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Publisher: John Wiley and Sons   (Total: 1582 journals)

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Showing 1 - 200 of 1583 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 11, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 53, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 43, SJR: 0.547, h-index: 30)
ACEP NOW     Free  
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 50, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 134, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 54, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 7, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 5, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 2)
Addiction     Hybrid Journal   (Followers: 32, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 12, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 24, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 24, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 47, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 247, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 4, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 4)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 14, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 9, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 14, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 44, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 28, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 49, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 130, 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: 89, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 30, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 15, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 3, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 5, SJR: 2.315, h-index: 79)
American J. of Orthopsychiatry     Hybrid Journal   (Followers: 4, SJR: 0.756, h-index: 69)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 35, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 237, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 14, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 15, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 118, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 11, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 15)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 154)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 204, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 34, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 5, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 8, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 42, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 12)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 24, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 16, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 14)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 92, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 45, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 6, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 66, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 130, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 47, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 13, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 34, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 14, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 24, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 205, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 48, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 13)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 318, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 7, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 3, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 3, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 4, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 13, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 12, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 10, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 7, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 42, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 21, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 13, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 16, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 384, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 4, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 64, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 11, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 31, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 9, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 3, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 7, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 21, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 14, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 2, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 44, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 137, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 13, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 17, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 10, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 33, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)

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Journal Cover American Journal of Medical Genetics Part A
  [SJR: 1.115]   [H-I: 61]   [15 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1552-4825 - ISSN (Online) 1552-4833
   Published by John Wiley and Sons Homepage  [1582 journals]
  • Endoplasmic reticulum retention of xylosyltransferase 1 (XYLT1) mutants
           underlying Desbuquois dysplasia type II
    • Authors: Nesreen K. Al-Jezawi; Bassam R. Ali, Lihadh Al-Gazali
      Abstract: Desbuquois syndrome is a heterogeneous rare type of skeletal dysplasia with a prevalence of less than 1 in 1,000,000 individuals. It is characterized by short-limbed dwarfism, dysmorphic facial features, and severe joint laxity. Two types have been recognized depending on the presence of distinctive carpal and phalangeal features. Mutations in the calcium activated nucleotidase 1 (CANT1) have been found to be responsible for type I and lately, for the Kim type of Desbuquois dysplasia. In addition, a number of Desbuquois dysplasia type II patients have been attributed to mutations in xylosyltransferase 1, encoded by the XYLT1 gene, an enzyme that catalyzes the transfer of UDP-xylose (a marker of cartilage destruction) to serine residues of an acceptor protein, essential for the biosynthesis of proteoglycans. We report here a patient with features consistent with Desbuquois dysplasia II including short long bones, flat face, mild monkey wrench appearance of the femoral heads. Whole exome sequencing revealed a novel homozygous duplication of a single nucleotide in XYLT1 gene (c.2169dupA). This variant is predicted to result in a frame-shift and stop codon p.(Val724Serfs*10) within the xylosyltransferase catalytic domain. Immunoflourescence staining of HeLa cells transfected with mutated XYLT1 plasmids constructs of the current as well as the previously reported missense mutations (c.1441C>T, p.(Arg481Trp) and c.1792C>T, p.(Arg598Cys)), revealed aberrant subcellular localization of the enzyme compared to wild-type, suggesting endoplasmic reticulum retention of these mutants as the likely mechanism of disease.
      PubDate: 2017-04-30T02:04:24.327945-05:
      DOI: 10.1002/ajmg.a.38244
  • Alterations in metabolic patterns have a key role in diagnosis and
           progression of primrose syndrome
    • Authors: Alberto Casertano; Paolo Fontana, Raoul C. Hennekam, Marco Tartaglia, Rita Genesio, Tina Barbaro Dieber, Lucia Ortega, Lucio Nitsch, Daniela Melis
      Abstract: Primrose syndrome is characterized by unusual facial features, macrocephaly, intellectual disability, enlarged, and calcified external ears, sparse body hair, and distal muscle wasting. Nine patients have been described in the literature. The disorder is due to missense mutations in ZBTB20. Here we describe one newly diagnosed 18-month-old patient and provide 10 year follow-up of an earlier reported patient, highlighting the progression and complexity of the disorder. Metabolic studies showed reduced glucose tolerance with prevalence of amino acids and fatty acids catabolism, ketogenesis, and gluconeogenesis, resulting in a Krebs cycle reversion.
      PubDate: 2017-04-30T02:04:20.241328-05:
      DOI: 10.1002/ajmg.a.38124
  • Somatic Mosaicism of PCDH19 in a male with early infantile epileptic
           encephalopathy and review of the literature
    • Authors: Dorian Perez; David T. Hsieh, Luis Rohena
      Abstract: Early infantile epileptic encephalopathy-9 (EIEE9) linked to mutations of the PCDH19 gene on the X chromosome was once thought to only affect females. Clinical features of the mutation include early onset of variable types and frequency of recurrent cluster of seizures, mild to profound intellectual disability, autistic traits, psychiatric features, and behavioral disturbances. PCDH19 pathogenic variants usually occur via an unusual X-linked pattern where heterozygous females are affected, but hemizygous males are asymptomatic. Somatic mosaic males for PCDH19 mutations are affected with EIEE9; since this discovery, four somatic mosaic males have been reported. We report the fifth confirmed male with somatic mosaicism of a novel pathogenic variant c.2147+2 T>C located in the splice site of Intron 1 of the PCDH19 gene, which continues to support that cellular interference is responsible for the pathogenic mechanism. The importance of our report is to provide significant knowledge about this rare cause of epilepsy in males, guide subsequent functional studies on males portraying an EIEE9 phenotype that have been potentially misdiagnosed, targeted therapeutic approaches, and further elucidation of this complex and interesting genetic disorder.
      PubDate: 2017-04-30T02:04:15.802478-05:
      DOI: 10.1002/ajmg.a.38233
  • KBG syndrome: An Australian experience
    • Authors: Natalia Murray; Bronwyn Burgess, Robin Hay, Alison Colley, Sulekha Rajagopalan, Julie McGaughran, Chirag Patel, Annabelle Enriquez, Linda Goodwin, Zornitza Stark, Tiong Tan, Meredith Wilson, Tony Roscioli, Mustafa Tekin, Himanshu Goel
      Abstract: In 2011, heterozygous mutations in the ANKRD11 gene were identified in patients with KBG syndrome. Since then, 100 cases have been described with the expansion of the clinical phenotype. Here we present 18 KBG affected individuals from 13 unrelated families, 16 with pathogenic mutations in the ANKRD11 gene. Consistent features included intellectual disability, macrodontia, and the characteristic broad forehead with hypertelorism, and a prominent nasal bridge. Common features included hand anomalies, cryptorchidism, and a large number of palate abnormalities. Distinctive findings in this series included malrotation of the abdominal viscera, bilateral inguinal herniae in two patients, basal ganglia calcification and the finding of osteopenia in three patients. Nine novel heterozygous variants were found and the genotype-phenotype correlation was explored. This report highlights the need for thorough examination and investigation of the dental and skeletal systems. The results confirm the specificity of ANKRD11 mutations in KBG and further evidence for this transcription repressor in neural, cardiac, and skeletal development. The description of further cases of KBG syndrome is needed to further delineate this condition, in particular the specific neurological and behavioral phenotype.
      PubDate: 2017-04-27T13:24:46.307724-05:
      DOI: 10.1002/ajmg.a.38121
  • Trisomy 18 and holoprosencephaly
    • Authors: Rafael F. M. Rosa; Elisa P. E. Correia, Cristina S. Bastos, Gabriela S. da Silva, Jamile D. Correia, Ernani B. da Rosa, Daniélle B. Silveira, Luciano V. Targa, André C. da Cunha, Paulo R. G. Zen
      PubDate: 2017-04-27T13:24:43.957755-05:
      DOI: 10.1002/ajmg.a.38129
  • The impact of a sibling's life-limiting genetic condition on adult
           brothers and sisters
    • Authors: Erica Brown; Jane Coad, Anita Franklin
      Abstract: It is estimated that rare diseases affect the lives of over three million people in the United Kingdom. Of these, a significant proportion are children and young people with genetic life-limiting or life-shortening conditions. This study used a qualitative approach with in-depth semi-structured interviews to explore the experiences of 10 adult siblings of a baby diagnosed with Trisomy 13 (Patau syndrome) or Trisomy 18 (Edward syndrome). Findings illustrate that parental grief from the time of their child's diagnosis onward is also experienced by siblings. Although young adults may have conflicting feelings as a bereaved sibling, there is evidence that the experience impacts on their world views and their attitudes about prospective and expectant parenthood. The study highlights the importance of providing siblings with short-term and long-term support from the time of their brother's or their sister's diagnosis onward and provides new understanding about benefit of professional and peer support in helping young adults develop resilience and coping strategies.
      PubDate: 2017-04-27T13:24:41.537083-05:
      DOI: 10.1002/ajmg.a.38213
  • A case of familial transmission of the newly described DNMT3A-Overgrowth
    • Authors: Gabrielle Lemire; Julie Gauthier, Jean-François Soucy, Marie-Ange Delrue
      Abstract: DNMT3A-Overgrowth Syndrome (also known as Tatton–Brown–Rahman Syndrome) (MIM 615879) has recently been described in 13 individuals with de novo heterozygous mutations in DNMT3A gene. This autosomal dominant condition is characterized by overgrowth, dysmorphic facial features and moderate intellectual disability. Missense and truncating point mutations, a small in-frame deletion, as well as microdeletion 2p23 have been reported. Moreover, DNMT3A is commonly somatically mutated in acute myeloid leukemia. We herein report a family with two siblings and their father affected by the syndrome. The proband is a 12 year-old boy with tall stature, macrocephaly, facial dysmorphism, and intellectual disability. His 10-year-old sister also has learning difficulties, overgrowth and mild facial dysmorphism. Their father is a 49 year-old man with tall stature, macrocephaly, learning difficulties, and minor facial dysmorphism. He had a right occipital osteoma removed at 20 years of age. A heterozygous splice site mutation NM_022552.4 (DNMT3A): c.2323-2A > T was found in the proband by whole exome sequencing analysis and by targeted Sanger Sequencing for the proband's sister and father. This mutation has not been previously reported and is believed to be pathogenic. Indeed, this substitution involves a highly conserved canonical splice site and is predicted to cause exon skipping. This is the first report of a familial transmission of DNMT3A-Overgrowth Syndrome, supporting the autosomal dominant inheritance. The proband's phenotype is more severe than that of his two other affected family members, which illustrates variable expressivity in the syndrome.
      PubDate: 2017-04-27T13:24:39.854399-05:
      DOI: 10.1002/ajmg.a.38119
  • Vascular twin nevi
    • Authors: Senay Agirgol; Hatice Nur Ozturk, Tugba Ozkok Akbulut, Ceyda Gunduzoglu, Leyli Kadriye Koc, Zafer Turkoglu
      Abstract: Vascular twin nevi (VTN) are characterized by the simultaneous dermatological manifestatiton of a telangiectatic naevus close to a nevus anemicus. Nevus anemicus (NA) is a vascular anomaly characterized by localized pale patches with normal melanine and melanocyte level. According to twin spotting phenomenon crossing-over in heterozygous somatic-cells during mitosis results in two different offspring homozygous cells. Consequent to this mechanism, two different vascular anomalies may occur at the same region. We present a patient with VTN and NA combination which we think serves as an example for a rare twin spotting phenomenon in the literature.
      PubDate: 2017-04-27T13:24:38.204727-05:
      DOI: 10.1002/ajmg.a.38117
  • Wiedemann–Rautenstrauch syndrome: A phenotype analysis
    • Authors: Stefano Paolacci; Debora Bertola, José Franco, Shehla Mohammed, Marco Tartaglia, Bernd Wollnik, Raoul C. Hennekam
      Abstract: Wiedemann–Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as “gold standard.” In 15 patients sufficient information and photographic evidence was available to confirm the clinical diagnosis. In 12 patients the diagnosis was suggestive but lack of data prevented a definite diagnosis, and in 24 patients an alternative diagnosis was likely. Core manifestations of the syndrome are marked pre-natal and severe post-natal growth retardation, an unusual face (triangular shape, sparse hair, small mouth, pointed chin), dental anomalies (natal teeth; hypodontia), generalized lipodystrophy with localized fat masses, and—in some cases—progressive ataxia and tremor. It has been suggested that the syndrome might be caused by biallelic variants in POLR3A, identified by exome sequencing in a single patient only. Therefore, we compared the WRS phenotype with characteristics of conditions known to be caused by autosomal recessively inherited POLR3A mutations. There are major differences but there are also similarities in phenotype, which sustain the suggestion that the syndrome can be caused by disturbed POLR3A functioning.
