Probable autosomal dominant Alport syndrome associated with a novel COL4A4 variant: A case report

Alport syndrome is a hereditary glomerular basement membrane disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5. Autosomal dominant forms are increasingly recognized but remain underdiagnosed due to their mild and heterogeneous presentation. We report the case of a 38-year-old woman referred for persistent proteinuria and microscopic hematuria with preserved renal function. Extensive immunological and infectious work-up was negative. Kidney biopsy revealed minimal abnormalities on light microscopy and negative immunofluorescence. Electron microscopy demonstrated irregular thinning of the glomerular basement membrane (GBM), with focal thickening, lamellation, and segmental splitting of the lamina densa, without immune-type deposits. These findings suggested a collagen IV-related nephropathy. Whole-exome sequencing identified a previously undescribed heterozygous missense variant in COL4A4 (c.4556C > G; p.Thr1519Arg). According to ACMG/AMP criteria, the variant is currently classified as a Variant of Uncertain Significance (VUS), fulfilling PM1, PM2, and PP3 evidence criteria. Nevertheless, the combination of the patient's phenotype, characteristic ultrastructural findings, and compatible family history strongly supports its clinical relevance and suggests that it represents the most likely molecular explanation for the disease. Clinical, ultrastructural, and genetic findings supported a diagnosis of probable autosomal dominant Alport syndrome. This case highlights the diagnostic value of integrating electron microscopy and genetic testing in adults with persistent hematuria, proteinuria, and non-specific biopsy findings.