Prevalence of Mendelian Kidney Disease Among Patients With High-Risk Genotypes Undergoing Commercial Genetic Testing in the United States.

Introduction: Among individuals with high-risk genotypes, the lifetime risk of developing kidney failure is ∼15%, indicating that other genetic variants or nongenetic modifiers likely contribute substantially to an individual patient's risk of progressive kidney disease. Here, we estimate the prevalence and distribution of Mendelian kidney diseases among patients with high-risk genotypes undergoing commercial genetic testing in the United States.

Methods: We analyzed clinical exome sequencing data from 15,181 individuals undergoing commercial genetic testing for Mendelian kidney disease in the United States from 2020 to 2021. We identified patients with high-risk genotypes by the presence of G1/G1, G1/G2, or G2/G2 alleles. Patients carrying single risk APOL1 alleles were identified as G1/G0, G2/G0; the remainder of patients were G0/G0. We estimated the prevalence and distribution of Mendelian kidney disease stratified by genotype and genetically predicted ancestry.

Results: Of 15,181 patients, 3119 had genetic testing results consistent with a molecular diagnosis of Mendelian kidney disease (20.5%). Of 15,181 patients, 1035 (6.8%) had high-risk genotypes. Among patients with recent genomic African ancestry, the prevalence of Mendelian kidney diseases was lower in those with high-risk genotypes (9.6%;  = 91/944) compared with single risk allele carriers (13.6%;  = 198/1453) and those with G0/G0 genotypes (16.6%;  = 213/1281). Among patients with Mendelian kidney disease and recent genomic African ancestry, we observed differences in the prevalence of pathogenic/likely pathogenic variants in (19.8% in high-risk vs. 30.2% in low-risk genotypes), and (24.2% in high-risk vs. 10.5% in low-risk genotypes).

Conclusion: In this selected population of patients undergoing clinical genetic testing, we found evidence of Mendelian kidney disease in ∼10% patients with high-risk genotypes.