      PubDate: 2017-04-26T23:40:52.806733-05:
      DOI: 10.1002/ajmg.a.38246
  • Response to: Toriello et al., “Update on the Toriello–Carey
           Syndrome.” Further delineation of a young woman with deletion
    • Authors: Alexandra Garza-Flores; Pamela Hawley, Jonathan Picker, Elizabeth Tannebring, Matthew A. Deardorff, Angela E. Lin
      PubDate: 2017-04-26T23:40:35.091187-05:
      DOI: 10.1002/ajmg.a.38203
  • Lissencephaly: Expanded imaging and clinical classification
    • Authors: Nataliya Di Donato; Sara Chiari, Ghayda M. Mirzaa, Kimberly Aldinger, Elena Parrini, Carissa Olds, A. James Barkovich, Renzo Guerrini, William B. Dobyns
      Abstract: Lissencephaly (“smooth brain,” LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS—LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).
      PubDate: 2017-04-25T07:26:26.572057-05:
      DOI: 10.1002/ajmg.a.38245
  • Phosphoglycerate dehydrogenase (PHGDH) deficiency without epilepsy
           mimicking primary microcephaly
    • Authors: Antoine Poli; Yoann Vial, Damien Haye, Sandrine Passemard, Manuel Schiff, Hala Nasser, Catherine Delanoe, Emma Cuadro, Rémi Kom, Narcisse Elanga, Anne Favre, Séverine Drunat, Alain Verloes
      Abstract: Phosphoglycerate dehydrogenase (PHGDH) deficiency (OMIM 256520) is a rare autosomal recessive disorder of serine synthesis, with mostly severe congenital microcephaly, caused by mutations in the PHGDH gene. Fourteen patients reported to date show severe, early onset, drug resistant epilepsy. In a cohort of patients referred for primary microcephaly, compound heterozygosity for two unreported variants in PHGDG was identified by exome sequencing in a pair of sibs who died aged 4.5 months and 4.5 years. They had severe neurological involvement with congenital microcephaly, disorganized EEG, and progressive spasticity, but never had seizures. Exome usage in clinical practice is likely to lead to an expansion of the clinical spectrum of known disorders.
      PubDate: 2017-04-25T07:26:14.541554-05:
      DOI: 10.1002/ajmg.a.38217
  • Variable developmental delays and characteristic facial features—A novel
           7p22.3p22.2 microdeletion syndrome?
    • Authors: Andrea C. Yu; Regina M. Zambrano, Ingrid Cristian, Sue Price, Birgitta Bernhard, Marc Zucker, Sunita Venkateswaran, Jean McGowan-Jordan, Christine M. Armour
      Abstract: Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients’ deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.
      PubDate: 2017-04-25T07:26:07.911552-05:
      DOI: 10.1002/ajmg.a.38241
  • DiGeorge-like syndrome in a child with a 3p12.3 deletion involving MIR4273
           gene born to a mother with gestational diabetes mellitus
    • Authors: Emilia Cirillo; Giuliana Giardino, Vera Gallo, Giovanni Galasso, Roberta Romano, Roberta D'Assante, Giulia Scalia, Luigi Del Vecchio, Lucio Nitsch, Rita Genesio, Claudio Pignata
      Abstract: Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T-box transcriptional regulators during midface development and Bmp-signaling. We report on a 7-year-old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb-interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243, and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA-4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesis including kidney and lung organogenesis and in insulin gene expression. Since, DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors.
      PubDate: 2017-04-24T06:00:49.009019-05:
      DOI: 10.1002/ajmg.a.38242
  • Natural history of aortic root dilation through young adulthood in a
           hypermobile Ehlers–Danlos syndrome cohort
    • Authors: Alyssa Ritter; Carrie Atzinger, Brandon Hays, Jeanne James, Amy Shikany, Derek Neilson, Lisa Martin, Kathryn Nicole Weaver
      Abstract: Hypermobile Ehlers–Danlos syndrome (hEDS) is a common inherited connective tissue disorder characterized by joint hypermobility. The natural history of aortic root dilation (AoD), a potential complication of EDS, has not been well characterized in this population. We describe the natural history of aortic root size in a large cohort of patients with hEDS. A cohort of 325 patients with HEDS was identified at Cincinnati Children's Hospital Medical Center (CCHMC), including 163 patients from a previous study. Medical records were reviewed and each participant's height, weight, and aortic dimensions from up to four echocardiograms were documented. Aortic root z-scores were calculated using two established formulas based on age (Boston or Devereux). Overall prevalence of AoD and prevalence by age were calculated and longitudinal regression was performed. The prevalence of AoD with a z-score ≥ 2.0 was 14.2% (46/325) and with a z-score of ≥3.0 was 5.5% (18/325). No significant increases in z-score were seen over time for patients with multiple echocardiograms. Participants under the age of 15 years had an average decline of 0.1 standard deviations (SDs)/year. No significant change was found after 15 of age. Between the ages of 15 and 21 years, Boston z-scores were 0.96 higher than Devereux z-scores. The nearly 1 z-score unit difference between formulas indicates caution prior to diagnosing AoD in patients with hEDS. In light of the low prevalence and lack of progression of AoD, routine echocardiograms may not be warranted for pediatric patients with hEDS.
      PubDate: 2017-04-24T06:00:41.489649-05:
      DOI: 10.1002/ajmg.a.38243
  • The path forward: 2015 International Children's Tumor Foundation
           conference on neurofibromatosis type 1, type 2, and schwannomatosis
    • Authors: Jaishri O. Blakeley; Annette Bakker, Anne Barker, Wade Clapp, Rosalie Ferner, Michael J. Fisher, Marco Giovannini, David H. Gutmann, Matthias A. Karajannis, Joseph L. Kissil, Eric Legius, Alison C. Lloyd, Roger J. Packer, Vijaya Ramesh, Vincent M. Riccardi, David A. Stevenson, Nicole J. Ullrich, Meena Upadhyaya, Anat Stemmer-Rachamimov
      Abstract: The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses.
      PubDate: 2017-04-24T02:25:39.911699-05:
      DOI: 10.1002/ajmg.a.38239
  • Compound heterozygous mutations in COL1A1 associated with an atypical form
           of type I osteogenesis imperfecta
    • Authors: Amanda M. Ackermann; Michael A. Levine
      Abstract: Heterozygous mutations in the genes encoding the proα1(I) or proα2(I) chains of type I procollagen (COL1A1 and COL1A2, respectively) account for most cases of osteogenesis imperfecta (OI), a disorder characterized by reduced bone strength and increased fracture risk. COL1A1 mutations can also cause rare cases of Ehlers–Danlos syndrome (EDS), a disorder that primarily affects connective tissue and often includes reduced bone mass. Here we present a kindred of three young siblings ages 1–4 years old whose mother has a history of mild type I OI. All three children are compound heterozygotes for COL1A1 mutations, with a novel frameshift mutation (c.2522delC; p.Pro841Leufs*266) from their mother and a known missense mutation (c.3196C>T; p.R1066C) from their clinically unaffected father, which has previously been described as causing a combined type I OI/EDS phenotype. The three children exhibit features of both COL1A1 mutations: early and frequent long bone fractures, joint hyperextensibility, and blue sclerae. We describe three siblings who are the first reported surviving subjects with biallelic pathogenic COL1A1 mutations. They have a more severe form of type I OI with features of EDS that represents their compound heterozygosity for two deleterious COL1A1 mutations. Their long-term outcomes are yet to be determined.
      PubDate: 2017-04-24T02:25:35.863885-05:
      DOI: 10.1002/ajmg.a.38238
  • Novel de novo FOXC1 nonsense mutation in an Axenfeld-Rieger syndrome
    • Authors: Susana Carmona; Maria da Luz Freitas, Hugo Froufe, Maria José Simões, Maria João Sampaio, Eduardo D. Silva, Conceição Egas
      PubDate: 2017-04-21T23:55:39.994436-05:
      DOI: 10.1002/ajmg.a.38234
  • Androgen receptor dysfunction as a prevalent manifestation in young male
           carriers of a FLNA gene mutation
    • Authors: Laura Carrera-García; Maximiliano Francisco Rivas-Crespo, María Soledad Fernández García
      Abstract: Androgenic actions require the proper signal transmission by the androgen receptor (AR), a nuclear transcription factor. This is initially located in the cell cytoplasm and should translocates to the nucleus to interact with DNA. AR functional impairment causes diverse blockage degrees of androgenic steroid action, known as androgen insensitivity syndromes. Filamin A, a protein coded by the FLNA gene, is a co-activator of various cytoplasmic factors, including AR. The mutational inactivation of the FLNA gene induces insufficiency of translocation and activation of AR. Consequently, it causes a developmental disorder of the male gonad and hypogonadism, similar to those observed in partial androgen insensitivity. We report two brothers carrying a loss-of-function mutation of FNLA with gonadal differentiation disorder and hypospadias. Specific staining for AR shows almost an absolute absence of these receptors in the testicular tissue. This association recommends investigating a possible mutational inactivation of the FLNA gene in patients with cryptorchidism and epididymo-testicular dissociation. The study is especially indicated when the family history, more often that of the mother, is suggestive. Likewise, growth and gonadal development of all male patients carrying this genetic trait should be monitored since childhood.
      PubDate: 2017-04-21T23:55:38.909048-05:
      DOI: 10.1002/ajmg.a.38230
  • Novel 3q27.2-qter deletion in a patient with Diamond–Blackfan anemia and
           immunodeficiency: Case report and review of literature
    • Authors: Ebba Alkhunaizi; Brett Schrewe, Reza Alizadehfar, Catherine Vézina, Grant S. Stewart, Nancy Braverman
      Abstract: 3q27.2-qter deletion syndromes feature an overlapping set of terminal and interstitial deletions with variable congenital malformations. Diamond–Blackfan anemia (DBA) is etiologically heterogeneous disorder in which one cause is dominant mutations of the RPL35A gene on 3q29. We report a child with a 3q27.2-qter deletion that contains the RPL35A gene. She had clinical and laboratory features consistent with DBA and as well, an unexplained immunodeficiency disorder. Given these unusual findings, we reviewed other patients in the literature with overlapping genomic deletions. In addition, we evaluated our patient for the immunodeficiency disorder, RIDDLE syndrome, due to recessive mutations in the RNF168 gene on 3q29. A PubMed search for case reports of 3q27.2-qter overlapping deletions was performed. To determine if RPL35A was in the deletion region, the chromosomal regions reported were mapped to genomic regions using the UCSC Genome Browser. We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had DBA. Interestingly, none of the reported cases had immunodeficiency. To evaluate RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties), we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. We show that RPL35A haploinsufficiency is a cause of DBA and we report a novel case with 3q27.2-qter deletion and immunodeficiency. The etiology for the immunodeficiency remains unsolved and could be caused by an unknown gene effect or consequent to the DBA phenotype.
      PubDate: 2017-04-21T23:55:37.436986-05:
      DOI: 10.1002/ajmg.a.38208
  • Expansion of the clinical phenotype of the distal 10q26.3 deletion
           syndrome to include ataxia and hyperemia of the hands and feet
    • Authors: Melanie Lacaria; Myriam Srour, Jacques L. Michaud, Asif Doja, Elka Miller, Jeremy Schwartzentruber, Claire Goldsmith, Jacek Majewski, , Kym M. Boycott
      Abstract: Distal deletion of the long arm of chromosome 10 is associated with a dysmorphic craniofacial appearance, microcephaly, behavioral issues, developmental delay, intellectual disability, and ocular, urogenital, and limb abnormalities. Herein, we present clinical, molecular, and cytogenetic investigations of four patients, including two siblings, with nearly identical terminal deletions of 10q26.3, all of whom have an atypical presentation of this syndrome. Their prominent features include ataxia, mild-to-moderate intellectual disability, and hyperemia of the hands and feet, and they do not display many of the other features commonly associated with deletions of this region. These results point to a novel gene locus associated with ataxia and highlight the variability of the clinical presentation of patients with deletions of this region.
      PubDate: 2017-04-21T23:55:33.748896-05:
      DOI: 10.1002/ajmg.a.38231
  • Aneurysms in neurofibromatosis type 2: Evidence for vasculopathy?
    • Authors: Shazia K. Afridi; Suki Thomson, Steve E. J. Connor, Daniel C. Walsh, Rosalie E. Ferner
      Abstract: There have been anecdotal reports of vasculopathy associated with Neurofibromatosis Type 2 (NF2). Given the increasing use of bevacizumab, a vascular endothelial growth factor inhibitor which results in an increased risk of bleeding, it is important to ascertain if there is a predisposition to vascular abnormalities in NF2. In our unit NF2 patients undergo annual MRI brain and internal auditory meatus imaging. We noted incidental intracranial aneurysms in some patients and sought to determine the prevalence of intracranial aneurysms in our cohort of NF2 patients. We conducted a retrospective audit of the MRI images of 104 NF2 patients from 2014 to 2016. Axial T2 brain MRI images were assessed for vascular abnormalities by two neuroradiologists blinded to patient's clinical details. Intracranial aneurysms were detected in four patients and an aneurysm clip related to previous surgery was noted in one additional patient. Using standard MRI imaging sequences alone we provide evidence of intracranial aneurysms in 4.4% of our cohort. This compares with an estimated overall prevalence of 3% in the general population. We discuss these findings as well as other evidence for a vasculopathy associated with NF2.
