Prevalence Estimates of Predicted Pathogenic COL4A3-COL4A5 Variants in the Chinese Population and Its Implications...

The α3α4α5 chain of type IV collagen, encoded by the COL4A3, COL4A4, and COL4A5 genes, is critical for the structural integrity and function of the glomerular basement membrane as well as ocular and auditory structures. This study estimated the prevalence of pathogenic variants of these 3 genes in the general Chinese population.

Cross-sectional study.

We analyzed genomic data from 10,588 participants in ChinaMAP (Metabolic Analytics Project) who were recruited through unbiased sampling across 27 Chinese provinces.

Pathogenic variants in COL4A3, COL4A4, and COL4A5 genes.

Prevalence and allele frequency of pathogenic COL4A3-COL4A5 variants.

Predicted pathogenic variants were identified through a filtering workflow that adhered to American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, using ANNOVAR and Variant Effect Predictor for annotation. Prevalence was calculated as the proportion of individuals carrying at least one pathogenic variant. Wilson's score method was used to calculate 95% confidence intervals (CIs).

93 pathogenic variants in COL4A3, COL4A4, or COL4A5 were identified in the ChinaMAP cohort. Prevalences were 0.99% for COL4A3, 0.41% for COL4A4, and 0.15% for COL4A5, yielding an overall prevalence of 1.55% (95% CI, 1.33%-1.80%). No significant difference in the allelic frequency of COL4A5 variants was observed between male and female participants (P = 0.548). Two COL4A3 missense variants, p.Leu1598Arg and p.Gly1286Arg, were identified as having notably high prevalences of 0.20% and 0.13%, respectively.

The lack of detailed clinical information precluded the definitive classification of many variants of uncertain significance, there was a lack of data on the presence of kidney disease, and there is uncertain generalizability to the Chinese population.

This study revealed a high prevalence of pathogenic COL4A3, COL4A4, and COL4A5 variants in the Chinese population-approximately 1.6-fold higher than that in the Genome Aggregation Database cohort-indicating a substantial genetic burden of collagen IV-related disorders in China. These findings may inform clinical management related to diagnosis and genetic testing.

Type IV collagen genes (COL4A3, COL4A4, and COL4A5) are essential for kidney function. When these genes carry harmful variants, they can cause Alport syndrome and other kidney disorders. Using genomic data from 10,588 Chinese adults, we found that 1 in 64 people (1.55%) carry these variants, approximately 1.6 times the rate reported in other populations. Two genetic variants were found to be particularly common in Chinese individuals. These findings may inform clinical practice related to diagnosis and genetic testing to enable more personalized kidney care.