Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

Brian O'Roak, Laura Vives, Santhosh Girirajan, Emre Karakoc, Niklas Krumm, Bradley P. Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith, Emily H. Turner, Ian B. Stanaway, Benjamin Vernot, Maika Malig, Carl Baker, Joshua M. Akey, Elhanan Borenstein, Mark J. Rieder, Deborah A. Nickerson, Raphael Bernier & 2 others Jay Shendure, Evan E. Eichler

Research output: Contribution to journalArticle

1187 Citations (Scopus)

Abstract

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes so-called sporadic or simplex families we sequenced all coding regions of the genome (the exome) for parent child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected I-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1, 703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

Original languageEnglish (US)
Pages (from-to)246-250
Number of pages5
JournalNature
Volume485
Issue number7397
DOIs
StatePublished - May 9 2012
Externally publishedYes

Fingerprint

Exome
Autistic Disorder
Mutation
Proteins
Paternal Age
Genes
Catenins
Chromatin Assembly and Disassembly
Point Mutation
Fathers
Autism Spectrum Disorder
Siblings
Genome
Phenotype

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

O'Roak, B., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., ... Eichler, E. E. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485(7397), 246-250. https://doi.org/10.1038/nature10989

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. / O'Roak, Brian; Vives, Laura; Girirajan, Santhosh; Karakoc, Emre; Krumm, Niklas; Coe, Bradley P.; Levy, Roie; Ko, Arthur; Lee, Choli; Smith, Joshua D.; Turner, Emily H.; Stanaway, Ian B.; Vernot, Benjamin; Malig, Maika; Baker, Carl; Akey, Joshua M.; Borenstein, Elhanan; Rieder, Mark J.; Nickerson, Deborah A.; Bernier, Raphael; Shendure, Jay; Eichler, Evan E.

In: Nature, Vol. 485, No. 7397, 09.05.2012, p. 246-250.

Research output: Contribution to journalArticle

O'Roak, B, Vives, L, Girirajan, S, Karakoc, E, Krumm, N, Coe, BP, Levy, R, Ko, A, Lee, C, Smith, JD, Turner, EH, Stanaway, IB, Vernot, B, Malig, M, Baker, C, Akey, JM, Borenstein, E, Rieder, MJ, Nickerson, DA, Bernier, R, Shendure, J & Eichler, EE 2012, 'Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations', Nature, vol. 485, no. 7397, pp. 246-250. https://doi.org/10.1038/nature10989
O'Roak, Brian ; Vives, Laura ; Girirajan, Santhosh ; Karakoc, Emre ; Krumm, Niklas ; Coe, Bradley P. ; Levy, Roie ; Ko, Arthur ; Lee, Choli ; Smith, Joshua D. ; Turner, Emily H. ; Stanaway, Ian B. ; Vernot, Benjamin ; Malig, Maika ; Baker, Carl ; Akey, Joshua M. ; Borenstein, Elhanan ; Rieder, Mark J. ; Nickerson, Deborah A. ; Bernier, Raphael ; Shendure, Jay ; Eichler, Evan E. / Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. In: Nature. 2012 ; Vol. 485, No. 7397. pp. 246-250.
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