      PubDate: 2017-04-21T07:18:03.432115-05:
      DOI: 10.1002/ajmg.a.38221
  • Recurrence of congenital heart defects among siblings—a nationwide
    • Authors: Kristoffer Brodwall; Gottfried Greve, Elisabeth Leirgul, Grethe S. Tell, Stein E. Vollset, Nina Øyen
      Abstract: Congenital heart defects (CHD) constitute the largest group of congenital malformations. In most families, only one person has CHD; however, the risk of CHD increases for children born into families already affected. In this study, all births from 1994 through 2009 were identified in the Medical Birth Registry of Norway, including supplemental information on CHD from clinical and administrative registers, as part of the CVDNOR project. By using the unique personal identification number of each parent we were able to link 16,078 pairs of twins, 445,584 pairs of full siblings, and 106,840 pairs of half-siblings. Sibling recurrence risk ratio (RRR) was calculated using CHD status in the oldest sibling as exposure and CHD status in the younger sibling as outcome, adjusted for year of birth, maternal age, and maternal diabetes. Among full sibling pairs with CHD in the older sibling, the younger sibling had CHD in 4.1% compared to 1.1% of the pairs without CHD in the older sibling (adjusted RRR 3.6; 95% confidence interval (CI) 3.1–4.1). In same-sex twins the RRR was 14.0 (95% CI 10.6–18.6), and in opposite-sex twins the RRR was 11.9 (95% CI 7.1–19.9). For half-siblings the RRR was 1.5 (95% CI 0.8–2.8). When restricting to severe types of CHD, the RRR was 6.9 (95% CI 4.9–9.8) for full siblings. In 50% of the pairs with recurrent CHD, the siblings had similar types of CHD. The high relative risk of recurrence indicates that familial risk factors are important in the etiology of CHD.
      PubDate: 2017-04-19T23:40:46.046023-05:
      DOI: 10.1002/ajmg.a.38237
  • Genotype–phenotype correlations in Cornelia de Lange syndrome:
           Behavioral characteristics and changes with age
    • Authors: Joanna Moss; Jessica Penhallow, Morad Ansari, Stephanie Barton, David Bourn, David R. FitzPatrick, Judith Goodship, Peter Hammond, Catherine Roberts, Alice Welham, Chris Oliver
      Abstract: Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder associated with unusual facial features, limb abnormalities, a wide range of health conditions, and intellectual disability. Mutations in five genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex have been identified in up to 70% of individuals. Genetic cause remains unknown for a proportion of individuals. There is substantial heterogeneity in all aspects of CdLS but very little is known about what predicts phenotypic heterogeneity. In this study, we evaluated genotype–phenotype associations in 34 individuals with CdLS. Participants with NIPBL mutations had significantly lower self help skills and were less likely to have verbal skills relative to those who were negative for the NIPBL mutation. No significant differences were identified between the groups in relation to repetitive behavior, mood, interest and pleasure, challenging behavior, activity, impulsivity, and characteristics of autism spectrum disorder whilst controlling differences in self help skills. Significant correlations indicating lower mood, interest and pleasure, and increased insistence on sameness with older age were identified for those who were NIPBL mutation positive. The findings suggest similarities in the behavioral phenotype between those with and without the NIPBL mutation once differences in self help skills are controlled for. However, there may be subtle differences in the developmental trajectory of these behaviors according to genetic mutation status in CdLS.
      PubDate: 2017-04-19T23:40:41.564296-05:
      DOI: 10.1002/ajmg.a.38228
  • Association studies of low-frequency coding variants in nonsyndromic cleft
           lip with or without cleft palate
    • Authors: Elizabeth J. Leslie; Jenna C. Carlson, John R. Shaffer, Carmen J. Buxó, Eduardo E. Castilla, Kaare Christensen, Frederic W. B. Deleyiannis, Leigh L. Field, Jacqueline T. Hecht, Lina Moreno, Ieda M. Orioli, Carmencita Padilla, Alexandre R. Vieira, George L. Wehby, Eleanor Feingold, Seth M. Weinberg, Jeffrey C. Murray, Mary L. Marazita
      Abstract: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The “missing” heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.
      PubDate: 2017-04-19T23:40:37.141662-05:
      DOI: 10.1002/ajmg.a.38210
  • Three families with mild PMM2-CDG and normal cognitive development
    • Authors: Mari-Anne Vals; Eva Morava, Kai Teeäär, Riina Zordania, Sander Pajusalu, Dirk J. Lefeber, Katrin Õunap
      Abstract: Congenital disorders of glycosylation (CDG) are caused by defective glycosylation of proteins and lipids. PMM2-CDG is the most common subtype among the CDG. The severity of PMM2-CDG is variable. Patients often have a recognizable phenotype with neurological and multisystem symptoms that might cause early death. We report six patients from three families who are diagnosed with a clinically mild PMM2-CDG and have normal cognitive development. All these patients had delayed gross motor skills with mild-to-moderate neurological findings. Cerebellar hypoplasia was detected in all siblings for whom brain MRI was performed. In 5/6 children the Wechsler Intelligence Scale for Children (WISC) showed normal cognitive development with full scale IQ scores ranging from borderline to average. Four patients were diagnosed with PMM2-CDG at the age of 8 years or later as their neurological symptoms were quite mild and they had been able to participate in regular school programs. We report patients with p.Val231Met/p.Arg239Trp and p.Ile120Thr/p.Gly228Cys genotypes which may cause milder variants of PMM2-CDG.
      PubDate: 2017-04-19T23:40:32.650675-05:
      DOI: 10.1002/ajmg.a.38235
  • Cover Image, Volume 173A, Number 5, May 2017
    • Authors: Toshiki Takenouchi; Tomu Kuchikata, Hiroshi Yoshihashi, Mineko Fujiwara, Tomoko Uehara, Sahoko Miyama, Shiro Yamada, Kenjiro Kosaki
      Abstract: The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype,
      DOI : 10.1002/ajmg.a.38167.
      PubDate: 2017-04-19T01:43:29.083237-05:
  • Neonatal characteristics and perinatal complications in neonates with Down
    • Authors: Zivanit Ergaz-Shaltiel; Offra Engel, Ira Erlichman, Yaron Naveh, Michael S. Schimmel, Ariel Tenenbaum
      Abstract: The annual rate of Down syndrome (DS) births in Jerusalem is stable, regardless of prenatal screening, and diagnostic measures. We aimed to evaluate our historical cohort for obstetrical characteristics and the neonatal course and complications. We reviewed computerized medical files of neonates with the diagnosis of DS born in the four main hospitals in Jerusalem between the years 2000 and 2010 and evaluated for maternal history and primary neonatal hospitalization. A total of 403 neonates were diagnosed with DS. The average maternal age was 35.6 years, 73% were born via spontaneous vaginal delivery. In all gestational ages, the mean birth weight and head circumference percentiles were significantly lower than the general population (P 
      PubDate: 2017-04-06T23:50:32.895323-05:
      DOI: 10.1002/ajmg.a.38165
  • Table of Contents, Volume 173A, Number 5, May 2017
    • Pages: 1131 - 1136
      PubDate: 2017-04-19T01:43:30.283303-05:
      DOI: 10.1002/ajmg.a.37905
  • Publication schedule for 2017
    • Pages: 1137 - 1137
      PubDate: 2017-04-19T01:43:28.794687-05:
      DOI: 10.1002/ajmg.a.37906
  • Foremost Prenatal Physician, Scientist Tapped to Lead National Child
           Health Agency
    • Pages: 1138 - 1139
      PubDate: 2017-04-19T01:43:25.31719-05:0
      DOI: 10.1002/ajmg.a.38264
  • De Novo Variants Associated With Developmental Disability
    • Pages: 1139 - 1140
      PubDate: 2017-04-19T01:43:24.57882-05:0
      DOI: 10.1002/ajmg.a.38265
  • In This Issue
    • Pages: 1141 - 1141
      PubDate: 2017-04-19T01:43:30.415767-05:
      DOI: 10.1002/ajmg.a.37907
  • Introduction Special Series: Professor John M. Opitz, Founding Editor of
           AJMG, Awarded the Order of Merit from the Federal Republic of Germany
    • Authors: John C. Carey; Edward B. Clark
      First page: 1143
      PubDate: 2017-03-28T07:10:44.668765-05:
      DOI: 10.1002/ajmg.a.38226
  • John M Opitz, Founder of AJMG, awarded the German Merit of Honor
    • Authors: Jürgen Spranger
      First page: 1145
      PubDate: 2017-03-29T08:28:56.412974-05:
      DOI: 10.1002/ajmg.a.38202
  • In gratitude for an undeserved gift*
    • Authors: John M. Opitz
      First page: 1147
      PubDate: 2017-03-29T08:28:54.004007-05:
      DOI: 10.1002/ajmg.a.38186
  • Variations on the theme of how to write a scientific article
    • Authors: Giovanni Neri
      First page: 1149
      PubDate: 2017-03-29T08:29:06.294956-05:
      DOI: 10.1002/ajmg.a.38187
  • Short stature, unusual face, delta phalanx, and abnormal vertebrae and
           ribs in a girl born to half-siblings
    • Authors: Robert Pogue; Felipe A. Marques, Cristiane Kopacek, Rosana C. M. Rosa, Luiza E. Dorfman, Juliana F. Mazzeu, José A. M. Flores, Paulo R. G. Zen, Rafael F. M. Rosa
      First page: 1152
      Abstract: Delta phalanx is a rare abnormality typically associated with additional features. We describe a patient with a phenotype resembling Catel–Manzke syndrome, but with delta phalanx and abnormal vertebrae and ribs. The patient was the only child of half siblings born with a marked prenatal growth deficiency. At 10 years of age, she had a short stature, long face, long and tubular nose with small alae nasi, high palate, short and broad thorax, and short index fingers with radial deviation. There were hyperpigmentations following Blaschko's lines. Radiology showed a proximal delta phalanx in the index finger of hands, abnormal vertebrae, and fused and small ribs. GTG-Banding karyotype and microarray analysis yielded normal results. Exome sequencing identified 25 genes that harbored homozygous variants, but none of these is assumed to be a good candidate to explain (part of) the phenotype. The here described patient may have a new condition, possibly following an autosomal recessive pattern of inheritance, although due to the high degree of consanguinity a compound etiology of the phenotype by variants in various genes may be present as well.
      PubDate: 2017-03-31T07:50:35.461191-05:
      DOI: 10.1002/ajmg.a.38172
  • The proceedings of the 15th professional conference on Williams Syndrome
    • Authors: Jennifer R. Walton; Marilee A. Martens, Barbara R. Pober
      First page: 1159
      Abstract: Williams Syndrome (WS) is a contiguous gene deletion disorder, caused by the deletion of approximately 26–28 genes from chromosome 7 (7q11.23). Individuals with WS have complex medical, developmental, and behavioral features, requiring multidisciplinary and interdisciplinary collaboration. Guidelines detailing the identification, evaluation, and monitoring of individuals with WS need clarification, especially for primary care providers who are first-line in their management. This report summarizes the proceedings of the 2016 Professional Conference on WS in Columbus, OH. Presentations were directed towards primary care providers and subspecialists, emphasizing evidence-based practices for treating the prevalent medical and behavioral features of WS. Included in this report are findings from a panel of cardiovascular experts discussing three case studies on treatment of hypertension and the use of sedation or anesthesia for non-cardiac procedures. s from individual expert presenters are included, covering various medical and behavioral topics, and providing updates in management of WS individuals. The following topics were discussed: differences in phenotypes of 7q11.23 deletion versus duplication, growth parameters, endocrine concerns, sleep difficulties, behaviors to monitor, and pharmacological options, the neurodevelopmental profile of WS individuals, and the importance of monitoring medical and behavioral concerns as WS individuals transition to adulthood.
      PubDate: 2017-03-29T04:40:27.121765-05:
      DOI: 10.1002/ajmg.a.38156
  • Cornelia de Lange syndrome and molecular implications of the cohesin
           complex: Abstracts from the 7th biennial scientific and educational
           symposium 2016
    • Authors: Antonie D. Kline; Ian D. Krantz, Matthew A. Deardorff, Katsuhiko Shirahige, Dale Dorsett, Jennifer L. Gerton, Meng Wu, Devanshi Mehta, Jason A. Mills, Cheri S. Carrico, Sarah Noon, Pamela S. Herrera, Julia A. Horsfield, Chiara Bettale, Jeremy Morgan, Sylvia A. Huisman, Jo Moss, Joseph McCleery, Marco Grados, Blake D. Hansen, Siddharth Srivastava, Emily Taylor-Snell, Lynne M. Kerr, Olivia Katz, Anne L. Calof, Antonio Musio, Alena Egense, Richard E. Haaland
      Pages: 1172 - 1185
      Abstract: Cornelia de Lange Syndrome (CdLS) is due to mutations in the genes for the structural and regulatory proteins that make up the cohesin complex, and is considered a cohesinopathy disorder or, more recently, a transcriptomopathy. New phenotypes have been recognized in this expanding field. There are multiple clinical issues facing individuals with all forms of CdLS, particularly in the neurodevelopmental system, but also gastrointestinal, cardiac, and musculoskeletal. Aspects of developmental and cell biology have found common endpoints in the biology of the cohesin complex, with improved understanding of the mechanisms, easier diagnostic tests, and the possibility of potential therapeutics, all major clinical implications for the individual with CdLS. The following abstracts are the presentations from the 7th Cornelia de Lange Syndrome Scientific and Educational Symposium, June 22–23, 2016, in Orlando, FL, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting. In addition to the scientific and clinical discussions, there were talks related to practical aspects of behavior including autism, transitions, communication, access to medical care, and databases. At the end of the symposium, a panel was held, which included several parents, affected individuals and genetic counselors, and discussed the greatest challenges in life and how this information can assist in guiding future research. The Research Committee of the CdLS Foundation organizes this meeting, reviews, and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board and publications. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.
