Prevalence of Mendelian kidney disease among patients with high-risk APOL1 genotypes undergoing commercial genetic testing in the United States

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 15181 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. ### Competing Interest Statement SP, LV, NS, DKK are full time employees of Natera, Inc. GMC serves on the Steering Committee of the AMPLITUDE trial, sponsored by Vertex. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We received an exemption from institutional review board review (study ID 20099-03) from Ethical & Independent Review Services, Corte Madera, California. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Partial restrictions to the data and/or materials apply. All available data is included in the manuscript and/or supporting information.