Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Madeleine R. Geisheker, Gabriel Heymann, Tianyun Wang, Bradley P. Coe, Tychele N. Turner, Holly Stessman, Kendra Hoekzema, Malin Kvarnung, Marie Shaw, Kathryn Friend, Jan Liebelt, Christopher Barnett, Elizabeth M. Thompson, Eric Haan, Hui Guo, Britt Marie Anderlid, Ann Nordgren, Anna Lindstrand, Geert Vandeweyer, Antonino AlbertiEmanuela Avola, Mirella Vinci, Stefania Giusto, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, Jacob J. Michaelson, Zdenek Sedlacek, Gijs W.E. Santen, Hilde Peeters, Hakon Hakonarson, Eric Courchesne, Corrado Romano, R. Frank Kooy, Raphael A. Bernier, Magnus Nordenskjöld, Jozef Gecz, Kun Xia, Larry S. Zweifel, Evan E. Eichler

Research output: Contribution to journalArticle

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1043-1051
Number of pages9
JournalNature Neuroscience
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2017

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Geisheker, M. R., Heymann, G., Wang, T., Coe, B. P., Turner, T. N., Stessman, H., Hoekzema, K., Kvarnung, M., Shaw, M., Friend, K., Liebelt, J., Barnett, C., Thompson, E. M., Haan, E., Guo, H., Anderlid, B. M., Nordgren, A., Lindstrand, A., Vandeweyer, G., ... Eichler, E. E. (2017). Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nature Neuroscience, 20(8), 1043-1051. https://doi.org/10.1038/nn.4589