      PubDate: 2017-02-12T11:05:26.152962-05:
      DOI: 10.1002/ajmg.a.38161
  • Beemer–Langer syndrome is a ciliopathy due to biallelic mutations in
    • Authors: Karina C. Silveira; Carolina A. Moreno, Denise P. Cavalcanti
      First page: 1186
      Abstract: Since most short-rib polydactyly phenotypes are due to genes involved with biogenesis and maintenance of the primary cilium, this group of skeletal dysplasias was recently designated as ciliopathies with major skeletal involvement. Beemer–Langer syndrome or short-rib polydactyly type IV, was first described in 1983, and has, thus far, remained without a defined molecular basis. The most recent classification of the skeletal dysplasias referred to this phenotype as an as-yet unproven ciliopathy. IFT122 is a gene that encodes a protein responsible for the retrograde transport along the cilium; it has been associated with this group of skeletal dysplasias. To date, mutations in this gene were only found in Sensenbrenner syndrome. Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 ([c.3184G>C];[c.3228dupG;c.3231_3233delCAT]) in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement.
      PubDate: 2017-03-28T07:10:43.580247-05:
      DOI: 10.1002/ajmg.a.38157
  • Mystery solved: Our son's autism and extreme self-injury is genetic and
    • Authors: Tanja Bartel
      First page: 1190
      Abstract: Our 17-year-old autistic son Jake is declining at the same rate his peers are developing. He has the pimples, the sudden height, and the hormones. But the right side of his body slumps like someone who has had a stroke. Once right handed, he now uses only his left hand. At 15, he knocked his eyes off their parallel tracks by slamming his temple into the corner of a wooden post. One eye looks straight ahead while the other looks up and to the side. Both optic nerves are damaged. All the damage is self-inflicted. He has been banging and punching his head since babyhood.
      PubDate: 2017-03-21T07:07:28.223248-05:
      DOI: 10.1002/ajmg.a.38198
  • Advanced cardiovascular imaging in Williams syndrome: Abnormalities,
           usefulness, and strategy for use
    • Authors: Jordan A. Hills; Yuri A. Zarate, Noelle R. Danylchuk, Tiffany Lepard, Jean Chi-Jen Chen, Ronnie Thomas Collins
      First page: 1194
      Abstract: Extracardiac arterial stenoses are not uncommon in Williams syndrome (WS); however, data on the utility of advanced cardiovascular imaging (CVI) to assess these stenoses are lacking. We retrospectively reviewed the frequency, indication, and diagnostic outcomes of CVI modalities performed in patients with WS evaluated at a single institution between 2001 and 2014. Data were collected and analyzed from 34 patients (56% female) who underwent CVI during the study period. The median age was 10 years (range 1.8–33 years). Excluding echocardiograms, 78 CVI studies “advanced” were performed in the 34 patients (mean 2.3 studies/patient). The most common advanced CVI was renal ultrasound with Doppler (29/34, 85%), followed by computed tomographic angiography (13/34, 38%) and magnetic resonance angiography in (9/34, 26%). Abnormalities were detected in 62% of patients (21/34). For the 20 patients in whom advanced CVI were performed for defined clinical indications, the rate of abnormalities were 73, 70, 57, and 100% when performed for anatomic delineation (15 patients), hypertension (10 patients), bruits (7 patients), and/or decreased peripheral pulses (2 patients), respectively. Advanced CVI in patients with WS reveals abnormalities in the majority of cases, and physical exam findings frequently indicate abnormalities on advanced CVI.
      PubDate: 2017-03-22T23:55:37.400071-05:
      DOI: 10.1002/ajmg.a.38138
  • Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational
           reinitiation in congenital central hypoventilation syndrome
    • Authors: Jacob T. Cain; Dae I. Kim, Megan Quast, Winnie G. Shivega, Ryan J. Patrick, Chuanpit Moser, Suzanne Reuter, Myrza Perez, Angela Myers, Jill M. Weimer, Kyle J. Roux, Megan Landsverk
      First page: 1200
      Abstract: Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.
      PubDate: 2017-03-29T04:40:40.496822-05:
      DOI: 10.1002/ajmg.a.38162
  • Maxillofacial features and systemic malformations in expanded spectrum
           Hemifacial Microsomia
    • Authors: Noah Cohen; Erica Cohen, Alberto Gaiero, Silvia Zecca, Graziella Fichera, Federica Baldi, Joseph Felix Giordanetto, Jacques Marie Mercier, Amnon Cohen
      Pages: 1208 - 1218
      Abstract: Hemifacial microsomia (HFM) is a rare, multisystemic congenital disease with estimated frequency of 1/26370 births in Europe. Most cases are sporadic and caused by unilateral abnormal morphogenesis of the first and second pharyngeal arches. The aim of this study is to define the types and frequency of maxillofacial and systemic malformations in HFM patients. This is a case series study of patients with HFM evaluated at a single institution. Data were acquired through history, physical examination, photographs, diagnostic radiology, and laboratory and analyzed by the FileMakerPro database on 95 patients (54F; 41M) of which 89 met the inclusion criteria. Mandibular hypoplasia was observed in 86 patients with right-side preponderance (50). One patient had bilateral mandibular hypoplasia. Seventy-four had external ear anomalies (anotia or microtia). Eleven had bilateral malformed ears. Hearing impairment, associated with stenosis or atresia of the external ear canal, was found in 69 patients (eight with bilateral canal defects). Ocular anomalies were seen in 41 (23 with dermoid cysts) and 39 had orbital malformations. Facial nerve paralysis was observed in 38 patients. Cleft lip/palate (10), preauricular tags (55), and macrostomia (41) were also described. A total of 73/86 had systemic malformations, mainly vertebral (40), genitourinary (25), and cardiovascular (28). Sixteen had cerebral anomalies (four with intellectual disability). All patients suspected of HFM should undergo a complete systematic clinical and imaging investigation to define the full scope of anomalies. Since the disease is rare and complex, affected patients should be monitored by specialized multidisciplinary team centers.
      PubDate: 2017-03-20T09:15:29.166018-05:
      DOI: 10.1002/ajmg.a.38151
  • Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and
           skin desquamation identified by ultrasound
    • Authors: Raymond J. Louie; Queenie K.-G. Tan, Jennifer B. Gilner, R. Curtis Rogers, Noelle Younge, Stephanie B. Wechsler, Marie T. McDonald, Barbara Gordon, Christopher A. Saski, Julie R. Jones, Shelley J. Chapman, Roger E. Stevenson, John W. Sleasman, Michael J. Friez
      Pages: 1219 - 1225
      Abstract: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.
      PubDate: 2017-03-20T00:15:45.225469-05:
      DOI: 10.1002/ajmg.a.38144
  • A height-for-age growth reference for children with achondroplasia:
           Expanded applications and comparison with original reference data
    • Authors: Julie Hoover-Fong; John McGready, Kerry Schulze, Adekemi Yewande Alade, Charles I Scott
      First page: 1226
      Abstract: The height-for-age (HA) reference currently used for children with achondroplasia is not adaptable for electronic records or calculation of HA Z-scores. We report new HA curves and tables of mean and standard deviation (SD) HA, for calculating Z-scores, from birth-16 years in achondroplasia. Mixed longitudinal data were abstracted from medical records of achondroplasia patients from a single clinical practice (CIS, 1967–2004). Gender-specific height percentiles (5, 25, 50, 75, 95th) were estimated across the age continuum, using a 2 month window per time point smoothed by a quadratic smoothing algorithm. HA curves were constructed for 0–36 months and 2–16 years to optimize resolution for younger children. Mean monthly height (SD) was tabulated. These novel HA curves were compared to reference data currently in use for children with achondroplasia. 293 subjects (162 male/131 female) contributed 1,005 and 932 height measures, with greater data paucity with age. Mean HA tracked with original achondroplasia norms, particularly through mid-childhood (2–9 years), but with no evidence of a pubertal growth spurt. Standard deviation of height at each month interval increased from birth through 16 years. Birth length was lower in achondroplasia than average stature and, as expected, height deficits increased with age. A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z-score calculations. This is an important contribution to clinical care and research endeavors for the achondroplasia population.
      PubDate: 2017-04-04T06:46:09.036578-05:
      DOI: 10.1002/ajmg.a.38150
  • The association of maternal lymphatic markers and critical congenital
           heart defects in the fetus—A population based case-control study
    • Authors: Martina A. Steurer; Mary E. Norton, Rebecca J. Baer, Gary M. Shaw, Sheila Keating, Anita J. Moon-Grady, Christina D. Chambers, Laura L. Jelliffe-Pawlowski
      First page: 1231
      Abstract: The objective ot this study was to investigate whether lymphatic markers measured in women during the second trimester are associated with critical congenital heart defects (CCHDs) in offspring. This is a retrospective cohort study of pregnant women who participated in the California Prenatal Screening Program. CCHD data in the offspring was captured by linking birth certificate data with hospital patient discharge records. Second trimester samples were assayed for vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) AA/BB, and PDGF AB. Logistic models were used to evaluate the association between lymphatic biomarkers and CCHD. Models were adjusted for other serum biomarkers and maternal characteristics. Results are presented in odds ratios (OR) with 95% confidence intervals (CI). We identified 93 cases with CCHDs and 194 controls without CCHDs. The crude and adjusted OR for log (ln) VEGF was 1.07 (95%CI 0.94–1.22) and 1.08 (95%CI 0.94–1.24), respectively; for ln PDGF AB/BB was 0.93 (95%CI 0.6–1.35) and 0.58 (95%CI 0.32–1.05), respectively. There was a significant association between ln PDFG AA and CCHDs (crude OR 1.83 (95%CI 1.05–3.2); adjusted OR 2.41 (95%CI 1.06–5.44)). Levels of circulating PDGF AA were highest in cases with hypoplastic left heart syndrome (HLHS) (mean 8.78 +/− 1.54 pg/ml). In this study, increased mid-pregnancy maternal serum levels of PDGF AA were associated with CCHDs in offspring. The highest PDGF AA levels were found in mothers of fetuses with HLHS. These findings may be useful in screening for CCHDs and offer insight into their association with nuchal translucency.
      PubDate: 2017-03-21T07:47:45.605229-05:
      DOI: 10.1002/ajmg.a.38152
  • Mortality in Joubert syndrome
    • Authors: Jennifer C. Dempsey; Ian G. Phelps, Ruxandra Bachmann-Gagescu, Ian A. Glass, Hannah M. Tully, Dan Doherty
      First page: 1237
      Abstract: Joubert syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.
      PubDate: 2017-03-28T07:10:38.982563-05:
      DOI: 10.1002/ajmg.a.38158
  • Oxytocin treatment in children with Prader–Willi syndrome: A
           double-blind, placebo-controlled, crossover study
    • Authors: Jennifer L. Miller; Roy Tamura, Merlin G. Butler, Virginia Kimonis, Carlos Sulsona, June-Anne Gold, Daniel J. Driscoll
      First page: 1243
      Abstract: Prader–Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale − Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P 
      PubDate: 2017-03-30T08:00:35.128379-05:
      DOI: 10.1002/ajmg.a.38160
  • A de novo nonsense mutation in ZBTB18 plus a de novo 15q13.3 microdeletion
           in a 6-year-old female
    • Authors: Nadja Ehmke; Sylvio Karge, Johannes Buchmann, Dirk Korinth, Denise Horn, Olaf Reis, Frank Häßler
      First page: 1251
      Abstract: ZBTB18 has been proposed as candidate gene for microcephaly and abnormalities of the corpus callosum based on overlapping microdeletions of 1q43q44. More recently, de novo mutations of ZBTB18 have been identified in patients with syndromic and non-syndromic intellectual disability. Heterozygous microdeletions of 15q13.3 encompassing the candidate gene CHRNA7 are associated with developmental delay or intellectual disability with speech problems, hypotonia, and seizures. They are characterized by significant variability and reduced penetrance. We report on a patient with a de novo ZBTB18 nonsense mutation and a de novo 15q13.3 microdeletion, both in a heterozygous state, identified by next generation sequencing and array-CGH. The 6-year-old girl showed global developmental delay, absent speech, therapy-refractory seizures, ataxia, muscular hypotonia, and discrete facial dysmorphisms. Almost all of these features have been reported for both genetic aberrations, but the severity could hardly been explained by the microdeletion 15q13.3 alone. We assume an additive effect of haploinsufficiency of ZBTB18 and CHRNA7 in our patient. Assembling the features of our patient and the published patients, we noted that only one of them showed mild anomalies of the corpus callosum. Moreover, we hypothesize that nonsense mutations of ZBTB18 are associated with a more severe phenotype than missense mutations. This report indicates that haploinsufficiency of additional genes beside ZBTB18 causes the high frequency of corpus callosum anomalies in patients with microdeletions of 1q43q44 and underlines the importance of an NGS-based molecular diagnostic in complex phenotypes.
