Frequency of ClinVar Pathogenic Variants in Chronic Kidney Disease Patients Surveyed for Return of Research Results at a Cleveland Public Hospital

Return of results is not common in research settings as standards are not yet in place for what to return, how to return, and to whom. As a pioneer of large-scale of return of research results, the Precision Medicine Initiative Cohort now known of All of Us plans to return pharmacogenomic results and variants of clinical significance to its participants starting late 2019. To better understand the local landscape of possibilities regarding return of research results, we assessed the frequency of pathogenic variants and APOL1 renal risk variants in a small diverse cohort of chronic kidney disease patients (CKD) ascertained from a public hospital in Cleveland, Ohio genotyped on the Illumina Infinium MegaEX. Of the 23,720 ClinVar-designated variants directly assayed by the MegaEX, 8,355 (35%) had at least one alternate allele in the 130 participants genotyped. Of these, 18 ClinVar variants deemed pathogenic by multiple submitters with no conflicts in interpretation were distributed across 27 participants. The majority of these pathogenic ClinVar variants (14/18) were associated with autosomal recessive disorders. Of note were four African American carriers of TTR rs76992529 associated with amyloidogenic transthyretin amyloidosis, otherwise known as familial transthyretin amyloidosis (FTA). FTA, an autosomal dominant disorder with variable penetrance, is more common among African-descent populations compared with European-descent populations. Also common in this CKD population were APOL1 renal risk alleles G1 (rs73885319) and G2 (rs71785313) with 60% of the study population carrying at least one renal risk allele. Both pathogenic ClinVar variants and APOL1 renal risk alleles were distributed among participants who wanted actionable genetic results returned, wanted genetic results returned regardless of actionability, and wanted no results returned. Results from this local genetic study highlight challenges in which variants to report, how to interpret them, and the participant's potential for follow-up, only some of the challenges in return of research results likely facing larger studies such as All of Us.