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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.

ABSTRACT: Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

SUBMITTER: Geisheker MR

PROVIDER: S-EPMC5539915 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.

Geisheker Madeleine R MR Heymann Gabriel G Wang Tianyun T Coe Bradley P BP Turner Tychele N TN Stessman Holly A F HAF Hoekzema Kendra K Kvarnung Malin M Shaw Marie M Friend Kathryn K Liebelt Jan J Barnett Christopher C Thompson Elizabeth M EM Haan Eric E Guo Hui H Anderlid Britt-Marie BM Nordgren Ann A Lindstrand Anna A Vandeweyer Geert G Alberti Antonino A Avola Emanuela E Vinci Mirella M Giusto Stefania S Pramparo Tiziano T Pierce Karen K Nalabolu Srinivasa S Michaelson Jacob J JJ Sedlacek Zdenek Z Santen Gijs W E GWE Peeters Hilde H Hakonarson Hakon H Courchesne Eric E Romano Corrado C Kooy R Frank RF Bernier Raphael A RA Nordenskjöld Magnus M Gecz Jozef J Xia Kun K Zweifel Larry S LS Eichler Evan E EE

Nature neuroscience 20170619 8

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with ...[more]

PMID: 28628100

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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.

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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.

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