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. 2024 Oct 1;5(10):1510-1517.
doi: 10.34067/KID.0000000000000547. Epub 2024 Aug 13.

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

Yuta Inoki  1 , Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Yuta Ichikawa, Yu Tanaka, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, China Nagano, Kandai Nozu
Affiliations

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

Yuta Inoki et al. Kidney360. .

Abstract

Key Points:

  1. Patients with both COL4A3 and COL4A4 variants exhibited poor renal prognosis compared with those with autosomal dominant Alport syndrome.

  2. 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 COL4A3 and COL4A4 and those with autosomal dominant Alport syndrome (ADAS) previously analyzed by our group.

Results: Eighteen patients from nine families with digenic variants in COL4A3 and COL4A4 and four male and five female patients with digenic variants in COL4A5 and COL4A3 or COL4A4 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 COL4A3 and COL4A4, 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; P = 0.073) and that at development of ESKD was significantly earlier (57.0 versus 72.0 years; P = 0.045) in patients with digenic Alport syndrome.

Conclusions: Overall, patients with digenic Alport syndrome harboring COL4A3 and COL4A4 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.

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A634.

Figures

None
Graphical abstract
Figure 1
Figure 1
Probability of each clinical symptom in Alport syndrome cases with digenic COL4A3 and COL4A4 variants compared with that in ADAS cases. (A) Probability of occurrence of proteinuria. No significant differences were observed between the digenic and ADAS cases (P = 0.073). (B) Probability of developing ESKD. Significant differences were observed between the digenic and ADAS cases (P = 0.045). ADAS, autosomal dominant Alport syndrome.
See this image and copyright information in PMC

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