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 B1,2, Coe BP1, Wang T3, Hoekzema K1, Fenckova M4,5, Kvarnung M6,7, Gerdts J8, Trinh S8, Cosemans N9, Vives L1, Lin J1, Turner TN1, Santen G10, Ruivenkamp C10, Kriek M10, van Haeringen A10, Aten E10, Friend K11,12, Liebelt J13, Barnett C13, Haan E11,13, Shaw M11, Gecz J11,12,14, Anderlid BM6,7, Nordgren A6,7, Lindstrand A6,7, 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 IE22,23,24, Delatycki MB22,25,26, Lockhart PJ22,26, Hormozdiari F27, Harich B4,5, Castells-Nobau A4,5, Xia K3, Peeters H9, Nordenskjöld M6,7, Schenck A4,5, Bernier RA8, Eichler EE1,28.
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
