Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
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 unknown1. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no pr...
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2012
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350576/ |
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pubmed-33505762012-11-10 Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O’Roak, Brian J. Vives, Laura Girirajan, Santhosh Karakoc, Emre Krumm, Nik Coe, Bradley P. Levy, Roie Ko, Arthur Lee, Choli Smith, Joshua D. Turner, Emily H. Stanaway, Ian B. Vernot, Benjamin Malig, Maika Baker, Carl Reilly, Beau Akey, Joshua M. Borenstein, Elhanan Rieder, Mark J. Nickerson, Deborah A. Bernier, Raphael Shendure, Jay Eichler, Evan E. Article 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 unknown1. 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 families2,3, we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported4. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19)4, for a total of 677 individual exomes from 209 families. Here we show 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 ASD5. Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling 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 suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics. 2012-04-04 /pmc/articles/PMC3350576/ /pubmed/22495309 http://dx.doi.org/10.1038/nature10989 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
O’Roak, Brian J. Vives, Laura Girirajan, Santhosh Karakoc, Emre Krumm, Nik Coe, Bradley P. Levy, Roie Ko, Arthur Lee, Choli Smith, Joshua D. Turner, Emily H. Stanaway, Ian B. Vernot, Benjamin Malig, Maika Baker, Carl Reilly, Beau Akey, Joshua M. Borenstein, Elhanan Rieder, Mark J. Nickerson, Deborah A. Bernier, Raphael Shendure, Jay Eichler, Evan E. |
| spellingShingle |
O’Roak, Brian J. Vives, Laura Girirajan, Santhosh Karakoc, Emre Krumm, Nik Coe, Bradley P. Levy, Roie Ko, Arthur Lee, Choli Smith, Joshua D. Turner, Emily H. Stanaway, Ian B. Vernot, Benjamin Malig, Maika Baker, Carl Reilly, Beau 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 |
| author_facet |
O’Roak, Brian J. Vives, Laura Girirajan, Santhosh Karakoc, Emre Krumm, Nik Coe, Bradley P. Levy, Roie Ko, Arthur Lee, Choli Smith, Joshua D. Turner, Emily H. Stanaway, Ian B. Vernot, Benjamin Malig, Maika Baker, Carl Reilly, Beau Akey, Joshua M. Borenstein, Elhanan Rieder, Mark J. Nickerson, Deborah A. Bernier, Raphael Shendure, Jay Eichler, Evan E. |
| author_sort |
O’Roak, Brian J. |
| title |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| title_short |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| title_full |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| title_fullStr |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| title_full_unstemmed |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| title_sort |
sporadic autism exomes reveal a highly interconnected protein network of de novo mutations |
| description |
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 unknown1. 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 families2,3, we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported4. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19)4, for a total of 677 individual exomes from 209 families. Here we show 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 ASD5. Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling 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 suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics. |
| publishDate |
2012 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350576/ |
| _version_ |
1611529161216622592 |