Whole Exome Sequencing on a multiplex family of Indian origin identifies mutations at 17p11.2 in siblings with autism spectrum disorders: implications to understanding the pathophysiology from syndromic variants.

Abstract

Abstract Autism Spectrum Disorders (ASDs) is a complex neurodevelopmental disorder characterized by restrictive repetitive behaviour and impairment in social and communication skills. It is extremely heterogeneous with a strong genetic preponderance. It’s clinically highly convoluted, represented with multiple comorbid conditions and syndromic features. More than 100 genes have been identified till date that are associated with syndromic ASDs. Whole exome sequencing (WES) has emerged as a valuable tool in evaluating the genetic underpinnings of ASDs, be it the syndromic or the idiopathic variants. The current study leverages the utility of WES in a multiplex family of Indian origin to identify the disease etiology in the siblings (01S1 (Female) and 01S2 (Male)) exhibiting ASD syndromic features, at both clinical and molecular levels. Our systematic bioinformatic analysis identified a missense mutation (NM_030665.4:c.5320C > T; p.Arg1774Trp) in 01S1 resulting in RAI1 haploinsufficiency. Validation by sanger sequencing confirmed the novelty of the said mutation and that it was true positive and maternally transmitted in the subject. Likewise, we report a missense mutation at the same locus (17p11.2) corresponding to the FLII gene (NM_002018.4:c.2030A > C;p.Glu677Ala) in the other sibling, 01S2. Both the mutations were reported in the Smith Magenis Syndrome (SMS) critical region justifying its contribution to the presentation of the syndromic SMS features. These WES findings were consistent with the clinical findings that imply SMS features in both siblings. The current study employs WES to provide insights into the complex molecular mechanism associated with syndromic ASD highlighting the different processes that contribute to the disease heterogeneity. Moving forward, combinatorial approaches and findings from syndromic ASDs can potentially act as indicators to understand the genetic and phenotypic variations seen in the idiopathic ASD.