The Phenotypic Spectrum of COL4A3 Heterozygotes

Kaushal V Solanki; Yirui Hu; Bryn S Moore; Vida Abedi; Venkatesh Avula; Tooraj Mirshahi; Regeneron Genetics Center; Natasha T Strande; Ion D Bucaloiu; Alexander R Chang

doi:10.1016/j.ekir.2023.07.010

The Phenotypic Spectrum of COL4A3 Heterozygotes

Kidney Int Rep. 2023 Jul 25;8(10):2088-2099. doi: 10.1016/j.ekir.2023.07.010. eCollection 2023 Oct.

Authors

Affiliations

¹ Center for Kidney Health Research, Geisinger, Danville, Pennsylvania, USA.
² Department of Population Health Sciences, Geisinger, Danville, Pennsylvania, USA.
³ Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA.
⁴ Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania, USA; Road, Tarrytown, New York, USA.
⁵ Autism and Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
⁶ Department of Nephrology, Geisinger, Danville, Pennsylvania, USA.

Abstract

Introduction: The penetrance and phenotypic spectrum of autosomal dominant Alport Syndrome (ADAS), affecting 1 in 106, remains understudied.

Methods: Using data from 174,418 participants in the Geisinger MyCode/DiscovEHR study, an unselected health system-based cohort with whole exome sequencing, we identified 403 participants who were heterozygous for likely pathogenic COL4A3 variants. Phenotypic data was evaluated using International Classification of Diseases (ICD) codes, laboratory data, and chart review. To evaluate the phenotypic spectrum of genetically-determined ADAS, we matched COL4A3 heterozygotes 1:5 to nonheterozygotes using propensity scores by demographics, hypertension, diabetes, and nephrolithiasis.

Results: COL4A3 heterozygotes were at significantly increased risks of hematuria, decreased estimated glomerular filtration rate (eGFR), albuminuria, and kidney failure (P < 0.05 for all comparisons) but not bilateral sensorineural hearing loss (P = 0.9). Phenotypic severity was more severe for collagenous domain glycine missense variants than protein truncating variants (PTVs). For example, patients with Gly695Arg (n = 161) had markedly increased risk of dipstick hematuria (odds ratio [OR] 9.50; 95% confidence interval [CI]: 6.32, 14.28) and kidney failure (OR 7.02; 95% CI: 3.48, 14.16) whereas those with PTVs (n = 119) had moderately increased risks of dipstick hematuria (OR 1.64; 95% CI: 1.03, 2.59) and kidney failure (OR 3.44; 95% CI: 1.28, 9.22). Less than a third of patients had albuminuria screening completed, and fewer than 1 of 3 were taking inhibitors of the renin-angiotensin-aldosterone system.

Conclusion: This study demonstrates a wide spectrum of phenotypic severity in ADAS due to COL4A3 with phenotypic variability by genotype. Future studies are needed to evaluate the impact of earlier diagnosis, appropriate evaluation, and treatment of ADAS.

Keywords: Alport Syndrome; Chronic Kidney Disease; Clinical Epidemiology; Genetic Renal Disease; Kidney Failure.

Grants and funding

R01 GM111913/GM/NIGMS NIH HHS/United States