Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Timothy W. Yu; Maria H. Chahrour; Michael E. Coulter; Sarn Jiralerspong; Kazuko Okamura-Ikeda; Bulent Ataman; Klaus Schmitz-Abe; David A. Harmin; Mazhar Adli; Athar N. Malik; Alissa M. D'Gama; Elaine T. Lim; Stephan J. Sanders; Ganesh H. Mochida; Jennifer N. Partlow; Christine M. Sunu; Jillian M. Felie; Jacqueline Rodriguez; Ramzi H. Nasir; Janice Ware; Robert M. Joseph; R. Sean Hill; Benjamin Y. Kwan; Muna Al-Saffar; Nahit M. Mukaddes; Asif Hashmi; Soher Balkhy; Generoso G. Gascon; Fuki M. Hisama; Elaine LeClair; Annapurna Poduri; Ozgur Oner; Samira Al-Saad; Sadika A. Al-Awadi; Laila Bastaki; Tawfeg Ben-Omran; Ahmad S. Teebi; Lihadh Al-Gazali; Valsamma Eapen; Christine R. Stevens; Leonard Rappaport; Stacey B. Gabriel; Kyriacos Markianos; Matthew W. State; Michael E. Greenberg; Hisaaki Taniguchi; Nancy E. Braverman; Eric M. Morrow; Christopher A. Walsh

doi:10.1016/j.neuron.2012.11.002

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Timothy W. Yu, Maria H. Chahrour, Michael E. Coulter, Sarn Jiralerspong, Kazuko Okamura-Ikeda, Bulent Ataman, Klaus Schmitz-Abe, David A. Harmin, Mazhar Adli, Athar N. Malik, Alissa M. D'Gama, Elaine T. Lim, Stephan J. Sanders, Ganesh H. Mochida, Jennifer N. Partlow, Christine M. Sunu, Jillian M. Felie, Jacqueline Rodriguez, Ramzi H. Nasir, Janice WareRobert M. Joseph, R. Sean Hill, Benjamin Y. Kwan, Muna Al-Saffar, Nahit M. Mukaddes, Asif Hashmi, Soher Balkhy, Generoso G. Gascon, Fuki M. Hisama, Elaine LeClair, Annapurna Poduri, Ozgur Oner, Samira Al-Saad, Sadika A. Al-Awadi, Laila Bastaki, Tawfeg Ben-Omran, Ahmad S. Teebi, Lihadh Al-Gazali, Valsamma Eapen, Christine R. Stevens, Leonard Rappaport, Stacey B. Gabriel, Kyriacos Markianos, Matthew W. State, Michael E. Greenberg, Hisaaki Taniguchi, Nancy E. Braverman, Eric M. Morrow, Christopher A. Walsh

Research output: Contribution to journal › Article › peer-review

325 Citations (Scopus)

Abstract

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Original language	English
Pages (from-to)	259-273
Number of pages	15
Journal	Neuron
Volume	77
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2012.11.002
Publication status	Published - Jan 23 2013

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2012.11.002

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Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., D'Gama, A. M., Lim, E. T., Sanders, S. J., Mochida, G. H., Partlow, J. N., Sunu, C. M., Felie, J. M., Rodriguez, J., Nasir, R. H., ... Walsh, C. A. (2013). Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron, 77(2), 259-273. https://doi.org/10.1016/j.neuron.2012.11.002

