Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases PMID: 28191889

Target-related Cytokines

2026-09-23

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

Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792.

Holly A F Stessman ¹ , Bo Xiong ¹ ² , Bradley P Coe ¹ , Tianyun Wang ³ , Kendra Hoekzema ¹ , Michaela Fenckova ⁴ ⁵ , Malin Kvarnung ⁶ ⁷ , Jennifer Gerdts ⁸ , Sandy Trinh ⁸ , Nele Cosemans ⁹ , Laura Vives ¹ , Janice Lin ¹ , Tychele N Turner ¹ , Gijs Santen ¹⁰ , Claudia Ruivenkamp ¹⁰ , Marjolein Kriek ¹⁰ , Arie van Haeringen ¹⁰ , Emmelien Aten ¹⁰ , Kathryn Friend ¹¹ ¹² , Jan Liebelt ¹³ , Christopher Barnett ¹³ , Eric Haan ¹¹ ¹³ , Marie Shaw ¹¹ , Jozef Gecz ¹¹ ¹² ¹⁴ , Britt-Marie Anderlid ⁶ ⁷ , Ann Nordgren ⁶ ⁷ , Anna Lindstrand ⁶ ⁷ , Charles Schwartz ¹⁵ , R Frank Kooy ¹⁶ , Geert Vandeweyer ¹⁶ , Celine Helsmoortel ¹⁶ , Corrado Romano ¹⁷ , Antonino Alberti ¹⁷ , Mirella Vinci ¹⁸ , Emanuela Avola ¹⁷ , Stefania Giusto ¹⁹ , Eric Courchesne ²⁰ , Tiziano Pramparo ²⁰ , Karen Pierce ²⁰ , Srinivasa Nalabolu ²⁰ , David G Amaral ²¹ , Ingrid E Scheffer ²² ²³ ²⁴ , Martin B Delatycki ²² ²⁵ ²⁶ , Paul J Lockhart ²² ²⁶ , Fereydoun Hormozdiari ²⁷ , Benjamin Harich ⁴ ⁵ , Anna Castells-Nobau ⁴ ⁵ , Kun Xia ³ , Hilde Peeters ⁹ , Magnus Nordenskjöld ⁶ ⁷ , Annette Schenck ⁴ ⁵ , Raphael A Bernier ⁸ , Evan E Eichler ¹ ²⁸

Affiliations

1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
2. Department of Forensic Medicine and Institute of Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3. State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
4. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
5. Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
6. Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
7. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
8. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
9. Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium.
10. Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
11. School of Medicine and the Robinson Research Institute, the University of Adelaide at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
12. Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
13. South Australian Clinical Genetics Service, SA Pathology (at the Women's and Children's Hospital), Adelaide, South Australia, Australia.
14. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
15. Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, South Carolina, USA.
16. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
17. Unit of Pediatrics &Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
18. Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
19. Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
20. Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, California, USA.
21. MIND Institute and the University of California Davis School of Medicine, Sacramento, California, USA.
22. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
23. Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
24. Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
25. Victorian Clinical Genetics Services, Parkville, Victoria, Australia.
26. Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
27. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, California, USA.
28. Howard Hughes Medical Institute, Seattle, Washington, USA.

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.