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Autosomal recessive Alport syndrome (ARAS) is caused by biallelic pathogenic variants in COL4A4, encoding the α4 chain of type IV collagen, leading to progressive hematuric nephritis and ultrastructural glomerular basement membrane (GBM) disruption. Multiple cohorts have documented ARAS in 148 unrelated patients with homozygous or compound heterozygous COL4A4 variants, with hematuria onset typically in early childhood (median 2.5 years) and progression to end-stage kidney disease in the second to third decade ([PMID:30717457]). Renal biopsy consistently shows characteristic GBM thinning, thickening, and lamellation, confirming definitive ultrastructural correlation.
Genetically, ARAS follows autosomal recessive inheritance. In a retrospective series of 30 patients from 24 pedigrees, all individuals carried either homozygous or compound heterozygous COL4A4 mutations identified via three-step genomic and mRNA analyses ([PMID:24633401]). Segregation analysis in these pedigrees demonstrated complete co-segregation of biallelic variants with disease. A recent case report described a two-year-old boy who was homozygous for a novel splice acceptor variant c.193-2A>C, with both parents as heterozygous carriers, underscoring autosomal recessive transmission ([PMID:31686460]).
The COL4A4 variant spectrum in ARAS is broad, encompassing splice-site, missense, nonsense, frameshift, and large indel mutations. Loss-of-function alleles predominate, including canonical splice acceptor changes (e.g., c.193-2A>C), and premature stop-codon variants, reflecting a haploinsufficiency mechanism when both alleles are affected. Although rare glycine substitutions can modulate phenotype severity, most pathogenic variants abolish α4 chain incorporation into the α3α4α5 heterotrimer, compromising GBM stability.
Genotype–phenotype correlations indicate that truncating variants often lead to earlier onset of proteinuria and more rapid decline in estimated glomerular filtration rate, whereas certain missense alleles may confer a milder, delayed phenotype. In a registry of 101 Chinese ARAS patients, those with non-missense variants showed earlier progression to CKD 5 compared with individuals harboring one or two missense variants, highlighting prognostic relevance of variant class ([PMID:33772369]). Early initiation of renin-angiotensin-aldosterone system inhibitors delayed progression to CKD 5, supporting targeted therapeutic intervention.
Functional studies of COL4A4 exonic changes demonstrate that presumed missense or synonymous variants can disrupt normal splicing. Minigene and patient mRNA analyses of COL4A4 c.735G>A (p.Pro245=) and c.870G>A (p.Lys290=) revealed exon skipping and truncated transcripts, confirming loss-of-function via aberrant splicing ([PMID:35386907]). These assays reinforce the molecular mechanism and support pathogenic classification under ClinGen functional criteria.
While heterozygous COL4A4 variants underlie benign familial hematuria or thin basement membrane nephropathy, these monoallelic changes generally do not lead to full-blown ARAS and exhibit incomplete penetrance. No publications have refuted biallelic COL4A4 involvement in ARAS; rather, heterozygous carriers present a milder phenotype, delineating distinct clinical spectra.
In summary, the robust genetic and experimental evidence supports a Strong association between COL4A4 and autosomal recessive Alport syndrome. ClinGen criteria are met with over 148 probands, multi-family segregation, and concordant functional data. Genetic testing for COL4A4 variants enables accurate diagnosis, prognosis, and informs family counseling, underpinning clinical utility for early intervention and therapeutic planning.
Gene–Disease AssociationStrongOver 148 unrelated patients including 30 genetically confirmed in 24 pedigrees, plus concordant biopsy and segregation data Genetic EvidenceStrong148 ARAS patients with biallelic COL4A4 variants across multiple families (systematic review)[PMID:30717457] Functional EvidenceModerateIn vitro splicing assays demonstrate aberrant splicing for exonic COL4A4 variants leading to loss-of-function[PMID:35386907] |