Identification of novel COL4A5 variants and prenatal diagnosis in three large families

Alport syndrome (AS) is the second-most frequent monogenic kidney disease and 85% of cases are caused by mutations in the genes of the α5 chains of collagen type IV (COL4A5). The early diagnosis and treatment are essential for the prognosis of AS. The clinical phenotypes of AS are very variable, which is challenging to diagnose. Genetic diagnosis is sensitive and accurate, which can recognize the affected individuals with mild phenotype for early diagnosis and predict the age at renal failure for early treatment. In addition, genetic testing will offer the available reproductive options, including prenatal diagnosis and preimplantation genetic testing (PGT). In this study, three novel COL4A5 variants (c.1834G > T, c.865G > A and c.1032 + 5G > A) were found. These variants co-segregated with the disease in multiple affected family members. In vitro splicing assay indicated that the c.1032 + 5G > A variant resulted in aberrant splicing involving exon 18 skipping. The healthy babies without these novel COL4A5 variants were born by PGT or prenatal diagnosis, respectively. Three novel variants in COL4A5 gene can provide insights into further genetic counseling or genotype-phenotype correlations.