A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability.

Anne-Laure Mosca-Boidron (1, 2) , Lucie Gueneau (2) , Guillaume Huguet (3, 4) , Alice Goldenberg (5) , Céline Henry (6) , Nadège Gigot (2) , Emilie Pallesi-Pocachard (7) , Antonio Falace (7) , Laurence Duplomb (2) , Julien Thevenon (2) , Yannis Duffourd (8, 2) , Judith St-Onge (2, 9) , Pascal Chambon (5) , Jean-Baptiste Rivière (8, 2) , Christel Thauvin-Robinet (2, 10) , Patrick Callier (1, 2) , Nathalie Marle (1, 2) , Muriel Payet (1, 2) , Clemence Ragon (1, 2) , Hany Goubran Botros (3) , Julien Buratti (3) , Sophie Calderari (3) , Guillaume Dumas (3, 4) , Richard Delorme (3, 11) , Nathalie Lagarde (6) , Jean-Michel Pinoit (6) , Antoine Rosier (12) , Alice Masurel-Paulet (10) , Carlos Cardoso (13) , Francine Mugneret (1) , Pascale Saugier-Veber (14) , Dominique Campion (14) , Laurence Faivre (10) , Thomas Bourgeron (3, 4, 15)

1 Laboratoire de cytogénétique (CHU de Dijon)
2 GAD - Génétique des Anomalies du Développement
3 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
4 CNRS - UMR3571 - Gènes, Synapses et Cognition
5 Service de génétique [Rouen]
6 CRAB - Centre Ressources Autisme de Bourgogne (CHU de Dijon)
7 IBDM - Institut de Biologie du Développement de Marseille
8 UB - Université de Bourgogne
9 CHU Dijon
10 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
11 Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré]
12 CRAHN - Centre de Ressources Autisme de Haute Normandie
13 INMED - INSERM U901 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
14 GMFC - Génétique du cancer et des maladies neuropsychiatriques
15 Fondation FondaMental [Créteil]

Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5A could be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novo translocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5A gene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5A in 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5A microdeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5A with susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.

Domaines: Génétique humaine; Médecine humaine et pathologie

Anne-Laure Mosca-Boidron, Lucie Gueneau, Guillaume Huguet, Alice Goldenberg, Céline Henry, et al.. A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability.. European Journal of Human Genetics, 2016, 24 (6), pp.838-43. ⟨10.1038/ejhg.2015.211⟩. ⟨pasteur-01342825⟩