Carrier frequency and incidence of aromatic L-amino acid decarboxylase deficiency: a gnomAD-based study.

backgroundAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter metabolism disorder and is clinically characterized by infancy hypotonia, ophthalmic crisis, and developmental delay. With the emergence of gene therapy for AADC deficiency, accurate prediction of AADC deficiency is required. This study aimed to analyze the carrier frequency and expected incidence of AADC deficiency using exome data from the Genome Aggregation Database (gnomAD).

methodsWe analyzed 125,748 exomes from gnomAD, including 9197 East Asian exomes, for the DDC gene. All identified variants were classified according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.

resultsThe worldwide carrier frequency of AADC deficiency was 0.17%; the highest frequency was observed in East Asians at 0.78%, and the lowest was in Latinos at 0.07%. The estimated incidence of AADC deficiency was 1 in 1,374,129 worldwide and 1 in 65,266 in East Asians.

conclusionThe results demonstrated that East Asians have a higher carrier frequency of AADC deficiency than other ethnic groups. The variant spectrum of DDC genes in East Asian populations differed greatly from those of other ethnic groups. Our data will serve as a reference for further investigation of AADC deficiency. IMPACT: This study analyzed exome data from the Genome Aggregation Database (gnomAD) to estimate the carrier frequency and expected incidence of aromatic L-amino acid decarboxylase (AADC) deficiency. The article provides updated carrier frequency and incidence estimates for AADC deficiency, particularly in East Asian populations, and emphasizes the significant differences in the variant spectrum of DDC genes in this population compared to other ethnic groups. The study provides important information for accurate prediction and early diagnosis of AADC deficiency, particularly in high-risk populations, and may aid in the development of more effective targeted screening programs and gene therapies for this disorder.