Yu, TW, Chahrour, MH, Coulter, ME, Jiralerspong, S, Okamura-Ikeda, K, Ataman, B, Schmitz-Abe, K, Harmin, DA, Adli, M, Malik, AN, D'Gama, AM, Lim, ET, Sanders, SJ, Mochida, GH, Partlow, JN, Sunu, CM, Felie, JM, Rodriguez, J, Nasir, RH, Ware, J, Joseph, RM, Hill, RS, Kwan, BY, Al-Saffar, M, Mukaddes, NM, Hashmi, A, Balkhy, S, Gascon, GG, Hisama, FM, LeClair, E, Poduri, A, Oner, O, Al-Saad, S, Al-Awadi, SA, Bastaki, L, Ben-Omran, T, Teebi, AS, Al-Gazali, L, Eapen, V, Stevens, CR, Rappaport, L, Gabriel, SB, Markianos, K, State, MW, Greenberg, ME, Taniguchi, H, Braverman, NE, Morrow, EM & Walsh, CA 2013, 'Using Whole-Exome Sequencing to Identify Inherited Causes of Autism', Neuron, vol. 77, no. 2, pp. 259-273. https://doi.org/10.1016/j.neuron.2012.11.002

@article{28a0281e30904a8bbf14e2dc0beb0e4d,

title = "Using Whole-Exome Sequencing to Identify Inherited Causes of Autism",

abstract = "Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.",

author = "Yu, {Timothy W.} and Chahrour, {Maria H.} and Coulter, {Michael E.} and Sarn Jiralerspong and Kazuko Okamura-Ikeda and Bulent Ataman and Klaus Schmitz-Abe and Harmin, {David A.} and Mazhar Adli and Malik, {Athar N.} and D'Gama, {Alissa M.} and Lim, {Elaine T.} and Sanders, {Stephan J.} and Mochida, {Ganesh H.} and Partlow, {Jennifer N.} and Sunu, {Christine M.} and Felie, {Jillian M.} and Jacqueline Rodriguez and Nasir, {Ramzi H.} and Janice Ware and Joseph, {Robert M.} and Hill, {R. Sean} and Kwan, {Benjamin Y.} and Muna Al-Saffar and Mukaddes, {Nahit M.} and Asif Hashmi and Soher Balkhy and Gascon, {Generoso G.} and Hisama, {Fuki M.} and Elaine LeClair and Annapurna Poduri and Ozgur Oner and Samira Al-Saad and Al-Awadi, {Sadika A.} and Laila Bastaki and Tawfeg Ben-Omran and Teebi, {Ahmad S.} and Lihadh Al-Gazali and Valsamma Eapen and Stevens, {Christine R.} and Leonard Rappaport and Gabriel, {Stacey B.} and Kyriacos Markianos and State, {Matthew W.} and Greenberg, {Michael E.} and Hisaaki Taniguchi and Braverman, {Nancy E.} and Morrow, {Eric M.} and Walsh, {Christopher A.}",

