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Abstract: TH-OR33

Phenotypic Spectrum of COL4A3 Variants: The Geisinger MyCode/DiscovEHR Study

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Solanki, Kaushal V., Geisinger Health, Danville, Pennsylvania, United States
  • Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States
  • Rheault, Michelle N., University of Minnesota Academic Health Center, Minneapolis, Minnesota, United States
  • Strande, Natasha T., Geisinger Health, Danville, Pennsylvania, United States
  • Bucaloiu, Ion D., Geisinger Health, Danville, Pennsylvania, United States
  • Chang, Alex R., Geisinger Health, Danville, Pennsylvania, United States
Background

Patients with heterozygous COL4A3 variants have been shown to be at increased risk of kidney disease, ranging from microscopic hematuria to focal segmental glomerulosclerosis (FSGS) and end-stage kidney disease (ESKD). Most studies of patients with COL4A3 variants have focused on individuals presenting with more severe manifestations, and thus the full phenotypic spectrum remains unclear.

Methods

We used data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing and EHR data. We identified participants with COL4A3 variants listed as pathogenic or likely pathogenic (P/LP) in ClinVar at minor allele frequency <0.01. Phenotypes were assessed using ICD diagnosis codes, linkage to the US Renal Data System, blood and urine laboratory data, and targeted chart review. Associations between COL4A3 P/LP variants and Alport syndrome-related phenotypic features were assessed using logistic regression. Additional analyses were done comparing carriers and related non-carriers for the most common variant (p.Gly695Arg) observed in our cohort.

Results

There were 329 (0.2%) participants with a previously reported P/LP rare COL4A3 variant. Individuals with a COL4A3 variant (mean age 58.8 years) were at increased risk of ESKD (OR 3.79, 95% CI: 2.36-6.08), hematuria (OR 1.99, 95% CI: 1.37-2.88), FSGS/renal sclerosis (OR 7.46, 95% CI: 3.31-16.84), and eGFR <60 ml/min/1.73m2 (OR 1.46, 95% CI: 1.07-1.99) but not hearing loss. The most common P/LP variant was p.Gly695Arg with 161 heterozygous individuals in 58 families (Table). Compared to 123 related non-carriers, those with the p.Gly695Arg variant were at increased risk of hematuria (OR 3.44, 95% CI: 1.34-8.86), and ESKD (OR 12.39 (1.59-96.33; P=0.02). Two patients had a known family history of Alport Syndrome, and only 1 patient had been diagnosed using clinical genetic testing.

Conclusion

In an unselected health system cohort, we demonstrate that rare P/LP variants in COL4A3 increase risks of hematuria, FSGS, and ESKD, and are undiagnosed in the vast majority of individuals.

Funding

  • NIDDK Support