Abstract Alport kidney diseases (AKDs) comprise a spectrum of hereditary nephropathies caused by pathogenic variants in COL4A3, COL4A4, or COL4A5, which encode the α3–α5 chains of type IV collagen in the glomerular basement membrane. Although regarded as monogenic disorders, multilocus inheritance is increasingly recognized and may contribute to the phenotypic heterogeneity; involvement of all three genes remains exceptionally rare. We report a multigenerational family with AKD in which heterozygous variants were identified in COL4A3, COL4A4, or COL4A5. The proband, carrying variants in all three genes, presented with a classic Alport syndrome phenotype, including proteinuric chronic kidney disease (CKD), sensorineural hearing loss (SNHL) and characteristic ocular abnormalities, ultimately progressing to kidney failure requiring transplantation. All four daughters exhibited hematuria and proteinuria; however, extrarenal manifestations were restricted to the daughter with a digenic COL4A3/COL4A5 genotype, who also developed SNHL. Two daughters with monogenic variants in COL4A3 or COL4A4 showed no extrarenal manifestations, although the COL4A3 variant carrier developed progressive CKD. Segregation analysis supported the pathogenic contribution of each variant. Several affected relatives showed a clinically relevant reduction in proteinuria following renin–angiotensin system blockade. This pedigree illustrates the clinical continuum of AKDs and the impact of oligogenic inheritance on phenotypic variability, particularly the extrarenal involvement. These findings highlight the limitations of single-gene testing and support broader sequencing approaches in families with heterogeneous presentations. Comprehensive molecular diagnosis improves genetic counselling and enables timely initiation of renoprotective therapy.
Silva et al. (Fri,) studied this question.