Le séquençage ciblé identifie 91 gènes à risque de trouble neurodéveloppemental avec des biais sur l'autisme et le trouble développemental

Aperçu: G.M.

 Les mutations perturbatrices de gènes contribuent à la biologie des troubles neurodéveloppementaux (NDD), mais la plupart des gènes pathogènes apparentés ne sont pas connus. Nous avons séquencé 208 gènes candidats de> 11 730 cas et> 2 867 témoins. Nous avons identifié 91 gènes, dont 38 nouveaux gènes NDD, avec un excès de mutations de novo ou des mutations perturbatrices privées dans 5,7% des cas. 

Les tests fonctionnels de la drosophile ont révélé un sous-ensemble avec une participation accrue aux NDD. Nous avons identifié 25 gènes montrant un biais pour l'autisme par rapport au handicap intellectuel et a mis en évidence un réseau associé à un autisme à haut fonctionnement (QI >100).  

Le suivi clinique pour NAA15, KMT5B et ASH1L a mis en évidence de nouvelles formes de maladie syndromiques et non syndromiques.

Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.

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

Stessman HA¹, Xiong B^1,2, Coe BP¹, Wang T³, Hoekzema K¹, Fenckova M^4,5, Kvarnung M^6,7, Gerdts J⁸, Trinh S⁸, Cosemans N⁹, Vives L¹, Lin J¹, Turner TN¹, Santen G¹⁰, Ruivenkamp C¹⁰, Kriek M¹⁰, van Haeringen A¹⁰, Aten E¹⁰, Friend K^11,12, Liebelt J¹³, Barnett C¹³, Haan E^11,13, Shaw M¹¹, Gecz J^11,12,14, Anderlid BM^6,7, Nordgren A^6,7, Lindstrand A^6,7, Schwartz C¹⁵, Kooy RF¹⁶, Vandeweyer G¹⁶, Helsmoortel C¹⁶, Romano C¹⁷, Alberti A¹⁷, Vinci M¹⁸, Avola E¹⁷, Giusto S¹⁹, Courchesne E²⁰, Pramparo T²⁰, Pierce K²⁰, Nalabolu S²⁰, Amaral DG²¹, Scheffer IE^22,23,24, Delatycki MB^22,25,26, Lockhart PJ^22,26, Hormozdiari F²⁷, Harich B^4,5, Castells-Nobau A^4,5, Xia K³, Peeters H⁹, Nordenskjöld M^6,7, Schenck A^4,5, Bernier RA⁸, Eichler EE^1,28.

Author information

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.

PMID: 28191889

PMCID: PMC5374041  [Available on 2017-08-13]

DOI: 10.1038/ng.3792