Frequency of Duarte Variant Allele and its Genetic Characteristics in the Korean Population

Background: Duarte variant (D2) allele of the galactose-1-phosphate uridylyltransferase (GALT) gene comprises five cis-acting variants: c.940A>G, c.378-27G>C, c.507+62G>A, c.508-24G>A, and c.-119_-116del.While c.-119_-116del is considered causative, it is often missed in exon-targeted direct sequencing.Studies demonstrated that alleles carrying c.940A>G were either D2 or Los Angeles variant (D1) allele, which carries c.940A>G and c.652C>T in cis, with various D2:D1 ratios across populations.This study explored D2 allele frequency and D2:D1 ratio in Koreans.Methods: Whole genome sequencing data from 4,975 Koreans (2,305 probands and 2,670 family members) were analyzed.Variants associated with D2 and D1 alleles were screened.Family-based phasing was utilized to determine D2 allele frequency.Five GALT variants were considered in cis if both proband and one of the parents carried all five variants.Results: A total of 99 individuals (69 probands and 26 family members) had one or more of D2-associated variants; none had D1-associated c.652C>T variant.Two individuals (one proband and one family member) carried only c.-119_-116del variant.Among 1,446 families where phase could be determined, D2 allele frequency was 0.00968 (28/2,892 alleles; 95% confidence interval, 0.00644-0.01396).No individuals with confirmed D2 alleles had pathogenic GALT variants in trans.The D1 allele was not detected.Conclusions: This study offers novel insights into D2 allele characteristics in Koreans, revealing an extremely low D1 to D2 ratio compared to other populations, including Europeans and Americans.Identification of isolated c.-119_-116del variants underscores the need for GALT promoter region sequencing.To evaluate the functional impact of isolated c.-119_-116del variant, further studies are warranted.