Germline GCM2 Mutation Screening in Chinese Primary Hyperparathyroidism Patients.

OBJECTIVE: Glial cell missing 2 (GCM2), the critical regulator in the development of parathyroid glands, has been associated with the pathogenesis of primary hyperparathyroidism (PHPT). Relevant data in Chinese and other Asian populations are still lacking. This study aimed to screen the germline mutations of GCM2 in Chinese PHPT patients.

METHODS: A total of 232 patients diagnosed with PHPT at the Peking Union Medical College Hospital from July, 2016, to February, 2019, were screened using targeted next-generation sequencing to identify rare variants of 8 candidate genes associated with PHPT, including GCM2. Luciferase assays were performed to determine the functional impact of the GCM2 variants.

RESULTS: Four male patients were found to carry 3 rare missense variants of the GCM2 gene, including c.1162A>G (p.K388E), c.1144G>A (p.V382M), and c.1247A>G (p.Y416C). Two variants (p.K388E and p.V382M) located within a highly conserved region were associated with GCM2 transactivation function. The 2 cases carrying the p.K388E mutation had a pathology of carcinoma, and the case with the p.V382M mutation had atypical adenoma.

CONCLUSION: This study determined an overall GCM2 gain-of-function mutation frequency of 1.3% in a relatively large-sample-sized Chinese PHPT cohort and supported a higher malignant tendency in cases carrying activating GCM2 mutations. Hence, preoperative screening for these GCM2 mutations might be beneficial to treatment decisions, and longer follow-up for such patients is recommended.