note = "Funding Information: We are grateful to Ed Gilmore, Chiara Manzini, Jenny Yang, and Mark Daly for stimulating discussions and helpful comments on the manuscript and Thomas Lehner for support from the National Institute of Mental Health (NIMH). We are also grateful for the participation of the many families that enrolled in our studies as well as for the collaborative support of the Kuwait Center for Autism and the Dubai Autism Center. T.W.Y. was supported by a National Institute of Health (NIH) T32 grant (T32 NS007484-08), the Clinical Investigator Training Program (CITP) at Harvard-MIT Health Sciences and Technology and Beth Israel Deaconess Medical Center in collaboration with Pfizer, Inc. and Merck and Company, Inc., and the Nancy Lurie Marks Junior Faculty MeRIT Fellowship. M.H.C. was supported by a NIH T32 grant (T32 NS007473-12). G.H.M. was supported by the Young Investigator Award of NARSAD as a NARSAD Lieber Investigator. A.P. was supported by the National Institutes of Neurological Disease and Stroke (K23NS069784). A.M.D. was supported by the National Institute of General Medical Sciences (T32GM07753). Research was supported by grants from the National Institute of Mental Health (RO1 MH083565; 1RC2MH089952) to C.A.W., the NIH to M.E.G. (RO1 NS048276), the NIMH to E.M.M. (1K23MH080954-01), the Dubai Harvard Foundation for Medical Research, the Nancy Lurie Marks Foundation, the Simons Foundation, the Autism Consortium, and the Manton Center for Orphan Disease Research. Sequencing at the Broad Institute was supported by the ARRA Grand Opportunities grant 1RC2MH089952. C.A.W. is an Investigator of the Howard Hughes Medical Institute. T.W.Y. identified AMT, PEX7, and SYNE1 mutations, helped design AMT and PEX7 functional studies, designed and performed exome sequencing analyses for candidate genes, contributed to CNV analyses, and wrote the manuscript. M.H.C. designed and performed exome sequencing analyses for candidate genes, analyzed Sanger validation data and SSC exome data, and wrote the manuscript. M.E.C. helped analyze AU-1700 and AU-3500. S.J. designed PEX7 functional experiments with N.E.B., and S.J. performed them. K.O.-I. designed and performed AMT functional studies and analyzed results. B.A. designed and analyzed RNAseq, ChIPseq, and qPCR experiments. D.A.H. analyzed RNAseq and qPCR experiments. M.A. performed ChIPseq experiments, and A.N.M. analyzed the data. A.M.D. performed RACE experiments for SYNE1. K.S.-A. and K.M. designed the CNV analysis, and K.S.-A. compiled the CNV catalog and identified pathogenic CNVs. E.T.L. and S.J.S. helped analyze SSC whole-exome data. G.H.M. performed clinical phenotyping of Middle Eastern families as well as detailed molecular analyses of AU-8600. J.N.P. organized clinical information and patient samples. C.M.S. assisted with exome sequencing analyses and performed follow-up Sanger validation. J.M.F. and J.R. performed follow-up Sanger validation. R.H.N. performed clinical phenotyping of AU-17800. J.W performed clinical phenotyping of AU-17700 and AU-17800. R.M.J. performed clinical phenotyping of AU-1600, AU-10000, and AU-10200. R.S.H. performed genome-wide linkage studies and homozygosity analyses. B.Y.K. assisted with characterization of the AMT mutation. M.A.-S. organized clinical information and patient samples and referred AU-17700 and AU-17800. N.M.M. referred and clinically characterized AU-4200, AU-4400, AU-4900, AU-5700, AU-6100, AU-6200, AU-6300, AU-8600, AU-11100, AU-11800, AU-11900, AU-12100, AU-12400, AU-14900, AU-15800, AU-16700, AU-20700, AU-22500, AU-23400, and AU-24300. A.H. referred and characterized AU-3500 and AU-3600. S.B. referred and characterized AU-1700. G.G. referred and characterized AU-1700, AU-3100, AU-4100, and AU-6000. F.M.H. helped characterize AU-17700 and AU-17800. E.L. and A.P. performed clinical phenotyping of AU-1600, AU-10000, and AU-10200. O.O. referred and characterized AU-13100, AU-13400, AU-18000, AU-20300, and AU-22000. S.A.-S., S.A.A.-A., and L.B. referred and characterized AU-1600. S.A.-S. referred and characterized AU-9600. T.B.-O. and A.S.T. referred and characterized AU-21100. L.A.-G. and V.E. referred and characterized AU-3200. C.R.S. organized and coordinated exome sequencing. L.R. evaluated the second compound heterozygous PEX7 family. S.B.G. directed exome sequencing. K.M. designed the CNV analysis. M.W.S. oversaw SSC exome analyses. M.E.G. oversaw SYNE1 RNAseq and qPCR experiments. H.T. designed and performed AMT functional experiments. N.E.B. designed PEX7 functional experiments, recruited the nonconsanguineous family with two sisters affected by PEX7 mutation, and contributed to interpretation of PEX7 sequencing data. E.M.M. helped characterize AU-1700, performed linkage studies on AU-1600, AU-1700, and AU-3500, helped design the exome sequencing experiment, and contributed to finding the SYNE1 mutation. C.A.W. directed the overall research and wrote the manuscript. ",

year = "2013",

month = jan,

day = "23",

doi = "10.1016/j.neuron.2012.11.002",

language = "English",

volume = "77",

pages = "259--273",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

AU - Yu, Timothy W.

