Supplementary Material for: Whole Exome Sequencing of a multiplex family of Indian origin identifies variants in the RAI1 and FLII genes within the 17p11.2 region in siblings with autism and Smith Magenis Syndrome

Introduction: 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 is clinically highly convoluted, represented with multiple comorbid conditions and syndromic features. More than 100 genes have been identified till date.
Method: 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. In the current study, we performed WES on a multiplex family of Indian origin to investigate the disease aetiology in the siblings (S1 (Female) and S2 (Male)) exhibiting ASD syndromic features, at both clinical and genetic aspects.
Results: Exome sequencing identified a missense variant (NM_030665.4:c.5320C>T; p.Arg1774Trp) in S1 resulting in RAI1 haploinsufficiency. Validation by Sanger Sequencing confirmed that the variant was true positive and maternally transmitted in the subject. Likewise, we report an inherited missense variant at the same locus (17p11.2) corresponding to the FLII gene (NM_002018.4:c.2030A>C;p.Glu677Ala) in the other sibling, S2. Both the variants 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.
Conclusions: The current study employs WES to provide insights into the genetic complexity associated with syndromic ASD and how 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.