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

<b>Background: </b>Variants in the <i>COL4A4</i> 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 <i>COL4A4</i> variants. <b>Methods: </b>19 children with <i>COL4A4</i> 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. <b>Results: </b>A total of 17 distinct <i>COL4A4</i> 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 <i>COL4A4</i> variants were related to varying degrees of Alport kidney disease and nonsense variants resulted in isolated hematuria. <b>Conclusion: </b>This is the first study to apply the new classification of Alport kidney disease to Chinese pediatric patients with <i>COL4A4</i> variants, substantially expanding the spectrum of <i>COL4A4</i> variants and providing new insights into genotype–phenotype correlations in this population.