Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Brian J. O'Roak; Pelagia Deriziotis; Choli Lee; Laura Vives; Jerrod J. Schwartz; Santhosh Girirajan; Emre Karakoc; Alexandra P. MacKenzie; Sarah B. Ng; Carl Baker; Mark J. Rieder; Deborah A. Nickerson; Raphael Bernier; Simon E. Fisher; Jay Shendure; Evan E. Eichler

doi:10.1038/ng.835

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Brian J. O'Roak, Pelagia Deriziotis, Choli Lee, Laura Vives, Jerrod J. Schwartz, Santhosh Girirajan, Emre Karakoc, Alexandra P. MacKenzie, Sarah B. Ng, Carl Baker, Mark J. Rieder, Deborah A. Nickerson, Raphael Bernier, Simon E. Fisher, Jay Shendure, Evan E. Eichler

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Abstract

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.

Original language	English (US)
Pages (from-to)	585-589
Number of pages	5
Journal	Nature genetics
Volume	43
Issue number	6
DOIs	https://doi.org/10.1038/ng.835
State	Published - Jun 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics

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O'Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., Karakoc, E., MacKenzie, A. P., Ng, S. B., Baker, C., Rieder, M. J., Nickerson, D. A., Bernier, R., Fisher, S. E., Shendure, J., & Eichler, E. E. (2011). Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature genetics, 43(6), 585-589. https://doi.org/10.1038/ng.835

O'Roak, BJ, Deriziotis, P, Lee, C, Vives, L, Schwartz, JJ, Girirajan, S, Karakoc, E, MacKenzie, AP, Ng, SB, Baker, C, Rieder, MJ, Nickerson, DA, Bernier, R, Fisher, SE, Shendure, J & Eichler, EE 2011, 'Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations', Nature genetics, vol. 43, no. 6, pp. 585-589. https://doi.org/10.1038/ng.835

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title = "Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations",

abstract = "Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.",

author = "O'Roak, {Brian J.} and Pelagia Deriziotis and Choli Lee and Laura Vives and Schwartz, {Jerrod J.} and Santhosh Girirajan and Emre Karakoc and MacKenzie, {Alexandra P.} and Ng, {Sarah B.} and Carl Baker and Rieder, {Mark J.} and Nickerson, {Deborah A.} and Raphael Bernier and Fisher, {Simon E.} and Jay Shendure and Eichler, {Evan E.}",

note = "Funding Information: We would like to thank and recognize the following ongoing studies that produced and provided exome variant calls for comparison: National Heart, Lung, and Blood Institute (NHBLI) Lung Cohort Sequencing Project (HL 1029230), NHLBI Women{\textquoteright}s Health Initiative (WHI) Sequencing Project (HL 102924), National Institute of Environmental Health Sciences (NIEHS) SNPs (HHSN273200800010C), NHLBI/ National Human Genome Research Institute (NHGRI) SeattleSeq (HL 094976), NHGRI Next Generation Mendelian Genetics (HG 005608) and the Northwest Genomics Center (HL 102926). We also thank M.C. King and S. Stray for processing and managing DNA samples, B.H. King and E. Bliss for their work in subject recruitment and phenotype collection, E. Turner, C. Igartua, I. Stanaway, M. Dennis and B. Coe for thoughtful discussions, M. State for providing SNP genotyping data and especially the families that volunteered their time to participate in this research. This work was supported by US National Institutes of Health grant HD065285 (E.E.E. and J.S.), Wellcome Trust core award 075491/Z/04 (S.E.F. and P.D.), the Max Planck Society (S.E.F.) and grants from the Simons Foundation Autism Research Initiative (SFARI) (191889, 137578 and 137593) (E.E.E., R.B., S.E.F. and P.D.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.",

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doi = "10.1038/ng.835",

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T1 - Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

AU - O'Roak, Brian J.

AU - Deriziotis, Pelagia

AU - Lee, Choli

AU - Vives, Laura

AU - Schwartz, Jerrod J.

AU - Girirajan, Santhosh

AU - Karakoc, Emre

AU - MacKenzie, Alexandra P.

AU - Ng, Sarah B.

AU - Baker, Carl

AU - Rieder, Mark J.

AU - Nickerson, Deborah A.

AU - Bernier, Raphael

AU - Fisher, Simon E.

AU - Shendure, Jay

AU - Eichler, Evan E.

N1 - Funding Information: We would like to thank and recognize the following ongoing studies that produced and provided exome variant calls for comparison: National Heart, Lung, and Blood Institute (NHBLI) Lung Cohort Sequencing Project (HL 1029230), NHLBI Women’s Health Initiative (WHI) Sequencing Project (HL 102924), National Institute of Environmental Health Sciences (NIEHS) SNPs (HHSN273200800010C), NHLBI/ National Human Genome Research Institute (NHGRI) SeattleSeq (HL 094976), NHGRI Next Generation Mendelian Genetics (HG 005608) and the Northwest Genomics Center (HL 102926). We also thank M.C. King and S. Stray for processing and managing DNA samples, B.H. King and E. Bliss for their work in subject recruitment and phenotype collection, E. Turner, C. Igartua, I. Stanaway, M. Dennis and B. Coe for thoughtful discussions, M. State for providing SNP genotyping data and especially the families that volunteered their time to participate in this research. This work was supported by US National Institutes of Health grant HD065285 (E.E.E. and J.S.), Wellcome Trust core award 075491/Z/04 (S.E.F. and P.D.), the Max Planck Society (S.E.F.) and grants from the Simons Foundation Autism Research Initiative (SFARI) (191889, 137578 and 137593) (E.E.E., R.B., S.E.F. and P.D.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.

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AB - Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.

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Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

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