Exploring the Clinical Utility of Genetic Testing in Patients with Primary Hyperparathyroidism

Abstract

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by increased levels of serum calcium and parathyroid hormone. Although frequently sporadic, a genetic etiology can be confirmed, usually through multi-gene panels, by the identification of germline pathogenic or likely pathogenic variants (GPVs) in at least ten genes in 10-30% of PHPT cases, with important implications for management. Recently published expert guidelines by the American Society for Bone and Mineral Research (ASBMR) recommend genetic testing for patients with PHPT who are under the age of 30, have multiglandular involvement, and/or a family history of hypercalcemia or a PHPT-related condition. We reviewed the medical records of 31 unrelated patients referred for a genetic evaluation for PHPT to calculate the diagnostic rate of testing and compare the phenotypes of patients by testing outcome. The diagnostic rate of genetic testing in patients with PHPT in this study was similar to other rates reported in the literature. As expected, six out of seven individuals with positive genetic testing results were found to meet ASBMR criteria. Importantly, exome sequencing (ES) performed in individuals identified to have an atypical phenotype identified GPVs in genes not included in PHPT multi-gene panels, which was the most common testing modality. These results highlight the utility of genetic testing in patients with PHPT and the role of ES in patients with atypical phenotypic presentations. Larger studies will be beneficial to further investigate the utility of ES in these disorders.