Exome Sequencing Applied to Discover Variants in Autism Spectrum Disorder and Neurodevelopmental Conditions

Abstract

Discovery of mutations aetiologically responsible for neurodevelopmental conditions such as autism spectrum disorder (ASD) help to elucidate pathophysiology and provide avenues for personalised therapeutic treatment. ASD is phenotypically heterogeneous, presenting as deficiencies in social and communication capabilities, restrictive or repetitive behaviours, and sensory sensitivities. A significant genetic contribution to ASD has been confirmed by twin studies. Research utilising next generation sequencing (NGS) of exomes has revealed causative mutations and assisted with defining the ASD-risk gene space. With the aim of contributing to the understanding of ASD and neurodevelopmental disorders, a methodology was developed to identify aetiologically significant mutations using exome NGS data. This consisted of constructing and testing computational pipelines for processing sequencing reads, identifying genetic variants, and annotating information. Filtering strategies were then devised to identify candidates. Application of this methodology to two patient cohorts resulted in the discovery of six causative mutations from 12 cases. The first cohort consisted of four sibling pairs each with a unique neurodevelopmental condition and two ASD individuals. Three sibling pairs had causative mutations discovered. Compound heterozygous stop-gain variants in PEX7 resulted in rhizomelic chondrodysplasia punctata, type 1. A recessive homozygous missense in the SLC18A2 caused brain dopamine-serotonin vesicular transport disease. Compound heterozygous missense and splice donor variants in ADCK3 resulted in cerebellar ataxia and coenzyme Q10 deficiency. Additionally, a de novo splice-site acceptor variant in KMT2A causing Wiedemann-Steiner syndrome was discovered in an ASD subject. The second cohort consisted of six trios, each comprised of a female ASD case from a reportedly simplex family and parents. Two definitive causative mutations were discovered; a de novo 2q37 deletion resulting in 2q37 deletion syndrome and a de novo frameshift in ASXL3 that caused Bainbridge-Ropers syndrome (BRS). Further characterization of the two causative mutations provided insights to the origin of the 2q37 deletion and the pathophysiological mechanism that induces BRS. Candidate variants with associations to neurodevelopmental processes were identified for all remaining subjects and await further investigation. In conclusion, NGS is a powerful approach for discovering the causes of ASD and neurodevelopmental disorders. Continued research will result in deeper understanding, more accurate diagnoses, and personalized therapeutic treatments.