Experience Completing Population Screening for Variants Associated With Endocrine Tumor Syndromes in a Large, Healthcare-Based Cohort

Abstract Hereditary endocrine tumor syndromes (ETS) including Multiple Endocrine Neoplasia Types 1 and 2 (MEN1 and MEN2), von Hippel-Lindau (VHL), and Hereditary Paraganglioma and Pheochromocytoma syndromes (PGL/PCC) have a collective prevalence of 1 in 8500. In current practice, patients’ personal and family histories are used to determine whether genetic testing for ETS is warranted. Population genetic screening for other actionable conditions implies that current practice can be enhanced to identify individuals with genetic variants and that identification of such individuals can lead to improvements in risk management and early-onset diagnoses. It is unknown whether such benefits occur when screening for ETS risk. We report on the rate of syndrome-related features and post-disclosure risk management in patients informed of a pathogenic/likely pathogenic (P/LP) variant in a gene associated with an ETS through the MyCode Community Health Initiative (MyCode). MyCode is a biobank of individuals from a health system who consent to health-related research and return of clinically actionable results. Exome sequences are analyzed for P/LP variants in actionable genes, confirmed by a clinical laboratory, and disclosed to participants and their providers. All participants are offered follow-up with a genetics provider post-disclosure. Here, we focus on participants that received a P/LP variant in MEN1, RET, VHL, or an SDHx gene from June 2016-October 2019. From May-July 2020 we performed dual, manual review of participants’ electronic health records to assess personal and family histories, risk management behaviors, and post-disclosure diagnoses of endocrine neoplasms. Of 87,493 participants with available exome data, P/LP variants in genes of interest were identified in and disclosed to 80 participants (65% female, 99% self-reported White race, 99% self-reported non-Hispanic ethnicity, median age 57 years at results disclosure, median time since disclosure 2 years). Eighty-one percent of participants (n=65) did not have a prior diagnosis of an ETS and were included in additional analyses. Five participants (8%) had a personal history of syndrome-related features; 16 (25%) had a positive family history. Only seven (11%) met existing clinical testing criteria pre-disclosure. Post-disclosure, 37 (57%) completed at least one recommended risk management behavior; 11 of these (17%) were diagnosed with a syndrome-related neoplasm (e.g., medullary thyroid cancer). Results of population screening in a healthcare cohort suggest genetic variants associated with ETS risk are more common than previously reported (1 in 1094). Though additional studies on clinical utility are needed, these results suggest that screening healthcare populations for genetic risk can enable detection of individuals at risk for ETS, lead to uptake of risk management, and facilitate relevant clinical diagnoses.