Renal Outcomes and Variant Effects in Monoallelic COL4A3/COL4A4–Related Alport Syndrome: A Single–Center Cohort Study

BACKGROUND: Autosomal dominant Alport syndrome (AD-AS) is caused by pathogenic/likely pathogenic (P/LP) variants in COL4A3 and COL4A4. Its clinical spectrum ranges from isolated hematuria to proteinuric chronic kidney disease (CKD) eventually progressing to kidney failure (KF). We aimed to characterize the clinical and genetic profile of AD-AS in northwest Portugal, with particular focus on the recurrent COL4A3 c.1219G>C p.(Gly407Arg) variant. METHODS: We conducted an observational cohort study at a major university hospital. Eligible participants were heterozygous for COL4A3 or COL4A4 variants. Demographic, clinical, and genetic data were collected. Time to CKD≥3 and CKD5/KF was estimated using the Kaplan-Meier method. Subcohorts were defined by gene, variant type, and variant of interest. RESULTS: A total of 218 individuals (16 children) from 123 families were included. Definitive molecular diagnosis was obtained in 75%. Among COL4A3 carriers, 117 had P/LP variants, predominantly missense; among COL4A4 carriers, 47 had P/LP variants, predominantly truncating. COL4A3 p.(Gly407Arg) represented 62% of COL4A3 P/LP variants and 44% of the patient cohort. History of microscopic hematuria was present in 93% of patients, whereas history of significant proteinuria was documented in 68% and hypertension in 48%. CKD≥3 developed in 33%, and 21% progressed to CKD5/KF. Proteinuria independently predicted CKD progression (p=0.001). Carriers of COL4A3 p.(Gly407Arg) had earlier onset of hypertension and higher prevalence of proteinuria than carriers of other COL4A3 P/LP variants. Glomerular basement membrane thinning was noted on electron microscopy in all biopsy specimens. Extrarenal manifestations were uncommon. CONCLUSIONS: Heterozygous COL4A3/4 P/LP variants are frequently associated with progressive CKD. COL4A3 p.(Gly407Arg) apparently confers a more penetrant renal phenotype. AD-AS demonstrates a continuum of phenotypes even among relatives, underscoring the importance of early identification, longitudinal monitoring, and renoprotective therapy.