      PubDate: 2017-03-27T05:07:32.147942-05:
      DOI: 10.1002/ajmg.a.38145
  • A novel aberrant splice site mutation in COL27A1 is responsible for Steel
           syndrome and extension of the phenotype to include hearing loss
    • Authors: Nesrin Gariballa; Afif Ben-Mahmoud, Makanko Komara, Aisha M. Al-Shamsi, Anne John, Bassam R. Ali, Lihadh Al-Gazali
      First page: 1257
      Abstract: Steel syndrome is an autosomal recessive disease characterized by skeletal abnormalities and dysmorphic features. The first mutation associated with this syndrome was reported in Puerto Rican children. In this study, we identified a novel homozygous splice site variant in COL27A1 (c.3556-2A>G) in a consanguineous Emirati family with a child affected by Steel syndrome. In addition, the affected child had severe non-progressive sensorineural hearing loss not reported previously. The variant segregated in the family in an autosomal recessive manner and we show that the variant alters mRNA splicing. Furthermore, relative quantitative analysis revealed a marked reduction in gene expression in the proposita compared to healthy controls. Segregation analysis of heterozygous variants, related to hearing loss, identified by whole exome sequencing in the child (ILDR1: c.1159T>C, SYNE4: c.313G>C, and GPR98: c.18746T>G) excluded them from being responsible for the hearing loss in the proposita. In addition, the products of these genes are not interacting in the same pathway and have only been reported to cause deafness in an autosomal recessive manner. Therefore, we conclude that the novel splice-site variant identified in COL27A1 is the most likely cause for Steel syndrome in this family and that the hearing loss is part of this syndrome's phenotype.
      PubDate: 2017-03-21T07:07:49.664624-05:
      DOI: 10.1002/ajmg.a.38153
  • MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent
           intragenic deletions due to parental mosaicism
    • Authors: Toshiyuki Yamamoto; Keiko Shimojima, Yumiko Ondo, Shuichi Shimakawa, Nobuhiko Okamoto
      First page: 1264
      Abstract: MED13L haploinsufficiency syndrome is a clinical condition manifesting intellectual disability and developmental delay in association with various complications including congenital heart defects and dysmorphic features. Most of the previously reported patients showed de novo loss-of-function mutations in MED13L. Additional three patients with MED13L haploinsufficiency syndrome were identified here in association with rare complications. One patient had a de novo deletion (c.257delT) and T2-weighted high intensity in the occipital white matter on magnetic resonance imaging. Two siblings exhibited an intragenic deletion involving exons 3–14, which led to an in-frame deletion in MED13L. The deletion was inherited from their carrier mother who possessed low frequency mosaicism. The older sister of the siblings showed craniosynostosis; this condition has never been reported in patients with MED13L haploinsufficiency syndrome. Dysmorphic features were observed in these patients; however, most of the findings were nonspecific. Further information would be necessary to understand this clinical condition better.
      PubDate: 2017-03-29T08:29:07.774439-05:
      DOI: 10.1002/ajmg.a.38168
  • Long-term functional and mobility outcomes for individuals with
           arthrogryposis multiplex congenita
    • Authors: Hirmand Nouraei; Bonita Sawatzky, Megan MacGillivray, Judith Hall
      First page: 1270
      Abstract: Arthrogryposis multiplex congenita (AMC) is a birth defect that involves congenital joint contractures in two or more joints including the limbs, spine, and jaw. The purpose of our study was to identify long-term outcomes of adults with AMC. We recruited 177 participants from over 15 countries, making this the largest international study of adults with AMC. Participants provided demographic information including living situation and mobility and completed two standardized outcome measures, of quality of life and physical activity, using an online survey format. The data were compiled and descriptive analyses were performed. The study group consisted of 72% females and a mean age of 39 years. Over 90% of participants had upper and lower limb involvement, 35% had scoliosis or lordosis while 16% had jaw problems. Participants had an average of nine (0–70) surgeries at the time of the study. The majority (75%) of respondents lived independently of family members (on their own or with a partner). Participants were nearly three times more likely to have a graduate degree than the general US population. Participants reported lower physical function scores than the general US population; however, they reported similar or higher scores for the other quality of life domains of the SF-36. They were considerably less physically active than able-bodied individuals. Half of participants experienced chronic back pain and 60% reported joint pain. Additionally, almost half of the participants took regular pain medications.
      PubDate: 2017-04-04T06:45:56.476289-05:
      DOI: 10.1002/ajmg.a.38169
  • A de novo deletion in a boy with cerebral palsy suggests a refined
           critical region for the 4q21.22 microdeletion syndrome
    • Authors: Mehdi Zarrei; Daniele Merico, Barbara Kellam, Worrawat Engchuan, Tara Scriver, Rikash Jokhan, Michael D. Wilson, Jeremy Parr, Edmond G. Lemire, Dimitri J. Stavropoulos, Stephen W. Scherer
      First page: 1287
      Abstract: We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.22 microdeletion syndrome region. He also carries a 436 kb maternally-inherited duplication impacting the first three exons of CHRNA7. The majority of previously published cases with 4q21.22 syndrome shared common features including growth restriction, muscular hypotonia, and absent or severely delayed speech. Using copy number variation (CNV) data available for other subjects, we defined a minimal critical region of 170.8 kb within the syndromic region, encompassing HNRNPD. We also identified a larger 2 Mb critical region encompassing ten protein-coding genes, of which six (PRKG2, RASGEF1B, HNRNPDL, HNRNPD, LIN54, COPS4) have a significantly low number of truncating loss-of-function mutations. Long-range chromatin interaction data suggest that this deletion may alter chromatin interactions at the 4q21.22 microdeletion region. We suggest that the deletion or misregulation of these genes is likely to contribute to the neurodevelopmental and neuromuscular abnormalities in 4q21.22 syndrome.
      PubDate: 2017-04-03T07:15:57.185691-05:
      DOI: 10.1002/ajmg.a.38176
  • Age-related differences in prevalence of autism spectrum disorder symptoms
           in children and adolescents with Costello syndrome
    • Authors: David D. Schwartz; Jennifer M. Katzenstein, Eric J. Highley, Deborah L. Stabley, Katia Sol-Church, Karen W. Gripp, Marni E. Axelrad
      First page: 1294
      Abstract: Dysregulation of the mitogen activated protein kinase (MAPK) pathway in Costello syndrome (CS) may contribute to increased risk for autism-spectrum disorder (ASD). We examined prevalence of ASD symptoms in 14 individuals (six females) age 1–18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M-CHAT) for ages 0–4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7). Age was associated with meeting ASD criteria: 5/7 (71.4%) younger children met the ASD cut-off on the MCHAT, compared to 0/7 older children on the SCQ. The following medical and developmental factors were strongly associated with ASD criteria on the M-CHAT: having a gastrostomy tube at time of assessment, not eating solid food, not walking, and not being toilet trained. Two children who met stricter ASD criteria had significantly lower adaptive functioning and were physically much more impaired. Among older participants, SCQ subscale scores in communication, socialization, and repetitive behavior domains were comparable to the typically-developing normative sample. ASD symptoms were highly elevated in younger CS individuals. Older children did not differ from typically developing samples in prevalence of ASD symptoms. CS individuals may appear to fall on the autism spectrum in early childhood due to severe feeding and orthopedic problems that improve by age four, suggesting many of these children may eventually emerge out of an ASD presentation.
      PubDate: 2017-04-04T06:45:49.759874-05:
      DOI: 10.1002/ajmg.a.38174
  • Growth characteristics and endocrine abnormalities in 22q11.2 deletion
    • Authors: Yael Levy-Shraga; Doron Gothelf, Zohar Goichberg, Uriel Katz, Raz Somech, Orit Pinhas-Hamiel, Dalit Modan-Moses
      Pages: 1301 - 1308
      Abstract: 22q11.2 deletion syndrome (22q11.2DS) has a wide range of clinical features including endocrine abnormalities. We aimed to characterize growth patterns, hypoparathyroidism, and thyroid dysfunction of individuals with 22q11.2DS. Anthropometric and laboratory measurements were obtained from the charts of 48 individuals (males=28, 8.0±6.8 visits/participant) followed at a national 22q11.2DS clinic between 2009 and 2016. Age at diagnosis was 4.3±4.9 years and age at last evaluation 11.2±7.2 years. Median height-SDS was negative at all ages. Height-SDS at last visit was correlated to the midparental height-SDS (r=0.52 P=0.002). Yet, participants did not reach their target height, with a difference of 1.06±1.07 SD (P 
      PubDate: 2017-02-16T00:15:54.82163-05:0
      DOI: 10.1002/ajmg.a.38175
  • Phenotypic spectrum of Costello syndrome individuals harboring the rare
           HRAS mutation p.Gly13Asp
    • Authors: Débora Bertola; Michelle Buscarilli, Deborah L. Stabley, Laura Baker, Daniel Doyle, Dennis W. Bartholomew, Katia Sol-Church, Karen W. Gripp
      First page: 1309
      Abstract: Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.
      PubDate: 2017-04-03T07:16:11.556384-05:
      DOI: 10.1002/ajmg.a.38178
  • De novo loss-of-function variants in STAG2 are associated with
           developmental delay, microcephaly, and congenital anomalies
    • Authors: Sureni V. Mullegama; Steven D. Klein, Milene V. Mulatinho, Tharanga Niroshini Senaratne, Kathryn Singh, , Dzung C. Nguyen, Natalie M. Gallant, Samuel P. Strom, Shahnaz Ghahremani, Nagesh P. Rao, Julian A. Martinez-Agosto
      Pages: 1319 - 1327
      Abstract: The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits: SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed “cohesinopathies.” Through clinical exome sequencing (CES) of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. The analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.
      PubDate: 2017-03-11T07:30:31.498312-05:
      DOI: 10.1002/ajmg.a.38207
  • Multigenerational pedigree with STAR syndrome: A novel FAM58A variant and
           expansion of the phenotype
    • Authors: Nicole J. Boczek; Teresa Kruisselbrink, Margot A. Cousin, Patrick R. Blackburn, Eric W. Klee, Ralitza H. Gavrilova, Brendan C. Lanpher
      First page: 1328
      Abstract: STAR syndrome is a rare X-linked dominant disorder characterized by toe Syndactyly, Telecanthus, Anogenital malformations, and Renal malformations, and is caused by loss-of-function variants in FAM58A. Our proband presented with the hallmark features of STAR syndrome, as well as some additional less typical features including tethered cord and hearing loss. The proband's mother and maternal half-sister had similar clinical histories, but had variability in phenotypic severity. Clinical whole exome sequencing revealed a novel pathogenic nonsense variant, c.651G>A (p.Trp217X; NM_152274), in FAM58A in the proband, mother, and maternal half-sister. This pedigree represents the 11–13th patients described with STAR syndrome and the third instance of familial inheritance. To our knowledge, this is the first occurrence of a nonsense variant in FAM58A described in individuals with STAR syndrome and the phenotype in this pedigree suggests that tethered cord and hearing loss are features of STAR syndrome.
      PubDate: 2017-03-21T07:07:42.246173-05:
      DOI: 10.1002/ajmg.a.38113
  • Functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 due
           to X;6 translocation with an atypical X-inactivation pattern
    • Authors: Anna Podolska; Albrecht Kobelt, Sigrid Fuchs, Karl Hackmann, Andreas Rump, Evelin Schröck, Kerstin Kutsche, Nataliya Di Donato
      First page: 1334
      Abstract: Pattern of X chromosome inactivation (XCI) is typically random in females. However, chromosomal rearrangements affecting the X chromosome can result in XCI skewing due to cell growth disadvantage. In case of an X;autosome translocation, this usually leads to an XCI pattern of 100:0 with the derivative X being the active one in the majority of females. A de novo balanced X;6 translocation [46,X,t(X;6)(p22.1;q27)] and a completely skewed XCI pattern (100:0) were detected in a female patient with microcephaly, cerebellar vermis hypoplasia, heart defect, and severe developmental delay. We mapped the breakpoint regions using fluorescence in situ hybridization and found the X-linked gene POLA1 to be disrupted. POLA1 codes for the catalytic subunit of the polymerase α-primase complex which is responsible for initiation of the DNA replication process; absence of POLA1 is probably incompatible with life. Consequently, by RBA banding we determined which of the X chromosomes was the active one in the patient. In all examined lymphocytes the wild-type X chromosome was active. We propose that completely skewed XCI favoring the normal X chromosome resulted from death of cells with an active derivative X that was caused by a non-functional POLA1 gene. In summary, we conclude that functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 are responsible for the clinical phenotype of the patient. This case demonstrates the importance of determining which one of the X chromosomes underwent inactivation to correlate clinical features of a female with an X;autosome translocation with the nature of the genetic alteration.
