Diagnostic utility of whole exome sequencing and chromosomal microarray in a clinically well-defined autism spectrum disorder cohort. K. Tammimies1, B. A. Fernandez2,3, S. Walker1, B. Thiruvahindrapuram1, G. Kaur1, A. C. Lionel1, W. Roberts4, R. Weksberg5, J. L. Howe1, M. Uddin1, R. K. C. Yuen1, Z. Wang1, L. Lau1, P. Szatmari6, K. Whitten7,8, C. Vardy7, V. Crosbie8, B. Tsang1, R. Liu1, L. D'Abate1, S. Luscombe7, T. Doyle7, S. Stuckless2, D. Merico1, D. J. Stavropoulos9, C. R. M. Marshall1,10, S. W. Scherer1,11 1) The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; 2) Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St Johns NL Canada; 3) Provincial Medical Genetic Program, Eastern Health, St. Johns NL, Canada; 4) The Autism Research Unit, Hospital for Sick Children, Toronto, Ontario, Canada; 5) Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada; 6) Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada; 7) Child Health Program, Eastern Health, St. Johns NL, Canada; 8) Discipline of Pediatrics, Memorial University of Newfoundland, St Johns NL Canada; 9) Cytogenetics Laboratory, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; 10) Molecular Genetics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; 11) Department of Molecular Genetics, McLaughlin Centre, University of Toronto, Toronto, Canada.

   Autism Spectrum Disorder (ASD) is a group of neuropsychiatric conditions affecting 1 in 68 children. Twin and family studies have demonstrated a strong genetic basis for ASD; however both the genetic factors involved and the clinical presentation are highly heterogeneous. Etiological genetic variants have been identified in ~20% of ASD individuals, including chromosomal rearrangements, monogenic syndromes and rare de novo and inherited copy number variants (CNVs). Recent genetic studies of ASD using whole exome sequencing (WES) and whole genome sequencing have highlighted de novo and inherited sequence level variants, but their etiological contributions and diagnostic detection rate are still largely undefined. As the presentation of ASD is highly variable, it has been suggested that clinical morphology can aid in stratifying individuals into more genetically meaningful subtypes. Therefore, we performed comprehensive genomic analyses, combining high resolution chromosomal microarray (CMA) and WES, in a cohort of 284 ASD cases. Established detailed dysmorphology scoring and assessment for major congenital anomalies were used to stratify this cohort into 182 essential (non-dysmorphic), 41 equivocal dysmorphic and 61 complex (significantly dysmorphic) ASD subjects. We aimed to assess the rate of clinically relevant variants across the three subgroups and explored the contributions of different types and combinations of genetic variants to the variability of the clinical phenotype. Similar to previous reports of CMA diagnostic yield, we detected pathogenic CNVs in 7.2% of ASD individuals. The yield of such CNVs was significantly higher in the complex group 17.3% (9/52) compared with the essential group 3.1%, (5/163) (p=0.0003). These pathogenic CNVs affected known ASD loci, disrupting genes such as SHANK3 and NRXN1. We also discovered novel CNVs with unknown clinical significance affecting genes for further follow up such as CTNND2 and GRK4. The analysis of diagnostic yield of rare de novo and inherited mutations from WES is ongoing. We have identified de novo point mutations in new candidate genes such as HTR5A and SCUBE2 as well as genes previously implicated in ASD such as SCN2A and ASH1L. Our data illustrates the value of detailed clinical information in the interpretation of genome-wide diagnostic test results of ASD. We also establish for the first time the combined diagnostic yield of WES and CMA genetic testing in an ASD cohort.

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