Genetic features and kidney morphological changes in women with X-linked Alport syndrome

Background X-linked Alport syndrome (XLAS) caused byCOL4A5pathogenic variants usually has heterogeneous phenotypes in female patients. The genetic characteristics and glomerular basement membrane (GBM) morphological changes in women with XLAS need to been further investigated. Methods A total of 83 women and 187 men with causativeCOL4A5variants were enrolled for comparative analysis. Results Women were more frequently carrying de novoCOL4A5variants compared with men (47% vs 8%, p=0.001). The clinical manifestations in women were variable, and no genotype–phenotype correlation was observed. Coinherited podocyte-related genes, includingTRPC6,TBC1D8B,INF2andMYH9, were identified in two women and five men, and the modifying effects of coinherited genes contributed to the heterogeneous phenotypes in these patients. X-chromosome inactivation (XCI) analysis of 16 women showed that 25% were skewed XCI. One patient preferentially expressing the mutantCOL4A5gene developed moderate proteinuria, and two patients preferentially expressing the wild-typeCOL4A5gene presented with haematuria only. GBM ultrastructural evaluation demonstrated that the degree of GBM lesions was associated with the decline in kidney function for both genders, but more severe GBM changes were found in men compared with women. Conclusions The high frequency of de novo variants carried by women indicates that the lack of family history tends to make them susceptible to be underdiagnosed. Coinherited podocyte-related genes are potential contributors to the heterogeneous phenotype of some women. Furthermore, the association between the degree of GBM lesions and decline in kidney function is valuable in evaluating the prognosis for patients with XLAS.