Genetic heterogeneity correlated with phenotypic variability in 6 Chinese families with Alport syndrome

Alport syndrome (AS) is a common hereditary kidney disease, mainly characterized by hematuria, progressive renal dysfunction, sensorineural hearing loss, and ocular symptoms, which significantly impacts patients the quality of life patients' quality of life and lifespan. However, due to its atypical and heterogeneous clinical features, the relationship between genotype and phenotype remains complex, posing AS diagnostic challenges.

Genetic variants were screened by whole exome sequencing (WES) followed by verification with Sanger sequencing. Genotype-phenotype analysis was also conducted, and a novel variant (COL4A3 c.3203G>A) was selected for in vitro functional studies.

We identified seven variants in six families, including autosomal dominant (COL4A3 c.352G>A, COL4A4 c.71 + 1G>C), autosomal recessive (COL4A3 c.2736dupA, c.4235G>T), X-linked (COL4A5 c.512del,COL4A5 c.3053del), and one spontaneous variant (COL4A3 c.3203G>A). Functional studies on the novel variants (COL4A3 c.3203G>A) demonstrated a significantly decrease significant decrease in the mRNA expression level in HEK293 T cells and the weakened cell migration ability.

We identified four novel pathogenic changes causing AS, revealing the genetic heterogeneity of AS and expanding its genotype phenotype spectrum, holding significant implications for prenatal diagnosis.