GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism

Context Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism (FIHP) and sporadic PHPT. However, as these previously-reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. Objective Determine the frequency of GCM2 variants-of-interest among patients with sporadic multigland or familial parathyroid disease, and assess their penetrance. Design and Patients DNA encoding PHPT-associated GCM2 germline-variants were PCR-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. Results GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and three (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33%, 1.04% respectively). Conclusions Observed in vitro activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared with the general population, yet penetrance values are very low i.e. most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.