CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (vol 9, 4619, 2018)

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Abstract

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
Original languageEnglish
Article number4619
Number of pages4
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 5 Nov 2018

Keywords

  • chromatin remodelling
  • clinical epigenetics
  • disease genetics
  • neurodevelopmental disorders

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