Abstract
Background: Multiple Endocrine Neoplasia Syndrome Type 2 (MEN2) is an inherited endocrine disorder characterized by the development of pheochromocytoma, medullary thyroid carcinoma (MTC) and parathyroid neoplasia. MEN2 is autosomal dominant and occurs from activating missense variants in the RET proto-oncogene. The estimated prevalence of MEN2 is thought to be 1 per 30,000 in the general population, and although rare, the identification of MEN2 can aid with early screening and prevention for patients and their families. Aim: The aim of our study was to investigate the prevalence and clinical manifestations of pathogenic RET variants in the multi-ethnic BioMe Biobank. Methods: We used exome sequencing and electronic health record (EHR) data from BioMe Biobank participants, who are recruited from primary care and specialty clinics across a single U.S. Health System. We evaluated exome sequence data from 30,000 BioMe participants for RET variants designated as pathogenic for MEN2 according to the clinical genetics database ClinVar. We reviewed EHR data for carriers of pathogenic RET variants. Results: In the BioMe Biobank, 5 ClinVar pathogenic variants were identified in the RET gene. Fifteen participants were heterozygous carriers of these variants; 5 were of self-reported African ancestry, 5 of Hispanic/Latino ancestry, 2 of European ancestry, and 3 of other or unknown ancestry. The age range of carriers was 23-78 years, and 60% were female. The estimated prevalence of pathogenic RET variant carriers in BioMe was ~1 in 2000. Based on EHRs, only 3 carriers (20%) were identified from usual clinical care as having the diagnosis of MEN2A. All 3 carriers with diagnosed MEN2A had the 10:43114500:T:C variant (rs75076352) and had a history of MTC and pheochromocytoma. One of the 3 carriers had a history of elevated parathyroid hormone levels and renal calculi without hypercalcemia. Two of the 3 carriers had a documented family history of MEN2A. Of the 12 pathogenic RET variant carriers without known MEN2, 9 (75%) were diagnosed with hypertension. 7 (58%) carried the 10:43119548:G:A variant (rs79658334). Of these 7 carriers, one had a thyroid nodule, three had autoimmune thyroid disease, one had an adrenal cortical adenoma with primary hyperaldosteronism and hypokalemic periodic paralysis, and two had no known endocrine conditions. Conclusions: These results from the BioMe Biobank reveal a higher prevalence of pathogenic RET variants than previously recognized. Carriers of pathogenic RET variants demonstrate highly variable expressivity for traits for which earlier diagnoses might improve outcomes; these findings have implications for cascade testing of family members. Genomic screening for pathogenic RET variants will likely improve our understanding of MEN2 on a more molecular basis.