Germline Mutations Related to Primary Hyperparathyroidism Identified by Next-Generation Sequencing

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Primary hyperparathyroidism (PHPT) involves parathyroid hormone overproduction and hypercalcemia.
• Hereditary forms account for 10% of PHPT, linked to genes like MEN1, RET, CASR, and CDC73.
• Genetic underpinnings of sporadic PHPT and parathyroid cancer remain largely unexplored.

Purpose of the Study:

• To identify genetic variants associated with PHPT, encompassing familial, benign sporadic, and cancerous forms.
• To utilize next-generation sequencing (NGS) for comprehensive genetic analysis in PHPT patients.

Main Methods:

• Enrolled 107 PHPT patients who underwent NGS between 2017 and 2021.
• Classified genetic variants (pathogenic, likely pathogenic, VUS) per ACMG-AMP criteria.
• Analyzed patient characteristics, focusing on those with positive genetic findings.

Main Results:

• Identified 3 pathogenic variants in CDC73 and MEN1.
• Detected 10 likely pathogenic variants in CASR, CDC73, LRP5, MEN1, SDHA, and VHL.
• Found 39 VUS variants and specific GCM2 and APC variants linked to PHPT subtypes.

Conclusions:

• NGS revealed potential genetic contributors to PHPT pathogenesis.
• Genetic variants identified may aid in diagnosing and managing PHPT.
• Specific patient features (young age, family history, multiglandular or recurrent disease) correlate with positive genetic findings.