1. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5 -related disease
- Author
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Allou , L., Julia , S., El Chehadeh , S., Lambert , L., Thevenon , Julien, Duffourd , Yannis, Saunier , A., Bouquet , P., Pere , S., Jonveaux , P., Philippe , C., Centre de géochimie de la surface (CGS), Institut national des sciences de l'Univers (INSU - CNRS)-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Department of Information Engineering and Computer Science (DISI), University of Trento [Trento], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique [CHRU Nancy], IFFSTAR, Centre de géochimie de la surface ( CGS ), Institut national des sciences de l'Univers ( INSU - CNRS ) -Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Service de Cardiologie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Information Engineering and Computer Science ( DISI ), Institut national des techniques de la documentation ( INTD-CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), and Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut national des sciences de l'Univers (INSU - CNRS)
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congenital, hereditary, and neonatal diseases and abnormalities ,Rett syndrome ,Genetic ,[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology ,NGS ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology - Abstract
International audience; Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next-generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in patients with variant forms of Rett or Rett-like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett-like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile-onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT-like phenotypes. Moreover, we report the first familial case of CDKL5-related disease., (C) 2016 John Wiley & Sons, Ltd
- Published
- 2016
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