Génétique du trouble du spectre de l'autisme

Aperçu: G.M.

Le " trouble du spectre de l'autisme" (TSA) est un trouble neurodéveloppemental prévalent caractérisé par une interaction sociale altérée et des comportements stéréotypés. Les TSA ont une composante génétique forte et complexe, avec de multiples profils d'hérédité familiale et une estimation de jusqu'à 1000 gènes potentiellement impliqués. Au cours de la dernière décennie, les technologies génomiques ont permis des progrès rapides dans l'identification des gènes à risque pour les TSA. Dans ce chapitre, les chercheurs examinent la délinéation des gènes du trouble à partir d'études génétiques traditionnelles telles que le lien et l'association, puis ils se focalisent sur des études plus récentes utilisant des technologies génomiques telles que le génotypage à haut débit et le séquençage d'exome.

Handb Clin Neurol. 2018;147:321-329. doi: 10.1016/B978-0-444-63233-3.00021-X.

Genetics of autism spectrum disorder

Ramaswami G¹, Geschwind DH².

Author information

1

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.

2

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States. Electronic address: dhg@mednet.ucla.edu.

Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impaired social interaction and stereotyped behaviors. ASD has a strong and complex genetic component, with multiple familial inheritance patterns and an estimate of up to 1000 genes potentially implicated. Over the past decade, genomic technologies have enabled rapid progress in the identification of risk genes for ASD. In this chapter, we review the delineation of ASD disease genes starting from traditional genetic studies such as linkage and association, and then focusing on more recent studies utilizing genomic technologies, such as high-throughput genotyping and exome sequencing.

PMID:29325621

DOI:10.1016/B978-0-444-63233-3.00021-X

Le Yin et Yang de la génétique de l'autisme: comment des variations de novo rares et des variantes communes affectent l'implication

Aperçu: G.M.

L'étiologie du trouble du spectre de l'autisme (TSA) est complexe, impliquant à la fois des contributions génétiques et environnementales et une implication individuelle et au niveau de la population.

Les premiers chercheurs ont émis l'hypothèse que les ASD proviennent d'un héritage polygénique, mais les résultats ultérieurs, tels que l'identification de mutations dans certains gènes qui sont responsables des syndromes associés à la TSA, ont amené d'autres à proposer que les mutations de novo d'effet majeur représenteraient la plupart des cas.

Le développement des techniques de génotypage et de séquençage à l'échelle du génome a entraîné des progrès remarquables dans notre compréhension de l'architecture génétique du risque de TSA. Les résultats combinés de la recherche fournissent des preuves solides que la TSA est un trouble polygénique complexe. Les variations de novo rares et  héritées agissent dans le contexte d'une charge génétique variante commune, et cette charge représente la plus grande partie de l'implication dans le TSA.   

Annu Rev Genomics Hum Genet. 2017 Apr 19. doi: 10.1146/annurev-genom-083115-022647.

The Yin and Yang of Autism Genetics: How Rare De Novo and Common Variations Affect Liability

Chaste P^1,2, Roeder K³, Devlin B⁴.

Author information

1

Centre de Psychiatrie et Neurosciences, 75014 Paris, France.

2

Centre hospitalier Sainte-Anne, 75674 Paris, France; email: p.chaste@ch-sainte-anne.fr

3

Department of Statistics and Department of Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213; email: roeder@andrew.cmu.edu.

4

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; email: devlinbj@upmc.edu.

Abstract

The etiology of autism spectrum disorder (ASD) is complex, involving both genetic and environmental contributions to individual and population-level liability. Early researchers hypothesized that ASD arises from polygenic inheritance, but later results, such as the identification of mutations in certain genes that are responsible for syndromes associated with ASD, led others to propose that de novo mutations of major effect would account for most cases. This yin and yang of monogenic causes and polygenic inheritance continues to this day. The development of genome-wide genotyping and sequencing techniques has resulted in remarkable advances in our understanding of the genetic architecture of risk for ASD. The combined research findings provide solid evidence that ASD is a complex polygenic disorder. Rare de novo and inherited variations act within the context of a common-variant genetic load, and this load accounts for the largest portion of ASD liability. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 18 is August 31, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 28426285

DOI: 10.1146/annurev-genom-083115-022647

Affiner le rôle des variants de tronc de protéine de novo dans les troubles du développement neurologique en utilisant des échantillons de référence de population

Aperçu: G.M.

Des recherches récentes ont révélé un rôle important pour la variation de novo dans les troubles du développement neurologique. En utilisant des données agrégées provenant de 9 246 familles avec un trouble du spectre de l'autisme, un handicap intellectuel ou un retard de développement, les chercheurs ont constaté que ~ 1/3 des variants de novo sont indépendamment présents en tant que variation permanente dans la cohorte du Consortium d'agrégation Exome de 60 706 adultes et ces variantes de novo ne contribuent pas au risque de développement neurologique.

Ces résultats illustrent l'importance des cohortes de référence fondées sur la population pour l'interprétation des variants pathogènes candidates, même pour les analyses de troubles complexes et les variations de novo.

Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples

Kosmicki JA^1,2,3,4,5, Samocha KE^1,2,3,5, Howrigan DP^1,2,3, Sanders SJ⁶, Slowikowski K^2,4,7,8, Lek M^1,2, Karczewski KJ^1,2, Cutler DJ⁹, Devlin B¹⁰, Roeder K¹¹, Buxbaum JD^{12,13,14,15,16,17}, Neale BM^1,2,3, MacArthur DG^1,2, Wall DP¹⁸, Robinson EB^1,2,3, Daly MJ^1,2,3.

Author information

1

Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

2

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

3

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

4

Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.

5

Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

6

Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.

7

Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

8

Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

9

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

10

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

11

Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

12

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

13

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

14

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

15

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

16

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

17

Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

18

Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry (by courtesy), Stanford University, Stanford, California, USA.

Abstract

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

PMID: 28191890

DOI: 10.1038/ng.3789