GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Multiglandular and familial disease account for significant primary hyperparathyroidism (PHPT) cases.
• Germline missense variants in GCM2, a parathyroid development regulator, have been linked to PHPT.
• Previous GCM2 variant studies lacked sufficient penetrance and functional data for clinical utility assessment.

Purpose of the Study:

• To determine the frequency of specific GCM2 variants in patients with multiglandular or familial parathyroid disease.
• To assess the penetrance of these GCM2 variants.
• To evaluate the clinical utility of GCM2 variant detection in PHPT.

Main Methods:

• DNA from 107 patients with sporadic multiglandular or familial parathyroid tumors was analyzed.
• Polymerase chain reaction amplification and sequencing were used to identify GCM2 germline variants.
• Variant frequencies and penetrance were compared to the general population.

Main Results:

• GCM2 variants were found in 8.4% of patients (9 out of 107).
• Y282D and Y394S variants were significantly enriched in PHPT patients compared to the general population.
• Both variants exhibited very low penetrance, with risk estimates below 2%.

Conclusions:

• In vitro-activating GCM2 alleles are overrepresented in PHPT patients but have low penetrance.
• Most individuals with these variants have a minimal risk of developing PHPT.
• Further research is needed to clarify the pathogenic role and clinical utility of these GCM2 variants.