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

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.