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Further Evidence for DLGAP2 As Strong Autism Spectrum Disorders

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Further Evidence for DLGAP2 As Strong Autism Spectrum Disorders : Open A sm cc ti e u s s A Autism - Open Access Poquet et al., Autism Open Access 2017, 6:6 DOI: 10.4172/2165-7890.1000197 ISSN: 2165-7890 Research Article Open Access Further Evidence for DLGAP2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene Hélène Poquet1-3#, Laurence Faivre1,3,4#, Salima El Chehadeh1,3,4, Jenny Morton5, Dominic McMullan5, Susan Hamilton5, Himanshu Goel6, Bertrand Isidor7, Cédric Le Caignec7, Joris Andrieux8, Bruno Delobel9, Eva Pipiras10, Anne-Claude Tabet10, Andrée Delahaye10, Loic Depontual11, Mathilde Lefebvre1,3,4, Caroline Jacquot1,4, Alice Masurel1,3,4, Frédéric Huet1,3,4, Jean-Michel Pinoit2, Vincent Meille12, Maud Benetti12, Eddy Ponavoy12, Jean-Christophe Chauvet- Gelinier12, Benoit Trojak12, Bernard Bonin12, Christine Juif13, Anne Collinet de la Salle13, Christel Thauvin-Robinet1,3,4, Nathalie Lagarde13, Céline Henry2,13, Nathalie Marle3,4,14, Patrick Callier3,4,14 and Anne-Laure Mosca-Boidron3,4,14* 1Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement et Syndromes Malformatifs de l’Interrégion Est’, Hôpital d’Enfants, CHU Dijon, France 2Service de Pédopsychiatrie, Hôpital d’Enfants, CHU Dijon, France 3EA 4271 GAD Génétique des Anomalies du Développement, IFR 100–Santé STIC, Université de Bourgogne, Dijon, France 4FHU TRANSLAD, CHU de Dijon et Université de Bourgogne-Franche Comté, Dijon, France 5Regional Genetics Department, Birmingham Women's Hospital, Edgbaston, Birmingham, UK 6Hunter Genetics Conjoint Lecturer, University of Newcastle, Australia 7Service de Génétique Médicale, CHU Nantes, France 8Institut de Génétique Médicale, Pôle de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, France 9Laboratoire de Cytogénétique, Centre de Génétique Chromosomique, Hôpital Saint-Vincent de Paul, Groupe Hospitalier de l’Institut Catholique de Lille, France 10Service d'Histologie Embryologie Cytogénétique BDR, Hôpital Jean Verdier, AP-HP, Bondy, France 11Service de pédiatrie, hôpital Jean-Verdier, AP-HP, université Paris XIII, Bondy, France 12Service de Psychiatrie Générale et Addictologie, Hôpital Général, CHU Dijon, France 13Centre de Ressources Autisme de Bourgogne, Hôpital d’Enfants, CHU Dijon, France 14Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon, France #Authors contributed equally *Corresponding author: Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon, France , Tel: +33380293489; Fax: +33380295079; E-mail: [email protected] Received date: 04 January 2017; Accepted date: 12 January 2017; Published date: 19 January 2017 Copyright: © 2017 Poquet H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract 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. Keywords: Autism spectrum disorders; Array-CGH; Copy number Introduction variation; Intellectual disability; Neurodevelopmental disorders; DLGAP2 Autism Spectrum Disorders (ASD) comprise a wide range of heterogeneous early-onset persistent neurodevelopmental conditions characterised by significant impairments in reciprocal social Abbreviations: CNV: Copy Number Variation; ASD/ID: Autism interaction, diminished verbal and non-verbal communication and Spectrum Disorders/Intellectual Disability; EO-SSD: Early-Onset repetitive restricted stereotyped behaviour [1]. The core symptoms of Schizophrenia Spectrum Disorder; ID: Intellectual Disability; EO-ND: ASD typically coexist with other medical conditions such as Early-Onset Neurodevelopmental Disorders Intellectual Disability (ID), seizures, abnormality in sensory stimuli Autism Open Access, an open access journal Volume 6 • Issue 6 • 1000197 ISSN:2165-7890 Citation: Poquet H, Faivre L, El Chehadeh S, Morton J, McMullan D, et al. (2017) Further Evidence for DLGAP2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene. Autism Open Access 6: 197. doi:10.4172/2165-7890.1000197 Page 2 of 8 information processing, Attention Deficit/Hyperactivity Disorder extraction (FE10.7.1.1) and Genomic Workbench (V5.0.1.4) software (ADHD), sleep and feeding disorders. ASD affect around 1% of the (Agilent Technologies) in the Hg19 genome assembly. For patient 4, population and are four times more common in males than in females image analysis and automated CNV calling was performed using [2]. GenomeStudio v.2010.3 and CNV Partition v.3.1.6. When 8p23.3 microduplication was identified through array-CGH, the confirmation ASD have a strong genetic component. Chromosomal and parental studies were performed using quantitative PCR (qPCR). rearrangements as well as rare and de novo Copy Number Variantions (CNVs) are present in 10-20% of individuals with ASD, compared with Patients 5 to 9 were studied with a 60K Oligo-arrays (BlueGnome) 1-2% in the general population and/or in unaffected siblings [3-6]. International Standard Cytogenomic Array (ISCA) and data were Genomic studies have highlighted a high degree of heterogeneity analysed with either BlueMulti (V2.5) or (V2.2) software. Test DNA implicating both de novo germline mutations and rare inherited was referenced against same-sex control DNA. In Australia, a second variants but converging in common pathways affecting neuronal and array (Agilent technologies, 15K custom design via e-array website) synaptic homeostasis [7-10]. In the absence of Mendelian inheritance was performed to confirm this chromosomal alteration in the proband patterns, ASD were first considered to be polygenic, i.e., a disorder and parental studies were performed using FISH with the probe caused by multiple genetic risk factors, each of weak effect. More RP11-439C15 obtained from The Centre of Applied Genomics, recently, an alternative model was proposed that considered ASD as a Hospital for Sick Children, Toronto, Canada. Informed consent was group of disorders caused by heterogeneous genetic risk factors obtained for all tested patients. influencing common neuronal pathways [9,11]. The occurrence of two or more deleterious CNV or variations in a subset of patients also Multidisciplinary phenotyping methods for index patient 1 suggested that independent loci could act in concert to induce the development of ASD [10,12–14]. Moreover, the observation that Global neurodevelopmental phenotyping was performed thanks to a patients with a deletion at 16p12.1 were more likely to carry an multidisciplinary assessment platform. The patient and his parents additional large CNV agrees with a ‘‘two-hit model’’ for developmental underwent retrospective semi-structured trio-interviews regarding disorders [12]. This model may help to explain the variability in their personal and familial medical, developmental and life-event expressivity of recurrent CNVs associated with neuropsychiatric history, and especially by the psychiatrist about ASD features, phenotypes. The genetic causes of ASD are diverse [15], but the main according to Autism Diagnostic Interview- Revised (ADI-R). category of genes associated with the disorder is related to the Communication and reciprocal social interaction on the one hand, as development and function of neuronal circuits [9,10]. well as interests, play and behaviour patterns on the other hand were explored. Verbal and non-verbal tasks tested intellectual ability The DLGAP2 (MIM 605438) gene encodes the SAPAP2 protein and (Wechsler Intelligence Scale for Children – Fourth Edition, WISC-IV), plays a role in synapse organization and neuronal cell signalling. attention and executive functions, and academic skills. Speech SHANK forms a huge protein complex with PSD95 and SAPAP phenotyping of receptive and expressive language, as well as
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