      PubDate: 2017-03-31T07:50:31.955257-05:
      DOI: 10.1002/ajmg.a.38183
  • Retinal dystrophy in two boys with Costello syndrome due to the HRAS
           p.Gly13Cys mutation
    • Authors: Mary Ella Pierpont; Mary Richards, W. Keith Engel, Nancy J. Mendelsohn, C. Gail Summers
      First page: 1342
      Abstract: Features of Costello Syndrome, a systemic disorder caused by germline mutations in the proto-oncogene HRAS from the RAS/MAPK pathway, include failure-to-thrive, short stature, coarse facial features, cardiac defects including hypertrophic cardiomyopathy, intellectual disability, and predisposition to neoplasia. Two unrelated boys with Costello syndrome and an HRAS mutation (p.Gly13Cys) are presented with their ophthalmologic findings. Both had early symptoms of nystagmus, photophobia, and vision abnormalities. Fundus examination findings of retinal dystrophy were present at age 3 years. Both boys have abnormal electroretinograms with reduced or undetectable rod responses along with reduced cone responses consistent with rod-cone dystrophy. Our observations suggest that early ophthalmic examination and re-evaluations are indicated in children with Costello syndrome.
      PubDate: 2017-03-23T23:40:26.832881-05:
      DOI: 10.1002/ajmg.a.38110
  • Novel compound heterozygous mutations in BCS1L gene causing Bjornstad
           syndrome in two siblings
    • Authors: Mariateresa Falco; Annamaria Franzè, Sandra Iossa, Luigia De Falco, Antonella Gambale, Elio Marciano, Achille Iolascon
      First page: 1348
      Abstract: Bjornstad syndrome is a rare condition characterized by pili torti and sensorineural hearing loss associated with pathological variations in BCS1L. Mutations in this gene are also associated with the more severe complex III deficiency and GRACILE syndrome. We report the first Italian patients with Bjornstad syndrome, two siblings with pili torti and sensorineural hearing loss, in whom we detected two novel compound heterozygous mutations in BCS1L. A thorough clinical evaluation did not reveal any features consistent with complex III deficiency or GRACILE syndrome.
      PubDate: 2017-03-21T07:07:50.960467-05:
      DOI: 10.1002/ajmg.a.38146
  • Diagnostic use of computational retrotransposon detection: Successful
           definition of pathogenetic mechanism in a ciliopathy phenotype
    • Authors: Toshiki Takenouchi; Tomu Kuchikata, Hiroshi Yoshihashi, Mineko Fujiwara, Tomoko Uehara, Sahoko Miyama, Shiro Yamada, Kenjiro Kosaki
      First page: 1353
      Abstract: Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel–Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel–Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.
      PubDate: 2017-04-04T06:46:07.303857-05:
      DOI: 10.1002/ajmg.a.38167
  • ZC4H2 deletions can cause severe phenotype in female carriers
    • Authors: Cristina Zanzottera; Donatella Milani, Enrico Alfei, Ambra Rizzo, Stefano D'Arrigo, Susanna Esposito, Chiara Pantaleoni
      First page: 1358
      Abstract: ZC4H2 is involved in human brain development, and, if mutated, can be responsible for a rare X-linked disorder, originally presented in literature as Wieacker–Wolff syndrome and Miles–Carpenter syndrome. In males, severe intellectual disability is associated with variable symptoms of central and peripheral nervous system involvement, such as spasticity, hyperreflexia, muscle weakness, and arthrogryposis. Female carriers are usually described as asymptomatic or only mildly affected. Here, we report on a girl carrying a de novo deletion of ZC4H2 detected by array-CGH analysis. She showed a complex neurodevelopmental disorder resembling the clinical picture commonly observed in male patients. X-inactivation was found to be random. Additionally, she had an unusual appearance of fingers and hand creases, and electromyography showed a peculiar pattern of both neurogenic and myopathic anomalies. The present patient confirms that female carriers can also be severely affected. Systematic clinical investigations of both males and females are needed to define the variety in nature and severity of phenotypes related to ZC4H2 variants.
      PubDate: 2017-03-27T05:06:07.465231-05:
      DOI: 10.1002/ajmg.a.38155
  • Intrafamilial phenotypic variability in a Polish family with Sensenbrenner
           syndrome and biallelic WDR35 mutations
    • Authors: Joanna Walczak-Sztulpa; Anna Wawrocka, Agata Sobierajewicz, Lukasz Kuszel, Jan Zawadzki, Ryszard Grenda, Anna Swiader-Lesniak, Beata Kocyla-Karczmarewicz, Anna Wnuk, Anna Latos-Bielenska, Krystyna H. Chrzanowska
      First page: 1364
      Abstract: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9-year-old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low-set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre-hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.
      PubDate: 2017-03-23T06:05:25.085797-05:
      DOI: 10.1002/ajmg.a.38163
  • DDX3X mutations in two girls with a phenotype overlapping
           Toriello–Carey syndrome
    • Authors: Nicola Dikow; Martin Granzow, Luitgard M. Graul-Neumann, Stephanie Karch, Katrin Hinderhofer, Nagarajan Paramasivam, Laura-Jane Behl, Lilian Kaufmann, Christine Fischer, Christina Evers, Matthias Schlesner, Roland Eils, Guntram Borck, Christiane Zweier, Claus R. Bartram, John C. Carey, Ute Moog
      First page: 1369
      Abstract: Recently, de novo heterozygous variants in DDX3X have been reported in about 1.5% of 2659 females with previously unexplained intellectual disability (ID). We report on the identification of DDX3X variants in two unrelated girls with clinical features of Toriello–Carey Syndrome (T-CS). In patient 1, the recurrent variant c.1703C>T; p.(P568L) was identified when reconsidering X-linked de novo heterozygous variants in exome sequencing data. In patient 2, the DDX3X variant c.1600C>G; p.(R534G) was also detected by exome sequencing. Based on these data, de novo heterozygous DDX3X variants should be considered not only in females with unexplained ID, but also in individuals with a clinical diagnosis of T-CS.
      PubDate: 2017-03-29T08:28:55.5225-05:00
      DOI: 10.1002/ajmg.a.38164
  • Oculo–facio–cardio–dental syndrome with craniosynostosis, temporal
           hypertrichosis, and deafness
    • Authors: James J. O'Byrne; Eoghan Laffan, Dylan J. Murray, William Reardon
      Pages: 1374 - 1377
      Abstract: We report the case of a 7-month-old girl with atypical oculo–facio–cardio–dental syndrome (OFCD). A novel de novo pathogenic mutation in the BCL6 interacting co-repressor gene (BCOR) (c.4540C>T; p.Arg1514*), was identified on the X chromosome. This case expands the phenotype of OFCD as it is the first report of a case presenting with craniosynostois, temporal hypertrichosis, supraorbital grooving, and underdevelopment of the midface.
      PubDate: 2017-03-20T00:15:40.859866-05:
      DOI: 10.1002/ajmg.a.38128
  • Alu-mediated deletion of PIGL in a Patient with CHIME syndrome
    • Authors: Amy Knight Johnson; Gerald Bradley Schaefer, Jennifer Lee, Ying Hu, Daniela del Gaudio
      First page: 1378
      Abstract: CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease-causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL.
      PubDate: 2017-03-28T07:10:42.36217-05:0
      DOI: 10.1002/ajmg.a.38181
  • Oral-facial-digital syndrome type 1 in males: Congenital heart defects are
           included in its phenotypic spectrum
    • Authors: Arjan Bouman; Mariëlle Alders, Roelof Jan Oostra, Elisabeth van Leeuwen, Nikki Thuijs, Anne-Marie van der Kevie-Kersemaekers, Merel van Maarle
      First page: 1383
      Abstract: Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.
      PubDate: 2017-04-03T07:16:16.060094-05:
      DOI: 10.1002/ajmg.a.38179
  • Inherited germline ATRX mutation in two brothers with ATR-X syndrome and
    • Authors: Jianling Ji; Catherine Quindipan, David Parham, Lishuang Shen, David Ruble, Moiz Bootwalla, Dennis T. Maglinte, Xiaowu Gai, Sulagna C. Saitta, Jaclyn A. Biegel, Leo Mascarenhas
      First page: 1390
      Abstract: We report a family in which two brothers had an undiagnosed genetic disorder comprised of dysmorphic features, microcephaly, severe intellectual disability (non-verbal), mild anemia, and cryptorchidism. Both developed osteosarcoma. Trio exome sequencing (using blood samples from the younger brother and both parents) was performed and a nonsense NM_000489.4:c.7156C>T (p.Arg2386*) mutation in the ATRX gene was identified in the proband (hemizygous) and in the mother's peripheral blood DNA (heterozygous). The mother is healthy, does not exhibit any clinical manifestations of ATR-X syndrome and there was no family history of cancer. The same hemizygous pathogenic variant was confirmed in the affected older brother's skin tissue by subsequent Sanger sequencing. Chromosomal microarray studies of both brothers’ osteosarcomas revealed complex copy number alterations consistent with the clinical diagnosis of osteosarcoma. Recently, somatic mutations in the ATRX gene have been observed as recurrent alterations in both osteosarcoma and brain tumors. However, it is unclear if there is any association between osteosarcoma and germline ATRX mutations, specifically in patients with constitutional ATR-X syndrome. This is the first report of osteosarcoma diagnosed in two males with ATR-X syndrome, suggesting a potential increased risk for cancer in patients with this disorder.
      PubDate: 2017-03-28T07:10:41.07825-05:0
      DOI: 10.1002/ajmg.a.38184
  • Further evidence for specific IFIH1 mutation as a cause of
           Singleton–Merten syndrome with phenotypic heterogeneity
    • Authors: Maria Pettersson; Birgitta Bergendal, Johanna Norderyd, Daniel Nilsson, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand
      Pages: 1396 - 1399
      Abstract: Singleton–Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton–Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton–Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton–Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.
      PubDate: 2017-03-20T09:15:32.343108-05:
      DOI: 10.1002/ajmg.a.38214
  • Molecular analysis of a novel intragenic deletion in GPC3 in three cousins
           with Simpson–Golabi–Behmel syndrome
    • Authors: Julia Schmidt; Ronja Hollstein, Frank J. Kaiser, Gabriele Gillessen-Kaesbach
      First page: 1400
      Abstract: Simpson–Golabi–Behmel syndrome (SGBS) is characterized by multiple congenital abnormalities, pre/postnatal overgrowth, distinctive craniofacial features intellectual disability (ID) of variable degree, and an increased risk for embryonal tumors. SGBS is X-linked recessive and caused by deletions, duplications, and point mutations in GPC3, encoding a membrane associated cell surface heparan sulfate proteoglycan named glypican 3. GPC3 plays essential roles in the regulation of cell growth signaling and cell division. Here, we report on a family with three affected cousins who show variable clinical signs of SGBS and ID. Initial microarray-CGH revealed a deletion of approximately 30–50 kb that includes at least one exon of GPC3. By subsequent Sanger sequencing of genomic DNA we could map the chromosomal break points to define a deletion size of 43,617 bp including exons 5 and 6 of the GPC3 gene. RT-PCR analysis on RNA derived from whole blood could further confirm the deletion of both exons on transcript level. This loss of two exons results in a frameshift and a premature stop of translation. Based on our results we have established a breakpoint spanning PCR that could identify the mutation in the mothers and grandmother of the patients. Thus, we provided a molecular test that allows accurate genetic counselling and prenatal diagnosis for this family.
      PubDate: 2017-03-29T08:28:57.848256-05:
      DOI: 10.1002/ajmg.a.38188
  • Genetic advances in craniosynostosis
    • Authors: Wanda Lattanzi; Marta Barba, Lorena Di Pietro, Simeon A. Boyadjiev
      Pages: 1406 - 1429
      Abstract: Craniosynostosis, the premature ossification of one or more skull sutures, is a clinically and genetically heterogeneous congenital anomaly affecting approximately one in 2,500 live births. In most cases, it occurs as an isolated congenital anomaly, that is, nonsyndromic craniosynostosis (NCS), the genetic, and environmental causes of which remain largely unknown. Recent data suggest that, at least some of the midline NCS cases may be explained by two loci inheritance. In approximately 25–30% of patients, craniosynostosis presents as a feature of a genetic syndrome due to chromosomal defects or mutations in genes within interconnected signaling pathways. The aim of this review is to provide a detailed and comprehensive update on the genetic and environmental factors associated with NCS, integrating the scientific findings achieved during the last decade. Focus on the neurodevelopmental, imaging, and treatment aspects of NCS is also provided.
