • Novel pregnancy‐triggered episodes of CAPOS syndrome
    • Authors: Irene J. Chang; Margaret P. Adam, Suman Jayadev, Thomas D. Bird, Niranjana Natarajan, Ian A. Glass
      First page: 235
      Abstract: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever‐induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na+/K+ ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.
      PubDate: 2017-11-01T00:05:26.658824-05:
      DOI: 10.1002/ajmg.a.38502
  • DOCK3‐related neurodevelopmental syndrome: Biallelic intragenic deletion
           of DOCK3 in a boy with developmental delay and hypotonia
    • Authors: Aiko Iwata-Otsubo; Alyssa L. Ritter, Brooke Weckselbatt, Nicole R. Ryan, David Burgess, Laura K. Conlin, Kosuke Izumi
      First page: 241
      Abstract: Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6–12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss‐of‐function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov ();]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.
      PubDate: 2017-11-12T07:40:55.61386-05:0
      DOI: 10.1002/ajmg.a.38517
  • Calvarial mass as a presenting feature of neurofibromatosis type 2 in a
           pediatric patient
    • Authors: Kalindi Y. Narine; Christopher C. Oh, Herbert E. Fuchs, David Van Mater
      First page: 246
      PubDate: 2017-11-12T07:40:34.788321-05:
      DOI: 10.1002/ajmg.a.38505
  • Short rib syndrome Beemer–Langer type, a short history
    • Authors: Frits A. Beemer
      First page: 248
      PubDate: 2017-11-12T07:40:35.814992-05:
      DOI: 10.1002/ajmg.a.38514
  • In reply to “Mast Cell Disorders in Ehlers–Danlos
    • Authors: Jaime Vengoechea
      First page: 250
      PubDate: 2017-11-12T07:40:52.808399-05:
      DOI: 10.1002/ajmg.a.38518
  • Response to: “In reply to: ‘Mast Cell Disorders in Ehlers–Danlos
           Syndrome’ (Jaime Vengoechea, Department of Human Genetics, Emory
    • Authors: Suranjith L. Seneviratne; Anne Maitland, Lawrence B. Afrin
      First page: 251
      PubDate: 2017-11-21T00:35:54.809262-05:
      DOI: 10.1002/ajmg.a.38528
  • Summary of the first inaugural joint meeting of the International
           Consortium for scoliosis genetics and the International Consortium for
           vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas
    • Authors: Philip F. Giampietro; Olivier Pourquie, Cathy Raggio, Shiro Ikegawa, Peter D. Turnpenny, Ryan Gray, Sally L. Dunwoodie, Christina A. Gurnett, Benjamin Alman, Kenneth Cheung, Kenro Kusumi, Nancy Hadley-Miller, Carol A. Wise
      First page: 253
      Abstract: Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). “Congenital” scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2‐day conference entitled “Genomic Approaches to Understanding and Treating Scoliosis” was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.
      PubDate: 2017-11-21T00:35:46.008215-05:
      DOI: 10.1002/ajmg.a.38550
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