The contribution of de novo coding mutations to autism spectrum disorder

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. © 2014 Macmillan Publishers Limited. All rights reserved.

Yazar Iossifov I.
O'Roak B.J.
Sanders S.J.
Ronemus M.
Krumm N.
Levy D.
Stessman H.A.
Yayın Türü Article
Tek Biçim Adres https://hdl.handle.net/20.500.12628/7885
Tek Biçim Adres 10.1038/nature13908
Koleksiyonlar Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed | SOBİAD
Scopus İndeksli Yayınlar Koleksiyonu
WoS İndeksli Yayınlar Koleksiyonu
Dergi Adı Nature
Dergi Cilt Bilgisi 515
Dergi Sayısı 7526
Sayfalar 216 - 221
Yayın Yılı 2014
Eser Adı
[dc.title]
The contribution of de novo coding mutations to autism spectrum disorder
Yazar
[dc.contributor.author]
Iossifov I.
Yazar
[dc.contributor.author]
O'Roak B.J.
Yazar
[dc.contributor.author]
Sanders S.J.
Yazar
[dc.contributor.author]
Ronemus M.
Yazar
[dc.contributor.author]
Krumm N.
Yazar
[dc.contributor.author]
Levy D.
Yazar
[dc.contributor.author]
Stessman H.A.
Yayın Yılı
[dc.date.issued]
2014
Yayıncı
[dc.publisher]
Nature Publishing Group
Yayın Türü
[dc.type]
article
Özet
[dc.description.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. © 2014 Macmillan Publishers Limited. All rights reserved.
Kayıt Giriş Tarihi
[dc.date.accessioned]
2019-12-23
Açık Erişim Tarihi
[dc.date.available]
2019-12-23
Yayın Dili
[dc.language.iso]
eng
Haklar
[dc.rights]
info:eu-repo/semantics/closedAccess
ISSN
[dc.identifier.issn]
0028-0836
Sponsor YAYINCI
[dc.description.sponsorship]
National Institutes of Health: P30CA016359 National Institutes of Health: R01MH101221 National Institutes of Health: RC2HL102923 National Institutes of Health: RC2HL102924 National Institutes of Health: RC2HL102925 National Institutes of Health: RC2HL102926 National Institutes of Health: RC2HL103010 National Institutes of Health: T32GM007266 National Institutes of Health: U54HD083091 National Institutes of Health: UC2HL102923 National Institutes of Health: UC2HL102924 National Institutes of Health: UC2HL102925 National Institutes of Health: UC2HL102926 National Institutes of Health: UC2HL103010 National Institutes of Health: UL1TR000142
İlk Sayfa Sayısı
[dc.identifier.startpage]
216
Son Sayfa Sayısı
[dc.identifier.endpage]
221
Dergi Adı
[dc.relation.journal]
Nature
Dergi Sayısı
[dc.identifier.issue]
7526
Dergi Cilt Bilgisi
[dc.identifier.volume]
515
Tek Biçim Adres
[dc.identifier.uri]
https://dx.doi.org/10.1038/nature13908
Tek Biçim Adres
[dc.identifier.uri]
https://hdl.handle.net/20.500.12628/7885
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targets affected mutations contribute females mutation overlap significantly simplex diagnoses missense number estimate intelligence higher overlaps quotient neither reserved rights Limited Publishers Macmillan latter significance expressed overlapping embryonically FMRP-associated modifiers chromatin enriched schizophrenia disability intellectual
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