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PMID: 30559488 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity.

Nature genetics ·Vol. 51 ·No. 1 ·2019-00-00 ·Pages 106-116

Coe BP, Stessman HAF, Sulovari A, Geisheker MR, Bakken TE, Lake AM, Dougherty JD, Lein ES, Hormozdiari F, Bernier RA, Eichler EE

Abstract

We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10-7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.

MeSH Terms
Animals Autistic Disorder/genetics Chromosome Aberrations DNA Copy Number Variations/genetics Developmental Disabilities/genetics Exome/genetics Humans Intellectual Disability/genetics Intracellular Signaling Peptides and Proteins/genetics Mi-2 Nucleosome Remodeling and Deacetylase Complex/genetics Mice Mutation/genetics Neurodevelopmental Disorders/genetics Phenotype Polymorphism, Single Nucleotide/genetics
Chemicals
Intracellular Signaling Peptides and Proteins Mi-2 Nucleosome Remodeling and Deacetylase Complex
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Coe Bradley P
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Stessman Holly A F
Department of Pharmacology, Creighton University Medical School, Omaha, NE, USA.
Sulovari Arvis
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Geisheker Madeleine R
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Bakken Trygve E
Allen Institute for Brain Science, Seattle, WA, USA.
Lake Allison M
Department of Genetics, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Dougherty Joseph D ORCID
Department of Genetics, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Lein Ed S ORCID
Allen Institute for Brain Science, Seattle, WA, USA.
Hormozdiari Fereydoun
Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, USA.
Bernier Raphael A
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
Eichler Evan E ORCID
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA. [email protected]. | Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. [email protected].
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/s41588-018-0288-4
Email
[email protected]
Published
2019-00-00
Epub
2018-00-17
Pages
106-116
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC6309590
Subset
IM
Grants
NICHD NIH HHS · U54 HD087011 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · T32 GM007266 · United States
NIMH NIH HHS · R01 MH101221 · United States
NIMH NIH HHS · R01 MH107515 · United States
External Links
PubMed source DOI: 10.1038/s41588-018-0288-4 PMC Full Text View journal details
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