The contribution of de novo coding mutations to autism spectrum disorder

Iossifov, I., O'Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., Smith, J. D., Paeper, B., Nickerson, D. A., Dea, J., Dong, S., Gonzalez, L. E., Mandell, J. D., Mane, S. M., Murtha, M. T., Sullivan, C. A., Walker, M. F., Waqar, Z., Wei, L., Willsey, A. J., Yamrom, B., Lee, Y. H., Grabowska, E., Dalkic, E., Wang, Z., Marks, S., Andrews, P., Leotta, A., Kendall, J., Hakker, I., Rosenbaum, J., Ma, B., Rodgers, L., Troge, J., Narzisi, G., Yoon, S., Schatz, M. C., Ye, K., McCombie, W. R., Shendure, J., Eichler, E. E., State, M. W., Wigler, M. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515 (7526). pp. 216-221. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/25363768
DOI: 10.1038/nature13908

Abstract

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > de novo mutation
CSHL Authors:
Communities: CSHL labs > Iossifov lab
CSHL labs > Levy lab
CSHL labs > McCombie lab
CSHL labs > Schatz lab
CSHL labs > Wigler lab
Stanley Institute for Cognitive Genomics
Depositing User: Matt Covey
Date Deposited: 14 Nov 2014 20:30
Last Modified: 06 Nov 2015 20:05
PMCID: PMC4313871
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30915

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving