Unveiling Maternal Germline Mosaicism in X-Linked Alport Syndrome by Advanced Genetic Testing

BACKGROUND X-linked Alport syndrome is a hereditary disease caused by mutations in the COL4A5 gene, resulting in structural and functional abnormalities in the alpha5 chains encoded by these genes. This leads to the loss of type IV collagen in the basement membrane, causing dysfunction in organs such as the glomerulus, retina, and cochlea. In most cases, the COL4A5 pathogenic variant is inherited from a heterozygous mother in an X-linked dominant manner. However, in rare instances, XLAS can result from maternal germline mosaicism, where even though the mother's somatic genetic testing detects no mutation, a subset of her germ cells carries a COL4A5 gene mutation, potentially leading to the birth of an affected child. This biological phenomenon can lead to the unexpected occurrence of affected offspring despite negative maternal carrier testing, with important implications for genetic counseling and recurrence risk assessment. CASE REPORT We report a case of maternal germline mosaicism in a family with X-linked Alport syndrome, where the proband - a 16-year-old male - carried a pathogenic variant in COL4A5 (NM_000495.5: exon 39: c. G3508A: p. G1170S). The proband's sister also had the same variant and exhibited microscopic hematuria, while the mother showed no variant at this specific location, suggesting the presence of asymptomatic germline mosaicism. CONCLUSIONS Currently, few asymptomatic or mildly symptomatic females have been identified timely as carriers of germline mosaicism in X-linked Alport syndrome patients, warranting novel laboratory tools with high specificity, sensitivity, and minimal invasiveness for detecting mosaic phenomena, especially germline mosaicism.