Whole exome sequencing identified a novel ALDH5A1 variant associated with SSADH Deficiency in an Iranian family with autism

Background and objective: Next Generation Sequencing with the application of Whole Exome Sequencing (WES) has fundamentally revised the concept of disease etiology and classification, and promisingly proposes novel therapeutic interventions. In Iran, this approach seems to be much more promising, due to the different ethnic background and probably to the involvement of novel genes.Material and methods: We performed WES in 2 sibship with Autism Spectrum Disorder whose parents were first cousins. The main clinical features included prominent expressive language deficit, infantile onset hypotonia, hyporeflexia and severe ataxia. Electrodiagnostic studies were suggestive of flaccid CP, and biochemical studies showed absence of metabolic acidosis with increased glycine concentration in plasma. No specific Metabolic disorder was identified.Results: Having filtered the WES data against genes associated with IEM, a homozygous novel variant was identified in ALDH5A1 which was a GABA Metabolic and Autism associated gene. Co-segregation analysis, furthermore, validated the variant as the causative mutation.Clinical reassessment supported the diagnosis of SSADH deficiency.Conclusion: This study is intended to discuss the impact of molecular genetics on precising the diagnosis. In addition, WES is the most favorable and preferred method once approaching single gene disorders in Iranian families because of the distinctness of our genetic background in comparison to western countries, as well as the low yield of genetic testing of known pathogenic variants.

کلیدواژه ها:

Whole exome sequencing ، Autism spectrum disorder ، ALDH5A1 novel mutation ، SSADH deficiency