Background X-linked Alport syndrome (XLAS) caused by COL4A5 pathogenic 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 causative COL4A5 variants were enrolled for comparative analysis.
Results Women were more frequently carrying de novo COL4A5 variants 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, including TRPC6, TBC1D8B, INF2 and MYH9, 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 mutant COL4A5 gene developed moderate proteinuria, and two patients preferentially expressing the wild-type COL4A5 gene 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.
- Inheritance Patterns
Data availability statement
Data are available upon reasonable request.
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HD, QW and DL contributed equally.
Contributors ZL, XY, HD, QW and DL designed the study; DL, EG and CZ collected the data; JZ and QW interpreted the data; HD performed the statistical analysis and wrote the manuscript; ZL and XY critically revised the manuscript. ZL is responsible for the overall content as the guarantor. All authors approved the final version of the manuscript. HD, QW and DL contributed equally to this work.
Funding This study was supported by National Key Research and Development Program of China (2017YFA0104500, 2016YFC0904100 and 2016YFC0904103) and The Open Project of Jiangsu Provincial Science and Technology Resources (Clinical Resources) Coordination Service Platform (JSRB2021-03 and TC2022B005).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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