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Multiple Rare Genetic Variants Can Deregulate Common Pathways in Autism Spectrum Disorders

Friday, 3 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
I. Cusco1,2,3, B. Rodríguez-Santiago4, J. Santoyo-Lopez5,6, M. Rigau1, G. Aznar Lain7, M. Codina1,2,3, A. Homs1,2,3, A. Gutíerrez1,2,3 and L. A. Pérez-Jurado1,2,3, (1)Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain, (2)The Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain, (3)Instituto de Investigación Sanitaria IMIM-Hospital del Mar, Barcelona, Spain, (4)Research and Development, Quantitative Genomic Medicine Laboratories, S.L. (qGenomics), Barcelona, Spain, (5)Andalusian Human Genome Sequencing Centre (CASEGH), Sevilla, Spain, (6)Medical Genome Project (MGP), Sevilla, Spain, (7)Servei de Pediatria, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain
Background:  Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with an increasing reported incidence over the past decade. There is strong evidence for a genetic etiology of ASD (90% of concordance rates in monozygotic twins) but it is thought to be a complex multifactorial disorder with several loci involved. Recent genetic findings using molecular karyotyping and next-generation sequencing support a possible double or multiple-hit model for ASD that could explain the heterogeneity in ASD.

Objectives:  Under the assumption that the genetic source of ASD phenotype is mainly the multiple-hit model, we try to identify both causative genes (de novo variants) and common altered pathways affected as a consequence of the multiple rare genetic variants (inherited variants).

Methods:  We have analyzed 30 idiopathic male ASD cases (DSM-IV and ADI-R evaluation) using the exome sequence approximation. We have only considered the rare genetic variants (indels and SNV) with theoretical severe functional implications (stop, non-synonymous and frame-shift mutations) under the dominant (private heterozygous variants), recessive (homozygous or compound heterozygous) and X-linked models. We have used Sanger sequencing and Sequenom technology for validation and co-segregation studies. Pathways enrichment studies were performed using the free available resource ConsensusPathDB (

Results:  We have detected some likely causative mutations with monogenic mendelian models in three cases: one de novo stop mutation in SCN2A and two X-linked mutations (MAOA and CDKL5). Exome data revealed on average 72.6 rare events per sample. We have detected that 4.2% of the affected genes had been previously described in relation with ASD (SFARI + AutismKb databases N=666 genes) with significant overrepresentation (p=0.001; OR=1.5). We have found 249 genes with multiple rare variants (in more than 1 ASD patient) being 11 of them strong candidates (CREBBP, ERBB4, GRIN2A, SCN2A, ANK3, CLTCL1, EML1, ESR1, SYNE1, CSMD3, TTN). We have detected that most of these variants are inherited from healthy parents, a fact that is consistent with an additive model rather than a sporadic event. Pathway studies have been performed individually, and we have detected common overrepresentation of 35 pathways (ex. Interaction between L1 and Ankyrins, NCAM signaling for neurite out-growth, axon guidance, Semaphorin interactions). Further investigations of overrepresented pathways detected in control sample are still in process in order to distinguish ASD specific pathways.

Conclusions:  We have identified presumably causative mutations in 10% of our patients compatible with monogenic ASD. The exome data also revealed rare variants in genes previously reported as strong candidates for ASD significantly enriched in our cohort of ASD patients. Eleven of those genes were altered in multiple samples indicating a common defect. Being most of the variants inherited our data support a multiple-hit model for ASD where the co-occurrence of several genetic variations altering common pathways are responsible for the phenotype. 

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