Autism-Open Access
Open Access

Abstract

Further Evidence for DLGAP2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

Hélène Poquet, Laurence Faivre, Salima El Chehadeh, Jenny Morton, Dominic McMullan, Susan Hamilton, Himanshu Goel, Bertrand Isidor, Cédric Le Caignec, Joris Andrieux, Bruno Delobel, Eva Pipiras, Anne-Claude Tabet, Andrée Delahaye, Loic Depontual, Mathilde Lefebvre, Caroline Jacquot, Alice Masurel, Frédéric Huet, Jean-Michel Pinoit, Vincent Meille, Maud Benetti, Eddy Ponavoy, Jean-Christophe Chauvet-Gelinier, Benoit Trojak, Bernard Bonin, Christine Juif, Anne Collinet de la Salle, Christel Thauvin-Robinet, Nathalie Lagarde, Céline Henry, Nathalie Marle, Patrick Callier and Anne-Laure Mosca-Boidron

Autism spectrum disorders are classified as neurodevelopmental disorders characterised by diminished social communication and interaction. The core symptoms typically coexist with other medical conditions such as intellectual disability. The involvement of rare copy number variations of varying expressivity and penetrance as risk factors in autism spectrum disorders/intellectual disability phenotypes has been highlighted in large series. The DLGAP2 gene, whose glutamatergic postsynaptic density product may play a role in synaptogenesis and plasticity, has been identified as a novel candidate on the basis of 2 de novo duplications in sporadic non-syndromic autism spectrum disorders/intellectual disability males. It has also been suggested that increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia spectrum disorders. Based on these results and after fine phenotyping of another patient with a de novo duplication involving DLGAP2 and presenting with autism spectrum disorder intersecting early-onset schizophrenia spectrum disorder, we gathered an international series of 9 cases (6 families) via international data sharing. Four sporadic males presented with autism spectrum disorders and one had other neurodevelopmental disorders. A family with 4 females displayed intellectual disability (2/4) and specific learning disorder (2/4). This study supports the hypothesis that rare copy number variations encompassing DLGAP2 with incomplete penetrance and variable expressivity could predispose to a broad range of early-onset neurodevelopmental disorders trajectories including autism spectrum disorders/intellectual disability, highlighting the existence of common predisposing factors to these overlapping phenotypic spectrums.