AU - Chahrour, Maria H.

AU - Coulter, Michael E.

AU - Jiralerspong, Sarn

AU - Okamura-Ikeda, Kazuko

AU - Ataman, Bulent

AU - Schmitz-Abe, Klaus

AU - Harmin, David A.

AU - Adli, Mazhar

AU - Malik, Athar N.

AU - D'Gama, Alissa M.

AU - Lim, Elaine T.

AU - Sanders, Stephan J.

AU - Mochida, Ganesh H.

AU - Partlow, Jennifer N.

AU - Sunu, Christine M.

AU - Felie, Jillian M.

AU - Rodriguez, Jacqueline

AU - Nasir, Ramzi H.

AU - Ware, Janice

AU - Joseph, Robert M.

AU - Hill, R. Sean

AU - Kwan, Benjamin Y.

AU - Al-Saffar, Muna

AU - Mukaddes, Nahit M.

AU - Hashmi, Asif

AU - Balkhy, Soher

AU - Gascon, Generoso G.

AU - Hisama, Fuki M.

AU - LeClair, Elaine

AU - Poduri, Annapurna

AU - Oner, Ozgur

AU - Al-Saad, Samira

AU - Al-Awadi, Sadika A.

AU - Bastaki, Laila

AU - Ben-Omran, Tawfeg

AU - Teebi, Ahmad S.

AU - Al-Gazali, Lihadh

AU - Eapen, Valsamma

AU - Stevens, Christine R.

AU - Rappaport, Leonard

AU - Gabriel, Stacey B.

AU - Markianos, Kyriacos

AU - State, Matthew W.

AU - Greenberg, Michael E.

AU - Taniguchi, Hisaaki

AU - Braverman, Nancy E.

AU - Morrow, Eric M.

AU - Walsh, Christopher A.

