Integrative variation analysis reveals that complex genotype may specify phenotype in syndromic autism spectrum disorder siblings

It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes contribute to the heterogeneity of ASD phenotypes. Microarray-based Comparative Genomic Hybridization (aCGH) and Exome sequencing, system genetics and network analysis are being used as a tool for the study of complex disorders with an unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to better characterize the complex genotype-phenotype relation we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features and intellectual disability, to search for de novo CNVs, de novo and rare inherited point variations – single nucleotide variations (SNVs) and indels – with a probable functional impact. With aCGH we identified a duplication in the 4p16.3 region and a deletion at 8p23.3 in both siblings, inherited by a paternal balanced translocation t(4, 8) (p16; p23). Exome variant analysis found a total of 312 variants, of which 102 were shared by both siblings, 125 were found in the male sibling exome data and 85 in the female. Our integrative network analysis showed that the siblings shared translocation could explain their similar syndromic phenotype, such as their overgrowth, macrocephaly and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, important to the robustness of the network and contributing for the broader spectrum of psychiatric symptoms. This study show the importance of a integrative approach to explore the genotype-phenotype variability