Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Mosca-Boidron AL

PROVIDER: S-EPMC4867450 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Mosca-Boidron Anne-Laure AL Gueneau Lucie L Huguet Guillaume G Goldenberg Alice A Henry Céline C Gigot Nadège N Pallesi-Pocachard Emilie E Falace Antonio A Duplomb Laurence L Thevenon Julien J Duffourd Yannis Y St-Onge Judith J Chambon Pascal P Rivière Jean-Baptiste JB Thauvin-Robinet Christel C Callier Patrick P Marle Nathalie N Payet Muriel M Ragon Clemence C Goubran Botros Hany H Buratti Julien J Calderari Sophie S Dumas Guillaume G Delorme Richard R Lagarde Nathalie N Pinoit Jean-Michel JM Rosier Antoine A Masurel-Paulet Alice A Cardoso Carlos C Mugneret Francine F Saugier-Veber Pascale P Campion Dominique D Faivre Laurence L Bourgeron Thomas T

European journal of human genetics : EJHG 20150923 6

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 brea ...[more]

PMID: 26395558

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Project description:Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies.

Dataset Information

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

Publications

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

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