Ethnicity of Patients With Germline -Activating Variants and Primary Hyperparathyroidism.

Context: Germline gain-of-function variants in the transcription factor GCM2 were found in 18% of kindreds with familial isolated hyperparathyroidism (FIHP). These variants [c.1136T>A (p.Leu379Gln) and c.1181A>C (p.Tyr394Ser)] were located in a 17-amino acid transcriptional inhibitory domain named C-terminal conserved inhibitory domain (CCID).

Objective: We investigated the ethnicity of individuals with germline variants in the CCID in our primary hyperparathyroidism (PHPT) patient samples and in the Genome Aggregation Database.

Design: Ethnicity information was obtained from an in-house clinical database and genetic counseling. Sanger sequencing of blood DNA was used to determine the genotype of the CCID region. Luciferase reporter assays were performed to determine the functional impact of variants.

Setting And Patients: National Institute of Diabetes and Digestive and Kidney Diseases endocrine clinic is a service that accepts PHPT referral patients.

Results: The p.Tyr394Ser variant was found in 41% [95% confidence interval (CI), 22% to 64%] of Ashkenazi Jewish (AJ) kindreds with FIHP and in 27% (95% CI, 17% to 40%) of AJ patients with sporadic PHPT. The p.Tyr394Ser variant was also found in sporadic PHPT patients of European ancestry, but at a lower prevalence. The p.Leu379Gln variant was found in 8% (95% CI, 1% to 26%) of European kindreds with FIHP and 0.5% (95% CI, 0% to 3.0%) of sporadic PHPT cases of European ancestry. The sporadic PHPT patients with -activating variants often had multigland involvement or postoperative recurrent or persistent disease.

Conclusions: Specific -activating variants enriched among various ethnic backgrounds could contribute to a large number of cases with FIHP or sporadic PHPT.