AIMS: West syndrome (WS) is a classic form of early infantile epileptic encephalopathy (EIEE) characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on electroencephalography. Genetic defects play a critical role in the pathology of WS, and 54 EIEE genes have been identified till date. This study was designed to uncover new candidate genes for West syndrome. METHODS: In this study, we recruited 56 Chinese families with WS of unknown etiology. Whole exome sequencing (WES) was performed to identify Mendelian inheritance rare or novel variants. The association between candidate genes and WS was analyzed from many aspects, including recurrent genes in patients, predicted variant effect on genes, human tolerance to deficient genes, gene expression in the nervous system, coexpression with EIEE genes, mutual interaction with known EIEE proteins, genes related to ion channel or fragile X mental retardation protein function, and mouse models with manifestation of seizures. Genes with supporting evidence from those aspects were defined as highlight candidate genes. RESULTS: Whole exome sequencing identified 112 candidate variants in 89 genes. Among the candidate genes, 33 were autosomal dominant, 22 were autosomal recessive, and 34 were X-linked. Complex bioinformatic analysis revealed 17 highlight candidate genes: ATP2A2, CD99L2, CLCN6, CYFIP1, CYFIP2, GNB1, GPT2, HUWE1, KMT2D, MYO18A, NOS3, RYR1, RYR2, RYR3, TAF1, TECTA, and UBA1. The majority of highlight candidate genes are calcium-signaling pathway and mental retardation genes. CONCLUSIONS: This is the first WES study of Chinese WS patients with unknown etiology. This combination of phenotypic and genomic data will enable further testing to elucidate mechanisms underlying the pathogenesis of WS.
AIMS: West syndrome (WS) is a classic form of early infantile epileptic encephalopathy (EIEE) characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on electroencephalography. Genetic defects play a critical role in the pathology of WS, and 54 EIEE genes have been identified till date. This study was designed to uncover new candidate genes for West syndrome. METHODS: In this study, we recruited 56 Chinese families with WS of unknown etiology. Whole exome sequencing (WES) was performed to identify Mendelian inheritance rare or novel variants. The association between candidate genes and WS was analyzed from many aspects, including recurrent genes in patients, predicted variant effect on genes, human tolerance to deficient genes, gene expression in the nervous system, coexpression with EIEE genes, mutual interaction with known EIEE proteins, genes related to ion channel or fragile X mental retardation protein function, and mouse models with manifestation of seizures. Genes with supporting evidence from those aspects were defined as highlight candidate genes. RESULTS: Whole exome sequencing identified 112 candidate variants in 89 genes. Among the candidate genes, 33 were autosomal dominant, 22 were autosomal recessive, and 34 were X-linked. Complex bioinformatic analysis revealed 17 highlight candidate genes: ATP2A2, CD99L2, CLCN6, CYFIP1, CYFIP2, GNB1, GPT2, HUWE1, KMT2D, MYO18A, NOS3, RYR1, RYR2, RYR3, TAF1, TECTA, and UBA1. The majority of highlight candidate genes are calcium-signaling pathway and mental retardation genes. CONCLUSIONS: This is the first WES study of Chinese WSpatients with unknown etiology. This combination of phenotypic and genomic data will enable further testing to elucidate mechanisms underlying the pathogenesis of WS.
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Authors: Dong Li; Hongjie Yuan; Xilma R Ortiz-Gonzalez; Eric D Marsh; Lifeng Tian; Elizabeth M McCormick; Gabrielle J Kosobucki; Wenjuan Chen; Anthony J Schulien; Rosetta Chiavacci; Anel Tankovic; Claudia Naase; Frieder Brueckner; Celina von Stülpnagel-Steinbeis; Chun Hu; Hirofumi Kusumoto; Ulrike B S Hedrich; Gina Elsen; Konstanze Hörtnagel; Elias Aizenman; Johannes R Lemke; Hakon Hakonarson; Stephen F Traynelis; Marni J Falk Journal: Am J Hum Genet Date: 2016-09-08 Impact factor: 11.025
Authors: Maya M Polovitskaya; Carlo Barbini; Diego Martinelli; Frederike L Harms; F Sessions Cole; Paolo Calligari; Gianfranco Bocchinfuso; Lorenzo Stella; Andrea Ciolfi; Marcello Niceta; Teresa Rizza; Marwan Shinawi; Kathleen Sisco; Jessika Johannsen; Jonas Denecke; Rosalba Carrozzo; Daniel J Wegner; Kerstin Kutsche; Marco Tartaglia; Thomas J Jentsch Journal: Am J Hum Genet Date: 2020-11-19 Impact factor: 11.025
Authors: Markus Zweier; Anaïs Begemann; Kirsty McWalter; Megan T Cho; Lucia Abela; Siddharth Banka; Bettina Behring; Andrea Berger; Chester W Brown; Maryline Carneiro; Jiani Chen; Gregory M Cooper; Candice R Finnila; Maria J Guillen Sacoto; Alex Henderson; Ulrike Hüffmeier; Pascal Joset; Bronwyn Kerr; Gaetan Lesca; Gloria S Leszinski; John Henry McDermott; Meira R Meltzer; Kristin G Monaghan; Roya Mostafavi; Katrin Õunap; Barbara Plecko; Zöe Powis; Gabriela Purcarin; Tiia Reimand; Korbinian M Riedhammer; John M Schreiber; Deepa Sirsi; Klaas J Wierenga; Monica H Wojcik; Sorina M Papuc; Katharina Steindl; Heinrich Sticht; Anita Rauch Journal: Eur J Hum Genet Date: 2019-01-21 Impact factor: 4.246
Authors: Hanyin Cheng; Simona Capponi; Emma Wakeling; Elaine Marchi; Quan Li; Mengge Zhao; Chunhua Weng; Piatek G Stefan; Helena Ahlfors; Robert Kleyner; Alan Rope; Aimé Lumaka; Prosper Lukusa; Koenraad Devriendt; Joris Vermeesch; Jennifer E Posey; Elizabeth E Palmer; Lucinda Murray; Eyby Leon; Jullianne Diaz; Lisa Worgan; Amalia Mallawaarachchi; Julie Vogt; Sonja A de Munnik; Lauren Dreyer; Gareth Baynam; Lisa Ewans; Zornitza Stark; Sebastian Lunke; Ana R Gonçalves; Gabriela Soares; Jorge Oliveira; Emily Fassi; Marcia Willing; Jeff L Waugh; Laurence Faivre; Jean-Baptiste Riviere; Sebastien Moutton; Shehla Mohammed; Katelyn Payne; Laurence Walsh; Amber Begtrup; Maria J Guillen Sacoto; Ganka Douglas; Nora Alexander; Michael F Buckley; Paul R Mark; Lesley C Adès; Sarah A Sandaradura; James R Lupski; Tony Roscioli; Pankaj B Agrawal; Antonie D Kline; Kai Wang; H T Marc Timmers; Gholson J Lyon Journal: Hum Mutat Date: 2019-10-23 Impact factor: 4.878