N1 - Funding Information: We are grateful to Ed Gilmore, Chiara Manzini, Jenny Yang, and Mark Daly for stimulating discussions and helpful comments on the manuscript and Thomas Lehner for support from the National Institute of Mental Health (NIMH). We are also grateful for the participation of the many families that enrolled in our studies as well as for the collaborative support of the Kuwait Center for Autism and the Dubai Autism Center. T.W.Y. was supported by a National Institute of Health (NIH) T32 grant (T32 NS007484-08), the Clinical Investigator Training Program (CITP) at Harvard-MIT Health Sciences and Technology and Beth Israel Deaconess Medical Center in collaboration with Pfizer, Inc. and Merck and Company, Inc., and the Nancy Lurie Marks Junior Faculty MeRIT Fellowship. M.H.C. was supported by a NIH T32 grant (T32 NS007473-12). G.H.M. was supported by the Young Investigator Award of NARSAD as a NARSAD Lieber Investigator. A.P. was supported by the National Institutes of Neurological Disease and Stroke (K23NS069784). A.M.D. was supported by the National Institute of General Medical Sciences (T32GM07753). Research was supported by grants from the National Institute of Mental Health (RO1 MH083565; 1RC2MH089952) to C.A.W., the NIH to M.E.G. (RO1 NS048276), the NIMH to E.M.M. (1K23MH080954-01), the Dubai Harvard Foundation for Medical Research, the Nancy Lurie Marks Foundation, the Simons Foundation, the Autism Consortium, and the Manton Center for Orphan Disease Research. Sequencing at the Broad Institute was supported by the ARRA Grand Opportunities grant 1RC2MH089952. C.A.W. is an Investigator of the Howard Hughes Medical Institute. T.W.Y. identified AMT, PEX7, and SYNE1 mutations, helped design AMT and PEX7 functional studies, designed and performed exome sequencing analyses for candidate genes, contributed to CNV analyses, and wrote the manuscript. M.H.C. designed and performed exome sequencing analyses for candidate genes, analyzed Sanger validation data and SSC exome data, and wrote the manuscript. M.E.C. helped analyze AU-1700 and AU-3500. S.J. designed PEX7 functional experiments with N.E.B., and S.J. performed them. K.O.-I. designed and performed AMT functional studies and analyzed results. B.A. designed and analyzed RNAseq, ChIPseq, and qPCR experiments. D.A.H. analyzed RNAseq and qPCR experiments. M.A. performed ChIPseq experiments, and A.N.M. analyzed the data. A.M.D. performed RACE experiments for SYNE1. K.S.-A. and K.M. designed the CNV analysis, and K.S.-A. compiled the CNV catalog and identified pathogenic CNVs. E.T.L. and S.J.S. helped analyze SSC whole-exome data. G.H.M. performed clinical phenotyping of Middle Eastern families as well as detailed molecular analyses of AU-8600. J.N.P. organized clinical information and patient samples. C.M.S. assisted with exome sequencing analyses and performed follow-up Sanger validation. J.M.F. and J.R. performed follow-up Sanger validation. R.H.N. performed clinical phenotyping of AU-17800. J.W performed clinical phenotyping of AU-17700 and AU-17800. R.M.J. performed clinical phenotyping of AU-1600, AU-10000, and AU-10200. R.S.H. performed genome-wide linkage studies and homozygosity analyses. B.Y.K. assisted with characterization of the AMT mutation. M.A.-S. organized clinical information and patient samples and referred AU-17700 and AU-17800. N.M.M. referred and clinically characterized AU-4200, AU-4400, AU-4900, AU-5700, AU-6100, AU-6200, AU-6300, AU-8600, AU-11100, AU-11800, AU-11900, AU-12100, AU-12400, AU-14900, AU-15800, AU-16700, AU-20700, AU-22500, AU-23400, and AU-24300. A.H. referred and characterized AU-3500 and AU-3600. S.B. referred and characterized AU-1700. G.G. referred and characterized AU-1700, AU-3100, AU-4100, and AU-6000. F.M.H. helped characterize AU-17700 and AU-17800. E.L. and A.P. performed clinical phenotyping of AU-1600, AU-10000, and AU-10200. O.O. referred and characterized AU-13100, AU-13400, AU-18000, AU-20300, and AU-22000. S.A.-S., S.A.A.-A., and L.B. referred and characterized AU-1600. S.A.-S. referred and characterized AU-9600. T.B.-O. and A.S.T. referred and characterized AU-21100. L.A.-G. and V.E. referred and characterized AU-3200. C.R.S. organized and coordinated exome sequencing. L.R. evaluated the second compound heterozygous PEX7 family. S.B.G. directed exome sequencing. K.M. designed the CNV analysis. M.W.S. oversaw SSC exome analyses. M.E.G. oversaw SYNE1 RNAseq and qPCR experiments. H.T. designed and performed AMT functional experiments. N.E.B. designed PEX7 functional experiments, recruited the nonconsanguineous family with two sisters affected by PEX7 mutation, and contributed to interpretation of PEX7 sequencing data. E.M.M. helped characterize AU-1700, performed linkage studies on AU-1600, AU-1700, and AU-3500, helped design the exome sequencing experiment, and contributed to finding the SYNE1 mutation. C.A.W. directed the overall research and wrote the manuscript.

PY - 2013/1/23

Y1 - 2013/1/23

N2 - Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

AB - Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

UR - http://www.scopus.com/inward/record.url?scp=84872696957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872696957&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2012.11.002

DO - 10.1016/j.neuron.2012.11.002

M3 - Article

C2 - 23352163

AN - SCOPUS:84872696957

SN - 0896-6273

VL - 77

SP - 259

EP - 273

JO - Neuron

JF - Neuron

IS - 2

ER -

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

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