Expanding the COL4A4 variant spectrum: genotype-phenotype correlation in 19 Chinese children using updated Alport kidney disease classification

Background: Variants in the COL4A4 gene have been identified as a significant cause of autosomal Alport syndrome. This study aimed to investigate the genetic features, clinical manifestations, and genotype-phenotype correlations in Chinese children with COL4A4 variants. Methods: 19 children with COL4A4 variants who presented with hematuria and/or proteinuria as their main complaints were included in our analysis. Genetic variants were identified using next-generation sequencing, Sanger sequencing and comprehensive bioinformatics analysis. Clinical data and family histories were retrospectively collected. Results: A total of 17 distinct COL4A4 variants were identified, 10 of which had not been previously described (10/17). Among these novel variants, 3 were likely pathogenic variants (3/10) and 1 was pathogenic variant (1/10). Among 19 patients, two carried compound heterozygous variants, one was homozygous, and the remainder were heterozygous. Most children presented with hematuria (4 had gross hematuria and 15 microscopic) and had a family history of kidney disease, with no extrarenal manifestations. In our cohort, frameshift, and missense COL4A4 variants were related to varying degrees of Alport kidney disease and nonsense variants resulted in isolated hematuria. Conclusion: This is the first study to apply the new classification of Alport kidney disease to Chinese pediatric patients with COL4A4 variants, substantially expanding the spectrum of COL4A4 variants and providing new insights into genotype–phenotype correlations in this population.