Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Holly A.F. Stessman; Bo Xiong; Bradley P. Coe; Tianyun Wang; Kendra Hoekzema; Michaela Fenckova; Malin Kvarnung; Jennifer Gerdts; Sandy Trinh; Nele Cosemans; Laura Vives; Janice Lin; Tychele N. Turner; Gijs Santen; Claudia Ruivenkamp; Marjolein Kriek; Arie Van Haeringen; Emmelien Aten; Kathryn Friend; Jan Liebelt; Christopher Barnett; Eric Haan; Marie Shaw; Jozef Gecz; Britt Marie Anderlid; Ann Nordgren; Anna Lindstrand; Charles Schwartz; R. Frank Kooy; Geert Vandeweyer; Celine Helsmoortel; Corrado Romano; Antonino Alberti; Mirella Vinci; Emanuela Avola; Stefania Giusto; Eric Courchesne; Tiziano Pramparo; Karen Pierce; Srinivasa Nalabolu; David G. Amaral; Ingrid E. Scheffer; Martin B. Delatycki; Paul J. Lockhart; Fereydoun Hormozdiari; Benjamin Harich; Anna Castells-Nobau; Kun Xia; Hilde Peeters; Magnus Nordenskjöld; Annette Schenck; Raphael A. Bernier; Evan E. Eichler

doi:10.1038/ng.3792

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Holly A.F. Stessman, Bo Xiong, Bradley P. Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N. Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie Van Haeringen, Emmelien Aten, Kathryn Friend, Jan LiebeltChristopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R. Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G. Amaral, Ingrid E. Scheffer, Martin B. Delatycki, Paul J. Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A. Bernier, Evan E. Eichler

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Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Original language	English
Pages (from-to)	515-526
Number of pages	12
Journal	Nature Genetics
Volume	49
Issue number	4
DOIs	https://doi.org/10.1038/ng.3792
State	Published - Mar 30 2017

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Stessman, H. A. F., Xiong, B., Coe, B. P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T. N., Santen, G., Ruivenkamp, C., Kriek, M., Van Haeringen, A., Aten, E., Friend, K., ... Eichler, E. E. (2017). Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature Genetics, 49(4), 515-526. https://doi.org/10.1038/ng.3792

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title = "Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases",

abstract = "Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.",

author = "Stessman, {Holly A.F.} and Bo Xiong and Coe, {Bradley P.} and Tianyun Wang and Kendra Hoekzema and Michaela Fenckova and Malin Kvarnung and Jennifer Gerdts and Sandy Trinh and Nele Cosemans and Laura Vives and Janice Lin and Turner, {Tychele N.} and Gijs Santen and Claudia Ruivenkamp and Marjolein Kriek and {Van Haeringen}, Arie and Emmelien Aten and Kathryn Friend and Jan Liebelt and Christopher Barnett and Eric Haan and Marie Shaw and Jozef Gecz and Anderlid, {Britt Marie} and Ann Nordgren and Anna Lindstrand and Charles Schwartz and Kooy, {R. Frank} and Geert Vandeweyer and Celine Helsmoortel and Corrado Romano and Antonino Alberti and Mirella Vinci and Emanuela Avola and Stefania Giusto and Eric Courchesne and Tiziano Pramparo and Karen Pierce and Srinivasa Nalabolu and Amaral, {David G.} and Scheffer, {Ingrid E.} and Delatycki, {Martin B.} and Lockhart, {Paul J.} and Fereydoun Hormozdiari and Benjamin Harich and Anna Castells-Nobau and Kun Xia and Hilde Peeters and Magnus Nordenskj{\"o}ld and Annette Schenck and Bernier, {Raphael A.} and Eichler, {Evan E.}",

note = "Funding Information: This research was supported in part by the following: the Simons Foundation Autism Research Initiative (SFARI 303241) and NIH (R01MH101221) to E.E.E.; VIDI and TOP grants (917-96-346, 912-12-109) from the Netherlands Organization for Scientific Research and Horizon 2020 Marie SklodowskaCurie European Training Network (MiND, 643051)",

