Cystic Phenotypes Associated with Monoallelic COL4A3/A4/A5 Pathogenic Variants Identified in a Population-Based Cohort

Background: In Alport syndrome, mono/biallelic COL4A3/COL4A4 or hemizygous COL4A5 pathogenic variants cause glomerular disease, leading to hematuria, proteinuria and kidney failure. A milder, monoallelic (including COL4A5), glomerular phenotype can be evident, while kidney cyst development has also been described. We screened the Mayo Clinic Biobank (MCBB) patients (pts) cohort with available electronic medical records (EMR) and whole exome sequencing (WES) for COL4A3/4/5 monoallelic individuals. Methods: We screened 52,786 MCBB individuals for likely pathogenic (LP) variants and renal/hepatic cyst-related ICD codes in the COL4A3/4/5 genes. Those with LP variants were evaluated using EMR and imaging to determine cystic phenotype penetrance. Results: We identified 459 individuals with single LP variants: 232: COL4A3, 201: COL4A4; 26, COL4A5. Phenotypes included hematuria (microscopic/gross) (COL4A3: 62%, COL4A4: 65.6%, COL4A5: 61.5%), proteinuria (>150 mg/day) (COL4A3: 36%, COL4A4: 233%, COL4A5: 42.3%) and hypertension (COL4A3: 52%, COL4A4: 57.7%, COL4A5: 65.3%). Using 15 renal/hepatic cyst related ICD codes in pts with imaging (n=281) we identified 27 (9.6%) pts with cysts, 8.6%: COL4A3, 11%: COL4A4, and 6.2%: COL4A5; 0.7% coded for ADPKD. By image analysis, kidney cysts were present 56% of COL4A3, 45.2% of COL4A4 and 30.7% of COL4A5 (see Fig1); median eGFR was 74, 75 and 78 ml/min/1.73 m2. Additionally, 2.5% COL4A4 and 7.7% COL4A5 monoallelic individuals had FSGS. Conclusion: Monoallelic LP variants in COL4A3/A4/A5 often have glomerular phenotypes and cyst development seen in 30-50% of cases, although multiple cysts are rarer. Therefore, genetic screening panels for PKD pts should encompass COL4A3/A4/A5. Funding: NIDDK SupportFig1: Kidney Cysts by age in COL4A3/A4/A5 mutation individuals