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Abstract: SA-PO556

New Insights on the Clinical Manifestations of COL4A4 Genetic Variants: A UK Biobank Analysis

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1303 Glomerular Diseases: Clinical‚ Outcomes‚ and Trials


  • Titan, Silvia M., Nephrology Division, Sao Paulo University Medical School, Sao Paulo, Sao Paulo, Brazil
  • da Costa Pereira, Alexandre, Harvard Medical School, Boston, Massachusetts, United States

The spectrum of clinical manifestations of COL4A4 is wide, with mutations in this gene being reported to be associated with Alport, thin membrane disease, and no kidney disease. Current literature is largely derived from phenotype-centered analysis but genetic data from populational studies offer us the opportunity to investigate the associations of genotypes and phenotypes in an unbiased manner. In this study, we aimed at describing the association of COL4A4 variants with albuminuria and other phenotypes in a large population study.


We used data from 200,069 UK-Biobank (UKB) participants with WES data to establish the prevalence of coding variants in COL4A4. We conducted burden analysis using SAIGE-GENE and WES and albuminuria data from 60,699 individuals adjusting for age and sex. Multiple iterations of conditional adjustment were applied to derive a set of independently associated genetic variants. Associated variants were annotated for their current ACMG classification using the ClinVar database. Finally, we explored other trait associations for selected variants.


Of the 2988 unique variants within the COL4A4 gene region, 1091 were coding: 56 LOF, 720 missense (434 damaging missense), and 315 synonymous. Rare variants in the coding region of COL4A4 were significantly associated with albuminuria in burden analysis (p.value = 8e-22 for LOF, and 2e-10 for missense). Most burden signals for albuminuria at the population level could be explained by only 3 variants: rs35138315 (a stop-gain variant seen in 1:1000 individuals), rs36121515 (a missense variant seen in 1:300 individuals), and rs79143859 (a missense variant seen in 1:300 individuals). While rs35138315 is classified in ClinVar as pathogenic for recessive Alport disease, both rs36121515 and rs79143859 are currently classified as benign. In addition, rs36121515 was significantly associated with hearing-related phenotypes and rs79143859 with eye-related phenotypes, suggesting potentially pleiotropic manifestations of Alport disease.


Based on the findings of this large-scale population study, we suggest that rs35138315, rs36121515, and rs79143859 can be disease-modifying variants and should be further characterized regarding pathogenicity.