year = "2017",

month = mar,

day = "30",

doi = "10.1038/ng.3792",

language = "English",

volume = "49",

pages = "515--526",

journal = "Nature Genetics",

issn = "1061-4036",

number = "4",

}

Stessman, HAF, Xiong, B, Coe, BP, Wang, T, Hoekzema, K, Fenckova, M, Kvarnung, M, Gerdts, J, Trinh, S, Cosemans, N, Vives, L, Lin, J, Turner, TN, Santen, G, Ruivenkamp, C, Kriek, M, Van Haeringen, A, Aten, E, Friend, K, Liebelt, J, Barnett, C, Haan, E, Shaw, M, Gecz, J, Anderlid, BM, Nordgren, A, Lindstrand, A, Schwartz, C, Kooy, RF, Vandeweyer, G, Helsmoortel, C, Romano, C, Alberti, A, Vinci, M, Avola, E, Giusto, S, Courchesne, E, Pramparo, T, Pierce, K, Nalabolu, S, Amaral, DG, Scheffer, IE, Delatycki, MB, Lockhart, PJ, Hormozdiari, F, Harich, B, Castells-Nobau, A, Xia, K, Peeters, H, Nordenskjöld, M, Schenck, A, Bernier, RA & Eichler, EE 2017, 'Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases', Nature Genetics, vol. 49, no. 4, pp. 515-526. https://doi.org/10.1038/ng.3792

TY - JOUR

T1 - Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

AU - Stessman, Holly A.F.

AU - Xiong, Bo

AU - Coe, Bradley P.

AU - Wang, Tianyun

AU - Hoekzema, Kendra

AU - Fenckova, Michaela

AU - Kvarnung, Malin

AU - Gerdts, Jennifer

AU - Trinh, Sandy

AU - Cosemans, Nele

AU - Vives, Laura

AU - Lin, Janice

AU - Turner, Tychele N.

AU - Santen, Gijs

AU - Ruivenkamp, Claudia

AU - Kriek, Marjolein

AU - Van Haeringen, Arie

AU - Aten, Emmelien

AU - Friend, Kathryn

AU - Liebelt, Jan

AU - Barnett, Christopher

AU - Haan, Eric

AU - Shaw, Marie

AU - Gecz, Jozef

AU - Anderlid, Britt Marie

AU - Nordgren, Ann

AU - Lindstrand, Anna

AU - Schwartz, Charles

AU - Kooy, R. Frank

AU - Vandeweyer, Geert

AU - Helsmoortel, Celine

AU - Romano, Corrado

AU - Alberti, Antonino

AU - Vinci, Mirella

AU - Avola, Emanuela

AU - Giusto, Stefania

AU - Courchesne, Eric

AU - Pramparo, Tiziano

AU - Pierce, Karen

AU - Nalabolu, Srinivasa

AU - Amaral, David G.

AU - Scheffer, Ingrid E.

AU - Delatycki, Martin B.

AU - Lockhart, Paul J.

AU - Hormozdiari, Fereydoun

AU - Harich, Benjamin

AU - Castells-Nobau, Anna

AU - Xia, Kun

AU - Peeters, Hilde

AU - Nordenskjöld, Magnus

AU - Schenck, Annette

AU - Bernier, Raphael A.

AU - Eichler, Evan E.

N1 - Funding Information: This research was supported in part by the following: the Simons Foundation Autism Research Initiative (SFARI 303241) and NIH (R01MH101221) to E.E.E.; VIDI and TOP grants (917-96-346, 912-12-109) from the Netherlands Organization for Scientific Research and Horizon 2020 Marie SklodowskaCurie European Training Network (MiND, 643051)

PY - 2017/3/30

Y1 - 2017/3/30

N2 - Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

AB - Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

UR - http://www.scopus.com/inward/record.url?scp=85012302367&partnerID=8YFLogxK

U2 - 10.1038/ng.3792

DO - 10.1038/ng.3792

M3 - Article

C2 - 28191889

AN - SCOPUS:85012302367

SN - 1061-4036

VL - 49

SP - 515

EP - 526

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

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