Clinical variability and genetic variants in alport spectrum: a retrospective cohort study

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are hereditary disorders characterized by glomerular basement membrane (GBM) abnormalities. Differentiating between them remains challenging due to overlapping clinical, and genetic features. We retrospectively identified 95 adult patients with AS and TBMN on kidney biopsy (2010–2024). Following prospective genetic testing and exclusion of four patients with non-classic gene variants (CD151, FN1, MYH9), the final cohort of 91 patients (37 males, 54 females) was analyzed for clinical course, histopathology, and genetic findings. GBM abnormalities were identified in 3.4% of native kidney biopsies. Of these patients, 21 (23%) were diagnosed with AS and 70 (77%) with TBMN; additional renal pathology beyond GBM abnormalities was present in 5/21 AS patients and 37/70 TBMN patients. At biopsy, serum creatinine, Estimated Glomerular Filtration Rate (eGFR), proteinuria, and hematuria were comparable between groups (all p ≥ 0.37). Additional renal pathology was more frequent in TBMN than AS (53% vs. 24%, p = 0.02). AS patients had significantly thicker GBM (333 vs. 203 nm, p = 0.009) and more glomerulosclerosis and interstitial fibrosis and tubular atrophy (IFTA) ( p = 0.05 and p = 0.02, respectively) than TBMN. A pathogenic or likely pathogenic genetic variant was identified in 90% of AS and 27% of TBMN patients ( p < 0.001); variants of uncertain significance (VUS) were found in a further 10% and 6%, respectively, and were not counted as positive. Positive genetic findings were associated with a more frequent family history of kidney disease (55% vs. 26%, p = 0.008) but not with hematuria or proteinuria. Disease progression occurred in 56% of AS and 25% of TBMN patients and was not confounded by the presence of additional renal pathology ( p = 0.37). Progression correlated with baseline eGFR ( p < 0.001) but not with genetic findings ( p = 0.25) or variant pathogenicity ( p = 0.58). AS and TBMN represent a clinical, genetic, and histopathological continuum within the Alport spectrum. Genetic testing aids diagnosis, but a binary positive/negative result alone does not predict disease progression, likely reflecting the limitation of this classification rather than a true absence of genotype-phenotype correlation. Precision management of these patients will require risk models that integrate genetic findings, variant-specific molecular effects, and clinical parameters — not genetic status alone.