Clinical, Pathological, and Genetic Characteristics of Patients with Digenic Alport Syndrome.

Key Points: Patients with both and variants exhibited poor renal prognosis compared with those with autosomal dominant Alport syndrome. The proportion of patients with digenic Alport syndrome was 1.7% among all patients with Alport syndrome.

Background: Digenic Alport syndrome could be associated with poor renal prognosis. However, the characteristics of patients with digenic Alport syndrome remain ambiguous.

Methods: We retrospectively investigated the clinical symptoms, pathological findings, genetic variants, and proportions of patients with digenic Alport syndrome. The ages at detection of proteinuria and development of ESKD were compared between patients with digenic Alport syndrome with disease-causing variants in and and those with autosomal dominant Alport syndrome (ADAS) previously analyzed by our group.

Results: Eighteen patients from nine families with digenic variants in and and four male and five female patients with digenic variants in and or were enrolled in this study. Next-generation sequencing revealed that the proportion of patients with digenic Alport syndrome was 1.7% among all patients with Alport syndrome. In patients with digenic variants in and , the median ages at detection of proteinuria and ESKD were 10.0 and 57.0 years, respectively. Compared with the patients with ADAS, the age at detection of proteinuria tended to be earlier (10.0 versus 20.0 years; = 0.073) and that at development of ESKD was significantly earlier (57.0 versus 72.0 years; = 0.045) in patients with digenic Alport syndrome.

Conclusions: Overall, patients with digenic Alport syndrome harboring and variants exhibited poor renal compared with the patients with ADAS. Therefore, timely identification of the two disease-causing variants is critical for the renal prognostic assessment and early treatment of patients with digenic Alport syndrome.