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

Holly 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 & 33 others 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

Research output: Contribution to journalArticle

84 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)515-526
Number of pages12
JournalNature Genetics
Volume49
Issue number4
DOIs
StatePublished - Mar 30 2017

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Developmental Disabilities
Autistic Disorder
Genes
Mutation
Intellectual Disability
Drosophila
Neurodevelopmental Disorders

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. / Stessman, Holly; Xiong, Bo; Coe, Bradley P.; Wang, Tianyun; Hoekzema, Kendra; Fenckova, Michaela; Kvarnung, Malin; Gerdts, Jennifer; Trinh, Sandy; Cosemans, Nele; Vives, Laura; Lin, Janice; Turner, Tychele N.; Santen, Gijs; Ruivenkamp, Claudia; Kriek, Marjolein; Van Haeringen, Arie; Aten, Emmelien; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Haan, Eric; Shaw, Marie; Gecz, Jozef; Anderlid, Britt Marie; Nordgren, Ann; Lindstrand, Anna; Schwartz, Charles; Kooy, R. Frank; Vandeweyer, Geert; Helsmoortel, Celine; Romano, Corrado; Alberti, Antonino; Vinci, Mirella; Avola, Emanuela; Giusto, Stefania; Courchesne, Eric; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Amaral, David G.; Scheffer, Ingrid E.; Delatycki, Martin B.; Lockhart, Paul J.; Hormozdiari, Fereydoun; Harich, Benjamin; Castells-Nobau, Anna; Xia, Kun; Peeters, Hilde; Nordenskjöld, Magnus; Schenck, Annette; Bernier, Raphael A.; Eichler, Evan E.

In: Nature Genetics, Vol. 49, No. 4, 30.03.2017, p. 515-526.

Research output: Contribution to journalArticle

Stessman, H, 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
Stessman, Holly ; Xiong, Bo ; Coe, Bradley P. ; Wang, Tianyun ; Hoekzema, Kendra ; Fenckova, Michaela ; Kvarnung, Malin ; Gerdts, Jennifer ; Trinh, Sandy ; Cosemans, Nele ; Vives, Laura ; Lin, Janice ; Turner, Tychele N. ; Santen, Gijs ; Ruivenkamp, Claudia ; Kriek, Marjolein ; Van Haeringen, Arie ; Aten, Emmelien ; Friend, Kathryn ; Liebelt, Jan ; Barnett, Christopher ; Haan, Eric ; Shaw, Marie ; Gecz, Jozef ; Anderlid, Britt Marie ; Nordgren, Ann ; Lindstrand, Anna ; Schwartz, Charles ; Kooy, R. Frank ; Vandeweyer, Geert ; Helsmoortel, Celine ; Romano, Corrado ; Alberti, Antonino ; Vinci, Mirella ; Avola, Emanuela ; Giusto, Stefania ; Courchesne, Eric ; Pramparo, Tiziano ; Pierce, Karen ; Nalabolu, Srinivasa ; Amaral, David G. ; Scheffer, Ingrid E. ; Delatycki, Martin B. ; Lockhart, Paul J. ; Hormozdiari, Fereydoun ; Harich, Benjamin ; Castells-Nobau, Anna ; Xia, Kun ; Peeters, Hilde ; Nordenskjöld, Magnus ; Schenck, Annette ; Bernier, Raphael A. ; Eichler, Evan E. / Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. In: Nature Genetics. 2017 ; Vol. 49, No. 4. pp. 515-526.
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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.",
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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

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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.

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AU - Delatycki, Martin B.

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AU - Harich, Benjamin

AU - Castells-Nobau, Anna

AU - Xia, Kun

AU - Peeters, Hilde

AU - Nordenskjöld, Magnus

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