Genotype and X-chromosome inactivation are associated with disease severity in females with X-linked Alport syndrome

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BACKGROUND: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. However, female patients show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. The factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort. METHODS: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leucocytes using the human androgen receptor assay method and analysed two cohorts. In 74 adult female patients we evaluated the correlation between kidney function [creatinine estimated glomerular filtration rate (Cr-eGFR) optimized for Japanese individuals] and genotype/XCI using multivariable linear regression analysis and in 65 paediatric female patients we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein:creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazards analysis. RESULTS: In adult female patients, the XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate -0.53, P = .004), whereas genotype was not (P = .892). In paediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria {hazard ratio [HR] 3.702 [95% confidence interval (CI) 1.681-8.150], P = .001 and HR 1.043 [95% CI 1.061-1.070], P = .001, respectively}, whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = .20 and P = .67, respectively). CONCLUSION: Genotype and XCI are factors associated with severity in females with XLAS.

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