Journal
NATURE GENETICS
Volume 51, Issue 1, Pages 106-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-018-0288-4
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Funding
- Simons Foundation Autism Research Initiative [SFARI 303241]
- US National Institutes of Health [NIH R01MH101221]
- NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation
- NIH [5R01MH107515-03]
- Howard Hughes Medical Institute
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD087011] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [T32HG000035] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007266] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH107515, R01MH101221] Funding Source: NIH RePORTER
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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 x 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.
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