Biallelic variants in ALDH5A1 were first reported in individuals with succinic semialdehyde dehydrogenase deficiency (SSADHD) in 1998. ALDH5A1 encodes the succinic semialdehyde dehydrogenase enzyme, which is involved in the degradation pathway of GABA. SSADHD is a rare neurometabolic disorder characterized by developmental delay, hypotonia, intellectual disability, ataxia, seizures, and behavioral problems. Approximately 50 pathogenic variants have been reported in the literature, including large deletions, and frameshift, nonsense and missense variants predicted or shown to cause loss or reduced enzyme function. There is experimental evidence to support this gene-disease relationship, including a mouse model. In summary, ALDH5A1 is definitively associated with autosomal recessive succinic semialdehyde dehydrogenase deficiency. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 4/27/2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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