Genetic Investigation of Inherited Variants in a Multiplex Autism Spectrum Disorder (ASD) Family Using Whole-Genome...

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by early-onset challenges in social communication, repetitive behaviors, and clinical diversity. ASD is a highly heritable disorder, however, the exact mechanism by which inherited variants contribute to ASD in multiplex families, where more than one affected individual within a family is presented, remains unclear. We aimed to identify inherited genes in patients with ASD in a family with two affected siblings using Whole Genome Sequencing (WGS).

We performed WGS on two patients from a single family diagnosed with ASD. All of the patients were diagnosed with ASD using the gold-standard Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We used various bioinformatics approaches to identify a list of prioritized candidate genes that may be associated with ASD or other neurodevelopmental disorders in this family.

Our WGS analysis identified three potential candidate genes (EVI5:c.-82+866C>T, RAPGEF1:c.668C>T;p. Thr223Ile and PDZD4:c. -457G>A)) associated with ASD shared by the two patients. Additionally, utilizing various in-silico prediction tools and analysis of bioinformatics databases revealed that these rare variants are predicted to be deleterious and may contribute to ASDs. The identified variants are the first variants reported in ASD patients in the Iranian population that could be subjected to further validation studies.

These findings shed light on the genetic diversity of ASD within multiplex families and emphasize the complexity of genetic basis of ASD. Understanding the underlying genetic architecture of ASD is pivotal for advancing precise diagnostics and tailored therapeutic strategies.