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De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.
Heinzen, Erin L; O'Neill, Adam C; Zhu, Xiaolin; Allen, Andrew S; Bahlo, Melanie; Chelly, Jamel; Chen, Ming Hui; Dobyns, William B; Freytag, Saskia; Guerrini, Renzo; Leventer, Richard J; Poduri, Annapurna; Robertson, Stephen P; Walsh, Christopher A; Zhang, Mengqi.
Afiliación
  • Heinzen EL; Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, United States of America.
  • O'Neill AC; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
  • Zhu X; Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, United States of America.
  • Allen AS; Center for Statistical Genetics and Genomics, Duke University Medical Center, Durham, North Carolina, United States of America.
  • Bahlo M; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America.
  • Chelly J; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Chen MH; Department of Medical Biology, School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
  • Dobyns WB; Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • Freytag S; IGBMC, INSERM U964, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
  • Guerrini R; Department of Cardiology and Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, United States of America.
  • Leventer RJ; Departments of Pediatrics and Neurology, University of Washington, Seattle, Washington, United States of America.
  • Poduri A; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
  • Robertson SP; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Walsh CA; Neuroscience Department, Children's Hospital Anna Meyer-University of Florence, Florence, Italy.
  • Zhang M; Department of Neurology Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
PLoS Genet ; 14(5): e1007281, 2018 05.
Article en En | MEDLINE | ID: mdl-29738522
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Heterotopia Nodular Periventricular / Mutación con Pérdida de Función / Proteínas Asociadas a Microtúbulos Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Heterotopia Nodular Periventricular / Mutación con Pérdida de Función / Proteínas Asociadas a Microtúbulos Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos