Pathogenic variants in the Alport genes are prevalent in the Singapore multiethnic population with highest frequency in the Chinese

Abstract

Abstract Alport syndrome is a common monogenic kidney disease resulting from pathogenic variants in COL4A3, COL4A4 or COL4A5 genes. The estimated global population prevalence is one in 106 individuals for autosomal dominant (AD) and one in 2,320 for sex-linked (XL) conditions. Here, we aimed to estimate the population prevalence of individuals carrying pathogenic variants that cause Alport syndrome in Singapore, and to stratify the prevalence by ancestry. We used population-scale genomic data of 9,051 unrelated subjects, comprising 5,443 (60.8%) Chinese, 1,922 (21.4%) Indian and 1,686 (17.8%) Malay individuals. The prevalence of individuals with pathogenic variants that cause AD and XL Alport syndrome are 1 in 165 and 1 in 2,262 respectively. Additionally, 0.8% of Chinese and 0.3% of Malay populations carry pathogenic Alport syndrome variants, with Chinese individuals being 2.7 times more affected than Malays (95% CI:1.147–6.437, P = 0.027). Interestingly, each pathogenic variant was associated with people of a single ancestry. The two most prevalent pathogenic variants, COL4A3: c.3856G > A (p.Gly1286Arg) (n = 8) and COL4A3: c.4793T > G (p.Leu1598Arg) (n = 4), were exclusively found in the Chinese population. In conclusion, AD Alport syndrome may be prevalent in Singapore, with higher frequencies among the Chinese. Furthermore, founder effects may exist within the ancestries.