Journal
JOURNAL OF CHILD NEUROLOGY
Volume 36, Issue 13-14, Pages 1218-1222Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/08830738211018902
Keywords
succinic semialdehyde dehydrogenase deficiency; neurometabolic disease; succinic semialdehyde dehydrogenase; SSADH; disease prevalence; carrier frequency
Categories
Funding
- Speragen, Inc
- SSADH Association
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Pathogenic variants in the ALDH5A1 gene lead to SSADH deficiency, with an estimated global prevalence of 1/460,000 and highest carrier frequencies in East Asian and South Asian populations. However, the pan-ethnic carrier frequency for SSADH deficiency may not be fully represented in gnomAD, requiring further analysis to assess the prevalence of this ultra-rare disease.
Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of similar to 1/340, supporting a prevalence of SSADH deficiency of similar to 1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease.
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