Background 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. Method 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.3203GA) was selected for in vitro functional studies. Results We identified seven variants in six families, including autosomal dominant ( COL4A3 c.352GA, COL4A4 c.71 + 1GC), autosomal recessive ( COL4A3 c.2736dupA, c.4235GT), X-linked ( COL4A5 c.512del, COL4A5 c.3053del), and one spontaneous variant ( COL4A3 c.3203GA). Functional studies on the novel variants ( COL4A3 c.3203GA) demonstrated a significantly decrease significant decrease in the mRNA expression level in HEK293 T cells and the weakened cell migration ability. Conclusion 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.
Gao et al. (Thu,) studied this question.