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Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
Pilarowski, Genay O; Vernon, Hilary J; Applegate, Carolyn D; Boukas, Leandros; Cho, Megan T; Gurnett, Christina A; Benke, Paul J; Beaver, Erin; Heeley, Jennifer M; Medne, Livija; Krantz, Ian D; Azage, Meron; Niyazov, Dmitriy; Henderson, Lindsay B; Wentzensen, Ingrid M; Baskin, Berivan; Sacoto, Maria J Guillen; Bowman, Gregory D; Bjornsson, Hans T.
Affiliation
  • Pilarowski GO; Predoctoral Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
  • Vernon HJ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • Applegate CD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • Boukas L; Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
  • Cho MT; Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • Gurnett CA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • Benke PJ; Predoctoral Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
  • Beaver E; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • Heeley JM; GeneDx, Gaithersburg, Maryland, USA.
  • Medne L; Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
  • Krantz ID; Joe DiMaggio Children's Hospital, Florida Atlantic School of Medicine, Hollywood, Florida, USA.
  • Azage M; Mercy Kids Genetics, Mercy Hospital, Saint Louis, Missouri, USA.
  • Niyazov D; Mercy Kids Genetics, Mercy Hospital, Saint Louis, Missouri, USA.
  • Henderson LB; Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Wentzensen IM; Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Baskin B; Department of Pediatrics, Ochsner Clinic, New Orleans, Louisiana, USA.
  • Sacoto MJG; Department of Pediatrics, Ochsner Clinic, New Orleans, Louisiana, USA.
  • Bowman GD; GeneDx, Gaithersburg, Maryland, USA.
  • Bjornsson HT; GeneDx, Gaithersburg, Maryland, USA.
J Med Genet ; 55(8): 561-566, 2018 08.
Article in En | MEDLINE | ID: mdl-28866611
BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Developmental Disabilities / DNA Helicases / Genetic Predisposition to Disease / Mutation, Missense / Chromatin Assembly and Disassembly / DNA-Binding Proteins / Genetic Association Studies Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limits: Child / Child, preschool / Female / Humans / Infant Language: En Journal: J Med Genet Year: 2018 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Developmental Disabilities / DNA Helicases / Genetic Predisposition to Disease / Mutation, Missense / Chromatin Assembly and Disassembly / DNA-Binding Proteins / Genetic Association Studies Type of study: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limits: Child / Child, preschool / Female / Humans / Infant Language: En Journal: J Med Genet Year: 2018 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido