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J Clin Endocrinol Metab. 2019 Jan 8. doi: 10.1210/jc.2018-02517. [Epub ahead of print]

Analysis of Activating GCM2 Sequence Variants in Sporadic Parathyroid Adenomas.

Author information

Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, CT, USA.
Biostatistics Center, Connecticut Institute for Clinical and Translational Science, University of Connecticut, Farmington, CT, USA.
Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
Division of Otolaryngology- Head & Neck Surgery, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT, USA.
Center for Regenerative Medicine and Skeletal Development, University of Connecticut School of Dental Medicine, Farmington, CT, USA.
Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, CT, USA.



Sporadic, solitary parathyroid adenoma is the commonest cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin dependent kinase inhibitor genes, and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally-activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID), of GCM2, encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT.


To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma.

Patients and Design:

Regions encoding hyperparathyroidism-associated activating GCM2 variants were PCR-amplified and sequenced in genomic DNA from 396 otherwise unselected cases of sporadic parathyroid adenoma.


Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in 6 of 396 adenomas (1.52%) and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, about 3-fold greater than their frequency in the general population.


The examined rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma.


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