Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism ?

Coppin L1, Dufosse M2, Romanet P3, Giraud S4, North MO5, Cardot-Bauters C6, Borson-Chazot F7, Duchesne L8, Metallo M9, Lovecchio T10, Barlier A11, Odou MF12.

Author information

1: L Coppin, Centre de biologie pathologie, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
2: M Dufosse, Service de Biochimie et Biologie moléculaire "Hormonologie, Métabolisme-Nutrition, Oncologie", Centre Hospitalier Régional Universitaire de Lille, Lille, France.
3: P Romanet, Laboratory of molecular biology, AP-HM, Marseille, France.
4: S Giraud, Genetics department, Hospices Civils de Lyon, Lyon, France.
5: M North, Hôpital Cochin, service de génétique et biologie moléculaire, Assistance Publique - Hopitaux de Paris, Paris, France.
6: C Cardot-bauters, Centre de biologie pathologie, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
7: F Borson-Chazot, HESPER, Universite Claude Bernard Lyon 1, Villeurbanne, France.
8: L Duchesne, Service d'endocrinologie, CHR Metz-Thionville, Metz, France.
9: M Metallo, Department of endocrinology, CHU Nancy, Nancy, France.
10: T Lovecchio, Service de Biochimie et Biologie moléculaire "Hormonologie, Métabolisme-Nutrition, Oncologie", CHRU de Lille, Lille, France.
11: A Barlier, Laboratory of molecular biology, AP-HM, Marseille, France.
12: M Odou, Service de Biochimie et Biologie moléculaire "Hormonologie, Métabolisme-Nutrition, Oncologie", CHRU de Lille, Lille, France.

Abstract

OBJECTIVE:

Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73=HRPT2 and CASR. During the last few years, new genes have been described as responsible for development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease. Design, and Methods: The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT).

RESULTS:

From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionnally, the investigation of a large family showed that GCM2 variants could be associated with low penetrancy.

CONCLUSION:

We provide a description and interpretation for GCM2 variants identified in French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of calcemia for asymptomatic patients carrying such variants.