      PubDate: 2017-02-04T01:50:43.608528-05:
      DOI: 10.1002/ajmg.a.38159
    • Authors: S. F. Gilbert; M. J. F. Barresi
      Pages: 1430 - 1430
      PubDate: 2017-03-20T09:15:22.557733-05:
      DOI: 10.1002/ajmg.a.38166
  • Bilateral second toe superposition associated with neurofibromatosis type
           1 and NF1 whole gene deletion
    • Authors: Luiz Rodrigues; Juliana Souza, Frederico Malta, Juliana Rodrigues, Patrícia Couto, Luíza Rodrigues, Nilton Rezende, Vincent Riccardi
      First page: 1431
      PubDate: 2017-03-29T04:40:35.047074-05:
      DOI: 10.1002/ajmg.a.38182
  • Adding value to genetic testing through utilization management: Commercial
           laboratory's experience
    • Authors: Gina K. Londre; Christina A. Zaleski, Jessie H. Conta
      Pages: 1433 - 1435
      PubDate: 2017-03-20T00:15:29.733721-05:
      DOI: 10.1002/ajmg.a.38147
  • Maternal uniparental disomy of chromosome 15 and concomitant STRC and
           CATSPER2 deletion-mediated deafness-infertility syndrome
    • Authors: Lisa Karger; Wahab A. Khan, Rafaela Calabio, Ram Singh, Bixia Xiang, Arvind Babu, Ninette Cohen, Amy C. Yang, Stuart A. Scott
      Pages: 1436 - 1439
      PubDate: 2017-03-20T00:15:37.172032-05:
      DOI: 10.1002/ajmg.a.38154
  • The HHID syndrome of hypertrichosis, hyperkeratosis, abnormal corpus
           callosum, intellectual disability, and minor anomalies is caused by
           mutations in ARID1B
    • Authors: Markus Zweier; Maarit M. Peippo, Minna Pöyhönen, Helena Kääriäinen, Anaïs Begemann, Pascal Joset, Beatrice Oneda, Anita Rauch
      First page: 1440
      PubDate: 2017-03-21T07:48:05.842974-05:
      DOI: 10.1002/ajmg.a.38143
  • Intragenic deletion of the WDR45 gene in a male with encephalopathy,
           severe psychomotor disability, and epilepsy
    • Authors: Sylvia Redon; Caroline Benech, Sacha Schutz, Aurore Despres, Paul Gueguen, Pauline Le Berre, Cédric Le Marechal, Sylviane Peudenier, Philippe Meriot, Philippe Parent, Claude Ferec
      First page: 1444
      PubDate: 2017-04-03T07:16:09.700792-05:
      DOI: 10.1002/ajmg.a.38180
  • Neurofibromatosis type 2: Multiple intra-dermal tumors in a toddler
    • Authors: Cecilie F. Rustad; Hilde M. Dahl, Naomi L. Bowers, Jan C. Sitek, Arvid Heiberg, Susan Huson, Trine Prescott, D. Gareth R. Evans
      First page: 1447
      PubDate: 2017-04-03T07:16:08.740558-05:
      DOI: 10.1002/ajmg.a.38177
  • NDUFS4-related Leigh syndrome in Hutterites
    • Authors: Josef Finsterer; Sinda Zarrouk-Mahjoub
      First page: 1450
      PubDate: 2017-03-28T07:10:46.764607-05:
      DOI: 10.1002/ajmg.a.38225
  • Response to correspondence of NDUFS4-related Leigh syndrome in Hutterites
    • Authors: Ryan E. Lamont; Chandree L. Beaulieu, Francois P. Bernier, Rebecca Sparkes, A. Micheil Innes, Candice Jackel-Cram, Carole Ober, Jillian S. Parboosingh, Edmond G. Lemire
      First page: 1452
      PubDate: 2017-03-28T07:10:49.350112-05:
      DOI: 10.1002/ajmg.a.38227
  • Corrigendum to “Having a son or daughter with Down syndrome:
           Perspectives from mothers and fathers. Am J Med Genet Part A
    • Authors: Brian G. Skotko; Susan P. Levine, Richard Goldstein
      Pages: 1453 - 1453
      PubDate: 2017-02-16T00:15:52.43274-05:0
      DOI: 10.1002/ajmg.a.38185
  • Correspondence to Gripp et al. nephroblastomatosis or Wilms tumor in a
           fourth patient with a somatic PIK3CA mutation
  • A mutation in GABRB3 associated with Dravet syndrome
    • Abstract: Dravet syndrome is a rare and severe type of epilepsy in infants. Approximately, 70–80% of patients with Dravet syndrome have mutations in SCN1A, the gene encoding the alpha-1 subunit of the sodium channel, while some simplex patients have variants in one of several other genes, including but not limited to GABRA1, SCN2A, STXBP1, GABRG2, and SCN1B. In this study, we performed exome sequencing in six patients with SCN1A-negative Dravet syndrome to identify other genes related to this disorder. In one affected individual, we detected a novel de novo heterozygous missense variant, c.695G>A, p.(Arg232Gln), in GABRB3, the gene encoding the β3-subunit of the gamma-aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signaling within the central nervous system. In summary, the data in this study identify GABRB3 as a candidate gene for Dravet syndrome.
  • 37th Annual David W. Smith Workshop on Malformations and Morphogenesis:
           Abstracts of the 2016 Annual Meeting
    • Abstract: The 37th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on September 9th–14th, 2016 at the University of California—Los Angeles Conference Center in Lake Arrowhead, CA. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted five themes besides mechanisms of morphogenesis and New Syndromes: Neural Crestopathies, Mosaicism, Disorders of Skin Pigmentation, Therapies, and Ear Malformations and Hearing Loss. This Conference Report includes the abstracts presented at the 2016 Workshop.
  • Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions
           including the SH2B1 gene
    • Abstract: A 200∼240 kb SH2B1-containing deletion region on 16p11.2 is associated with early-onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microdeletion on 16p11.2 including 9 Refseq genes, including SH2B1, was identified in the twins. The novel findings in monozygotic twins may expand the phenotypic spectrum of 16p11.2 microdeletion. Further studies are needed to strengthen the correlation between genotypes and abnormal clinical features.
  • Obstructive sleep apnea in Down syndrome: Benefits of surgery and
           noninvasive respiratory support
    • Abstract: Children with Down syndrome are at increased risk of obstructive sleep apnea (OSA). The aim of the study was to describe the management of OSA in a large cohort of children with Down syndrome. A retrospective analysis of sleep studies and consequent management was performed for all consecutive Down syndrome patients evaluated between September 2013 and April 2016. The data of 57 patients were analyzed: 51/53 had an interpretable overnight polygraphy and 4 the recording of nocturnal gas exchange. Mean age at baseline sleep study was 6.2 ± 5.9 years. Eighteen patients (32%) had prior upper airway surgery. Mean apnea-hypopnea index (AHI) was 14 ± 16 events/hr with 41 of the 51 (80%) patients having OSA with an AHI >1 event/hr and 20 patients (39%) having an AHI ≥10 events/hr. Consequently, eight patients (14%) had upper airway surgery. OSA improved in all patients except two who needed noninvasive respiratory support. Nineteen (33%) patients required noninvasive respiratory support. Mean age at noninvasive respiratory support initiation was 7 ± 7 years. On 11 patients with objective adherence data available, mean compliance at 2 ± 1 years of treatment was excellent with an average use per night of 8 hr46 ± 3 hr59 and 9 patients using the noninvasive respiratory support >4 hr/night. Noninvasive respiratory support was associated with an improvement of nocturnal gas exchange. The prevalence of OSA is high in Down syndrome. Upper airway surgery is not always able to correct OSA. Noninvasive respiratory support represents then an effective treatment for OSA and good compliance may be achieved in a majority of patients.
  • Haploinsufficiency of NR4A2 is associated with a neurodevelopmental
           phenotype with prominent language impairment
    • Abstract: Non-recurrent deletions in 2q24.1, minimally overlapping two genes, NR4A2 and GPD2, were recently described in individuals with language impairment and behavioral and cognitive symptoms. We herewith report on a female patient with a similar phenotype of severe language and mild cognitive impairment, in whom we identified a de novo deletion covering only NR4A2. NR4A2 encodes a transcription factor highly expressed in brain regions critical for speech and language and implicated in dopaminergic neuronal development. Our findings of a de novo deletion of NR4A2 in an individual with mild intellectual disability and prominent speech and language impairment provides further evidence for NR4A2 haploinsufficiency being causative for neurodevelopmental and particularly language phenotypes.
  • A novel variant in MED12 gene: Further delineation of phenotype
    • Abstract: MED12 is a multiprotein mediator complex, which has a role in cell growth and differentiation and has been implicated in three distinct X-linked intellectual disability syndromes with distinctive clinical features. These include Opitz–Kaveggia syndrome (FG syndrome), Lujan syndrome, and X-linked Ohdo syndrome. Recently MED12 variants have been implicated in isolated X-linked intellectual disability. We describe a 5-year-old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype–phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12-related disorders.
  • Renal anomalies and lymphedema distichiasis syndrome. A rare
    • Abstract: Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.
  • Identification of a de novo variant in CHUK in a patient with an EEC/AEC
           syndrome-like phenotype and hypogammaglobulinemia
    • Abstract: The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here.
  • CMIP haploinsufficiency in two patients with autism spectrum disorder and
           co-occurring gastrointestinal issues
    • Abstract: Autism spectrum disorder (ASD) is a genetically heterogeneous group of disorders characterized by impairments in social communication and restricted interests. Though some patients with ASD have an identifiable genetic cause, the cause of most ASD remains elusive. Many ASD susceptibility loci have been identified through clinical studies. We report two patients with syndromic ASD and persistent gastrointestinal issues who carry de novo deletions involving the CMIP gene detected by genome-wide SNP microarray and fluorescence in situ hybridization (FISH) analysis. Patient 1 has a 517 kb deletion within 16q23.2q23.3 including the entire CMIP gene. Patient 2 has a 1.59 Mb deletion within 16q23.2q23.3 that includes partial deletion of CMIP in addition to 12 other genes, none of which have a known connection to ASD or other clinical phenotypes. The deletion of CMIP is rare in general population and was not found among a reference cohort of approximately 12,000 patients studied in our laboratory who underwent SNP array analysis for various indications. A 280 kb de novo deletion containing the first 3 exons of CMIP was reported in one patient who also demonstrated ASD and developmental delay. CMIP has previously been identified as a susceptibility locus for specific language impairment (SLI). It is notable that both patients in this study had significant gastrointestinal issues requiring enteral feedings, which is unusual for patients with ASD, in addition to unusually elevated birth length, further supporting a shared causative gene. These findings suggest that CMIP haploinsufficiency is the likely cause of syndromic ASD in our patients.
  • Autosomal dominant frontometaphyseal dysplasia: Delineation of the
           clinical phenotype
    • Abstract: Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.
  • Adaptive and maladaptive functioning in Kleefstra syndrome compared to
           other rare genetic disorders with intellectual disabilities
    • Abstract: Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.
  • Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis
           verruciformis of Hopf from the allelic condition Darier disease
    • Abstract: Darier disease and Acrokeratosis Verruciformis of Hopf (AKV) are rare disorders of keratinization with autosomal dominant inheritance and very distinct clinical pictures. Both have been shown to be caused by mutations in ATP2A2 (ATPase, Ca++ transporting, cardiac muscle, slow-twitch) a gene encoding one of the SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase2) intracellular pumps with a crucial role in cell-to-cell adhesion in both skin and heart. While hundreds of different missense and nonsense mutations cause Darier disease, only one missense mutation, p.(Pro602Leu), has been identified in families with AKV. We report a family with AKV due to the p.(Pro602Leu) mutation and discuss implications for this recurrent mutation on knowledge of ATP2A2 structure and function.
  • A rapid gene sequencing panel strategy to facilitate precision neonatal
  • Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis
           caused by a novel pathogenic AMER1 frameshift mutation
    • Abstract: Osteopathia striata with cranial sclerosis (OSCS; OMIM #300373) is a rare X-linked dominant condition caused by mutations in the AMER1 gene (also known as WTX or FAM123B). It is a condition which usually affects females in whom the clinical phenotype can be extremely variable. Conversely affected males typically die in utero or during the neonatal period [Perdu et al. (); Clinical Genetics 80: 383-388; Vasiljevic et al. (); Prenatal Diagnosis 35: 302-304]. There have been a small number of reported cases of surviving males, including three patients who are somatic mosaic for the condition [Chénier, Noor, Dupuis, Stavropoulos, & Mendoza-Londono, (); American Journal of Medical Genetics Part A 158A: 2946-2952; Holman et al. (); American Journal of Medical Genetics Part A 155A: 2397-2408; Joseph, Shoji, & Econs, (); The Journal of Clinical Endocrinology and Metabolism 95: 1506-1507]. We report a case of a male child who has proven somatic mosaicism for OSCS associated with a novel pathogenic frameshift mutation, c.607_611delAGGCC (p.Arg203 fs) in AMER1. We describe the multisystemic clinical features which include macrocephaly with ventriculomegaly and requirement for ventriculoperitoneal shunt, cleft palate, and respiratory difficulties after birth requiring tracheostomy insertion, persistent patent ductus arteriosus, failure to thrive and gastrostomy insertion, growth retardation, ophthalmoplegia, kidney malformation, cryptorchidism, and developmental delay. The use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism in rare conditions.
