Whole exome sequencing in familial isolated primary hyperparathyroidism

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Familial isolated hyperparathyroidism (FIHP) is a rare inherited condition, representing 1% of primary hyperparathyroidism (PHPT) cases.
• FIHP exhibits genetic heterogeneity, with known mutations in genes such as MEN1, CDC73, CASR, and GCM2.

Purpose of the Study:

• To investigate the molecular pathogenesis of FIHP in Italian kindreds.
• To identify novel genetic variants associated with FIHP.

Main Methods:

• Whole exome sequencing (WES) was performed on probands from seven unrelated FIHP kindreds.
• Family-based exome analysis was conducted on a large family with PHPT and unrelated tumors.
• Selected variants were screened in 18 additional FIHP kindreds.

Main Results:

• Three GCM2 variants were identified in two families; one pathogenic variant (p.Tyr394Ser) segregated with the disease.
• Seven heterozygous missense mutations in FAT3, PARK2, HDAC4, ITPR2, and TBCE genes were found in six probands.
• An APC gene variant (p.Val530Ala) co-segregated with PHPT in a family with additional tumors, including colonic polyposis.

Conclusions:

• The study confirms the role of GCM2 germline mutations in FIHP pathogenesis, though at a lower frequency than previously reported.
• Novel variants in additional genes may contribute to FIHP predisposition, warranting further investigation.
• The findings highlight the genetic complexity of FIHP and the need for continued molecular research.