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Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment.
Chen, Xiaowei Sylvia; Reader, Rose H; Hoischen, Alexander; Veltman, Joris A; Simpson, Nuala H; Francks, Clyde; Newbury, Dianne F; Fisher, Simon E.
Afiliação
  • Chen XS; Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
  • Reader RH; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • Hoischen A; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Veltman JA; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Simpson NH; Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands.
  • Francks C; Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
  • Newbury DF; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • Fisher SE; Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
Sci Rep ; 7: 46105, 2017 04 25.
Article em En | MEDLINE | ID: mdl-28440294
A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential "multiple-hit" cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Sequenciamento de Nucleotídeos em Larga Escala / Transtornos do Desenvolvimento da Linguagem / Mutação Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Predisposição Genética para Doença / Sequenciamento de Nucleotídeos em Larga Escala / Transtornos do Desenvolvimento da Linguagem / Mutação Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2017 Tipo de documento: Article