  • Neuropsychological phenotypes of 76 individuals with Joubert syndrome
           evaluated at a single center
    • Abstract: Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p 
  • Unclassifiable pattern of hypopigmentation in a patient with mosaic
           partial 12p tetrasomy without Pallister–Killian syndrome
    • Abstract: Pallister–Killian syndrome (PKS-#OMIM601803) is a multisystem developmental disorder typically due to the presence of an aneuploidy cell line, consisting of a supernumerary tetrasomic chromosomal marker (SCM) arisen from the short arm of chromosome 12 (12p isochromosome). The clinical phenotype, which is strictly related to the percentage and tissue distribution of aneuploid cells, is characterized by craniofacial dysmorphisms, pigmentary skin anomalies, limb shortening, congenital heart defects, diaphragmatic hernia, hypotonia, intellectual disability, and epilepsy. We report on a 4 year-old girl harboring a 12p partial isochromosome, involving the PKS critical region, affecting about 70% of circulating lymphocytes, urine, and saliva cells and fibroblast from a hyperpigmented skin spot, and 100% of fibroblasts from a hypopigmented skin spot. Interestingly, despite the high proportion of affected cells this patient did not present with PKS, and a pattern of linear and patchy pigmentary mosaicism was the sole clinical manifestation. The present observation suggests that partial 12p SCM can also result in mild phenotypes, and its prevalence in the human population could have been underestimated. Accurate dermatologic evaluation could be a major handle for genetic testing.
  • Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's
    • Abstract: Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior. The “eye-of-the tiger-sign,” a characteristic hypointense spot within the hyperintense globi pallidi on MRI found in the most common subtype of NBIA (Pantothenate Kinase-Associated Neurodegeneration, PKAN), was not present. Instead, bilateral hyperintensity and swelling of caudate nucleus, putamen, and thalamus were found. In addition, our patients showed a small corpus callosum and frontotemporal and parietal white matter changes, expanding the brain phenotype of patients with CoPAN. Metabolic investigations showed increased free carnitine and decreased acylcarnitines in the patientś dried blood samples. Carnitine palmitoyl transferase 1 (CPT1) deficiency was excluded by further enzymatic and metabolic investigations. As CoA and its derivate Acetyl-CoA play an essential role in fatty acid metabolism, we assume that abnormal acylcarnitine profiles are a result of the COASY mutations. This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN.
  • Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and
           molecular diagnostic rates in a retrospective cohort
    • Abstract: Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.
  • Sclerotic bone lesions in tuberous sclerosis complex: A
           genotype–phenotype study
    • Abstract: Tuberous sclerosis complex (TSC) is due to pathogenic variants in TSC1 or TSC2 genes resulting in hyperactivation of the mTOR pathway. Many organ systems can be affected, such as brain, skin, eye, heart, bone, kidney, or lung. Sclerotic bone lesions have been reported as frequent findings in TSC although they are not considered diagnostic criteria. The objective of this study is to characterize sclerotic bone lesions detected by chest CT in a large cohort of adult TSC patients and to correlate with genotype. Chest CT scans of 92 adult patients with a definite clinical diagnosis of TSC were reviewed. Sclerotic bone lesions were found in 82 cases (89%) and affected mainly the posterior vertebral elements. Patients without bone lesions had negative mutational studies of TSC1/TSC2 in 86%. Awareness of these lesions in TSC is important to avoid misdiagnosis with osteoblastic metastases.
  • A comparison of the functional health of children with Costello syndrome
           in 1999 and in 2015
    • Abstract: Costello Syndrome is a rare congenital condition characterized by failure-to-thrive, cardiac abnormalities, distinctive facial features, predisposition to malignant tumors, and developmental delay. In 1999, we analyzed the functional health in a cohort of 18 patients. Since then, a mutation in the HRAS gene has been found to be causative, medical management has been refined, and the level of awareness has increased. The purpose of this study is to compare the functional health outcomes from the 1999 cohort with data prospectively collected from a comparable cohort in 2015. The Pediatric Outcome Data Collection Instrument (PODCI) was administered to parents of children with Costello syndrome during the 2015 International Costello Syndrome Conference. The same instrument and setting were used in the 1999 study. We compared functional health scores from the two groups. A total of 21 participants were included in the 2015 cohort; 15 females (71%) and 6 males (29%). Average age was 5.8 years (range 2–16). When comparing functional health outcomes, we found that the 2015 cohort scored slightly higher in Upper Extremity and Physical Function (57 vs. 54) and Comfort scales (86 vs. 82). However, there was no significant difference in any of the PODCI scales between the two groups. When compared with normative scores, both groups scored significantly lower in every scale except for happiness (p = 0.2952). Despite recent advancements, functional health outcomes in 2015 were similar to those measured in a different cohort in 1999.
  • Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis
           associated with 7q34-q36.3 heterozygous terminal deletion
    • Abstract: Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.
  • Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with
           intellectual disability, limb abnormalities, and cardiac malformation
    • Abstract: A male child, born from consanguineous parents and having intellectual disability, short stature, dysmorphic facial features, synpolydactyly, and cardiac malformations is reported. Chromosomal microarray analysis showed that the patient presents with an 8p23.1 homozygous deletion, containing the microRNA miR-4660, the exoribonuclease 1 (ERI1), and malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) genes. The microRNA miR-4660 has no known function. MFHAS1 is an immunomodulatory protein involved in Toll-like receptor signaling, erythropoiesis, and cancer. ERI1 is a ribonuclease involved in RNA metabolism and is required for the correct patterning of the skeleton by defining the HOXC8 expression. We discuss the involvement of these deleted genes to the patient's features and highlight differential diagnoses with syndromes implicating limb extremity abnormalities such as synpolydactyly, including the monosomy 8p.
  • Left ventricular noncompaction cardiomyopathy in a patient with trisomy
           13: A report and review of the literature
    • Abstract: Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent trabecular meshwork, and it is thought to result from arrest of the normal compaction process during embryogenesis. Patients with LVNC may be asymptomatic or have symptoms ranging from heart failure to stroke, life-threatening arrhythmias, or sudden death. The frequency of LVNC in children has increased with longer clinical courses. About 80% of patients with trisomy 13 have a congenital cardiac abnormality, but a clinical description of LVNC with trisomy 13 is lacking because of its poor prognosis and lack of awareness about LVNC. We described a patient with trisomy 13 who was diagnosed with LVNC-dilated phenotype and died suddenly, as well as two additional patients with LVNC. All three patients had chronic heart failure without congenital heart disease and were treated with diuretics. To manage trisomy 13 with or without congenital heart disease, cardiac disease such as LVNC may present at any ages, and therefore cardiac evaluation should be considered as a part of their appropriate management.
  • Artificial reproductive techniques and epigenetic alterations: Additional
           comments to the article by Arcos-Machancoses et al. ()
  • Incidence, puberty, and fertility in 45,X/47,XXX mosaicism: Report of a
           patient and a literature review
    • Abstract: Turner syndrome (TS), characterized by short stature and premature ovarian failure, is caused by chromosomal aberrations with total or partial loss of one of the two X chromosomes. Spontaneous puberty, menarche, and pregnancy occur in some patients depending on the abnormality of the X. Moreover, spontaneous pregnancy is uncommon (
  • Expanding the phenotypic spectrum of truncating POGZ mutations:
           Association with CNS malformations, skeletal abnormalities, and
           distinctive facial dysmorphism
    • Abstract: Exome sequencing has led to the comprehension of the molecular bases of several forms of neurodevelopmental disorders, a clinically heterogeneous group of diseases characterized by intellectual disability (ID) and autism spectrum disorder (ASD). De novo mutations in POGZ has been causally linked to isolated ASD and syndromic ID, only recently. Here we report on a 15 year-old girl in whom exome sequencing allowed to identify a de novo POGZ truncating mutation as the molecular cause underlying a complex phenotype apparently not fitting any recognized syndrome. We describe the evolution of her clinical features with age, and review published clinical data of patients with POGZ mutations to systematically analyze the clinical spectrum associated with mutations. Our finding expands the clinical and molecular spectrum of POGZ mutations. Revision of the literature indicate that moderate to severe ID, microcephaly, variable CNS malformations, reduced growth, brachytelephalangy, and facial dysmorphism represent recurrent features associated with POGZ mutations.
  • Acne conglobata in a long-term survivor with trisomy 13, accompanied by
           selective IgM deficiency
    • Abstract: Trisomy 13 (T13) is a congenital chromosomal disorder that is usually fatal within 2 years of birth, and only a few patients have been reported to reach adolescence. Here, we report a male long-term survivor of T13, currently 15 years of age, with a several-year history of extensive acne conglobata (AC) with abscesses on the face and neck. Methicillin-resistant Staphylococcus aureus was consistently isolated from the pustular lesions. Serum IgM levels were extremely low at 10 mg/dl. There were no abnormalities in neutrophil and total B cell number, or in serum IgA and IgG levels. Increased CD8+ T cell counts and inversion of the CD4/CD8 ratio were observed repeatedly. The patient's clinical features and laboratory data support a diagnosis of selective IgM deficiency (SIgMD) with concurrent AC. Immunoglobulin replacement therapy elevated serum IgM levels to the normal range and reduced the severity of AC. We suggest that T13 may represent a syndromic disorder associated with multiple organ malformation and a risk of developing immunodeficiency involving SIgMD. Because pediatric SIgMD is rare and an immunological abnormality in T13 patients has not previously been reported, we describe the patient's clinical course.
  • Whole exome sequencing of families with 1q21.1 microdeletion or
    • Abstract: Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication. We found mutations in five genes (SMPD1, WNK3, NOS1, ATF6, and EFHC1) that could contribute to the more severe phenotype in the probands in comparison to their mildly affected or unaffected 1q21.1 CNV carrying relatives. Interestingly, all genes have roles in stress responses (oxidative/Endoplasmic Reticulum (ER)/osmotic). One of the variants was in an X-linked gene WNK3 and segregated with the developmental features and X inactivation pattern in the family with 1q21.1 deletion transmitted from maternal grandmother. In silico analysis of all rare deleterious variants in both probands identified enrichment in nervous system diseases, metabolic pathways, protein processing in the ER and protein export. Our studies suggest that rare deleterious variants outside of the 1q21.1 CNV, individually or as a pool, could contribute to phenotypic variability in carriers of this CNV. Rare deleterious variants in stress response genes are of interest and raise the possibility of susceptibility of carriers to variable environmental influences. Next generation sequencing of additional familial cases with 1q21.1 CNV could further help determine the possible causes of phenotypic variability in carriers of this CNV.
  • Response to: Milosavljevic et al. “Two cases of RIT1 associated Noonan
           syndrome: Further delineation of the clinical phenotype and review of the
  • Nomenclature and definition in asymmetric regional body overgrowth
    • Abstract: We designate a novel term “isolated lateralized overgrowth” (ILO) for the findings previously described as “isolated hemihypertrophy” and “isolated hemihyperplasia.” ILO is defined as lateralized overgrowth in the absence of a recognized pattern of malformations, dysplasia, or morphologic variants. ILO is likely genetically heterogeneous. Further study is required to determine more of the underlying genetic etiologies and potential associations with currently unrecognized patterns of malformation.
  • Novel features of Helsmoortel–Van der Aa/ADNP syndrome in a boy with a
           known pathogenic mutation in the ADNP gene detected by exome sequencing
  • PLXNA1 developmental encephalopathy with syndromic features: A case report
           and review of the literature
    • Abstract: Developmental encephalopathies constitute a broad and genetically heterogeneous spectrum of disorders associated with global developmental delay, intellectual disability, frequent epilepsy, and other neurofunctional abnormalities. Here, we report a male presenting with infantile onset epilepsy and syndromic features resembling Dubowitz syndrome identified to have a de novo PLXNA1 variant by whole exome sequencing. This constitutes the second report of PLXNA1 sequence variation associated with early onset epilepsy, and the first to expand on the clinical features of this emerging disorder. This reports suggests that nonsynonymous de novo sequence variations in PLXNA1 are associated with a novel human phenotype characterized by intractable early onset epilepsy, intellectual disability, and syndromic features.
  • 6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and
    • Abstract: Congenital heart defects (CHD) are the most frequent type of congenital anomaly and are often associated with genetic and chromosomal syndromes. Haploinsufficiency of TAB2 (TGF-beta activated kinase 1/MAP3K7 binding protein 2) has been proposed to cause valvular and cardiac outflow tract structural abnormalities. In this study, we describe 13 newly identified individuals with microdeletions of chromosome 6q25.1 that involve TAB2. One of the patients in our study cohort has the smallest deletion yet reported, affecting only TAB2. These were compared to 27 other patients reported in the published literature or DECIPHER to have similar microdeletions, for a total study group of 40 patients. Our study shows that individuals with TAB2 deletions are predisposed to developing a primary cardiomyopathy with reduced systolic function, even in the absence of CHD. Our study cohort also shares a number of non-cardiac phenotypic findings: characteristic dysmorphic facial features, intrauterine growth restriction and/or postnatal proportionate short stature, hypotonia, developmental delay and/or intellectual disability, and connective tissue abnormalities. We conclude that a microdeletion of 6q25.1 that includes TAB2 causes a distinctive, multi-systemic syndrome. The 6q25.1 microdeletion syndrome should be considered in a patient with cardiomyopathy or a CHD, especially valve and/or atrial or ventricular septal abnormalities, and with phenotypic features described in this study. We recommend that patients with a TAB2 deletion be screened longitudinally for systolic heart failure, even if an initial echocardiogram is normal.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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