Background Among individuals with high-risk APOL1 genotypes, the lifetime risk of developing kidney failure is ∼15%, indicating that other genetic variants or non-genetic modifiers likely contribute substantially to an individual patient’s risk of progressive kidney disease. Here we estimate the prevalence and distribution of molecularly diagnosed Mendelian kidney diseases among patients with high-risk APOL1 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 2020-2021. We identified patients with high-risk APOL1 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 molecularly diagnosed Mendelian kidney disease stratified by APOL1 genotype.

Results Of 15,181 patients, 3119 had genetic testing results consistent with a molecular diagnosis of Mendelian kidney disease (20.5%). 1035 (6.8%) had high-risk APOL1 genotypes. The prevalence of molecularly diagnosed Mendelian kidney diseases was lower in individuals with high-risk APOL1 genotypes (9.2%; n=95/1035) compared to single risk APOL1 allele carriers (14.4%; n=243/1687) and those with G0/G0 APOL1 genotypes (22.3%; n=2781/12459). The distribution of molecularly diagnosed Mendelian kidney diseases was broadly similar among patients with and without high-risk APOL1 genotypes.

Conclusions Among patients undergoing clinical genetic testing, we found a relatively high rate of molecularly diagnosed Mendelian kidney disease in patients with high-risk APOL1 genotypes. Mendelian kidney disease may contribute to wide variation in rates of progression observed among patients with high-risk APOL1 genotypes.

SP, LV, NS, DKK are full time employees of Natera, Inc. GMC serves on the Steering Committee of the AMPLITUDE trial, sponsored by Vertex.

This study did not receive any funding.

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We received an exemption from institutional review board review (study ID 20099-03) from Ethical & Independent Review Services, Corte Madera, California.

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