Abstract: FR-OR078
Global Mutational Landscape in COL4A3, COL4A4, and COL4A5 and Estimating the Alport Syndrome (AS) Population
Session Information
- Noncystic Genetic Diseases: Multi-Omic Discovery and Emerging Therapeutic Approaches
October 23, 2026 | Location: Mile High Ballroom 4D, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Erlandsson, Fredrik, Purespring Therapeutics Limited, London, England, United Kingdom
- Leenders, Matthijs Bart, Genescape, Leyden, Netherlands
- Clark, Dinah, Natera, Austin, Texas, United States
- Malone, Karen E., Genescape, Leyden, Netherlands
- Smith-Moore, Sarah, Purespring Therapeutics Limited, London, England, United Kingdom
- Schaefer, Franz, Universitat Heidelberg, Heidelberg, Germany
Background
AS is caused by COL4A3, COL4A4 and COL4A5 variants, and genotype affects clinical presentation. COL4A5 is located on the X-chromosome. The global prevalence of pathogenic variants remains to be systematically investigated.
Methods
We leveraged >1.2M genomes from the US (NIH Topmed, All of Us), UK (UKBB), Europe (NFE_gnomad) and Japan (TogoVAR) and classified variants as pathogenic based on ACMG and 5 algorithms, including SpliceAI and AlphaMissense. RenaSight and European Rare Kidney Disease registry (ERKReg) were leveraged to validate model findings for US and Europe respectively. Population age distribution and genotype-phenotype correlation were used to estimate prevalence of each genotype.
Results
We found 136k, 141k, 159k unique variants in COL4A3, COL4A4 and COL4A5 respectively, and 856, 739, and 260 variants were classified as pathogenic. The highest prevalence variants were identical in EU and US for all three genes, while UK and Japan exhibited marked differences.
COL4A5 loss of function variants causing more severe disease were present in 15.5, 23.8, 16.7 and 0% of pathogenic variants in US, EU, UK and Jpn. The late onset COL4A5 Gly624Asp variant accounted for 24.9, 46.9, 6.2 and 0% of pathogenic variants in US, EU, UK and Jpn.
COL4A5 hemizygosity was ~9.6x, 19x, 3.3x more common than COL4A3/4 homozygosity or compound heterozygosity (H/CH) in US, EU and UK. COL4A3 H/CH was 1.5-2.5x as common as COL4A4 H/CH, except Jpn where it was 0.23x as common.
COL4A3/4 heterozygosity was noted in 1.12% of US population, but present in 4.2% of the Renasight cohort.
Deep intronic variants undetectable with exome sequencing are expected to account for 16, 25 and 4% of pathogenic variants in COL4A3, COL4A4 and COL4A5 respectively.
Conclusion
The lower number of COL4A5 pathogenic variants compared to COL4A3/4 is likely due to X-linked inheritance. Despite lower pathogenic variant prevalence COL4A5 causes majority of AS kidney failure.
The COL4A5 Gly624Asp variant will be expected to account for up to half of European and 1/3 of US cases with remaining kidney function due to much later onset and high prevalence. Genetic testing may be warranted also in older men when XLAS is suspected.
The marked overrepresentation of COL4A3/4 heterozygosity in the Renasight cohort compared to the US population suggests the genotype may contribute significantly to kidney disease.
Funding
- Commercial Support – Purespring Therapeutics