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. 2025 Jun 16.
doi: 10.1007/s40620-025-02321-6. Online ahead of print.

The complexity of kidney disease secondary to collagen IV variants: insights into phenotypic variability from a large Sicilian pedigree

Elisa Longhitano  1 , Giulia Margherita Brach Del Prever  2   3 , Claudia Spinella  4 , Valeria Bracciamà  2   3 , Vincenzo Calabrese  4 , Antonio Amoroso  2   3 , Giovanni Conti  5 , Giuseppe Remuzzi  6 , Thorsten Wiech #  7 , Marina Noris #  6 , Silvia Deaglio #  2   3 , Domenico Santoro #  4
Affiliations

The complexity of kidney disease secondary to collagen IV variants: insights into phenotypic variability from a large Sicilian pedigree

Elisa Longhitano et al. J Nephrol. .

Abstract

Background: Collagen type IV (COL IV) is a crucial component of basement membranes, including the glomerular basement membrane (GBM), essential for kidney function. COL4A3, COL4A4, and COL4A5 variants lead to a broad spectrum of kidney disorders. This paper investigates the clinical and genetic characteristics of a large Sicilian family with COL4A gene abnormalities.

Methods: Starting from a male patient with digenic Alport Syndrome, we collected clinical data through genealogical research and performed genetic analyses on nineteen members of his family. Kidney biopsies were available for three of them.

Results: We identified variants in COL4A5 and COL4A3 genes. Clinical and histological manifestations varied widely, even among individuals with the same variant, highlighting the remarkable phenotypic heterogeneity of collagen IV-related nephropathies.

Conclusions: Our findings underscore the pivotal role of genetic testing in guiding clinical management and advancing the understanding of collagen IV-related kidney diseases. Moreover, this study emphasizes the need for further research to elucidate the intricate interplay between genetic variants and histological and clinical phenotypes, thereby paving the way for personalized therapeutic approaches in collagen IV-associated nephropathies.

Keywords: Alport syndrome; COL4A3; COL4A5; Familial IgAN.

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Conflict of interest statement

Declarations. Conflict of interest: The work presented in this paper has not been published previously. The authors have nothing to declare. Ethical approval: According to the Italian law, given the descriptive and non-interventional nature of the study, formal approval by the ethics committee was not requested. Human and animal rights: The present study complies with the guideline for human studies. This study does not contain any studies with animals. Informed consent: All patients gave written informed consent with permission to use their data pseudonymized for research purposed.

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