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

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 the 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. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance. Conclusion We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.

Genetics of monogenic disorders of calcium and bone metabolism

“…57 and increased risk of PC in such families. 14,[63][64][65] The majority of genetically unexplained FIHP kindreds have low numbers of affected individuals, 59 suggesting either a low penetrance genetic aetiology, or the chance occurrence of sporadic cases within a family. Germline variants in several of the cyclin-dependent kinase inhibitor genes (e.g., CDKN1A, CDKN1B, CDKN2B, CDKN2C)…”

“…However, the finding of an inactivating CASR mutation in a kindred with hereditary hypercalcaemia usually indicates a diagnosis of FHH (see below). The genetic basis of the majority of FIHP cases remains unexplained, although 15%–20% of kindreds are reported to harbour GCM2 mutations, and may have an increased prevalence of multi‐gland parathyroid disease, lesser rates of surgical cure, and increased risk of PC in such families 14,63–65 . The majority of genetically unexplained FIHP kindreds have low numbers of affected individuals, 59 suggesting either a low penetrance genetic aetiology, or the chance occurrence of sporadic cases within a family.…”

Hereditary Primary Hyperparathyroidism

“…HPT-JT due to CDC73 variants, FIHP due to GCM2 variants) are not fully penetrant such that some 'affected' family members (i.e., those harboring the diseaseassociated variant) may remain disease-free. 16,27,28 Although the majority of familial PHPT disorders have an autosomal dominant mode of inheritance, in some instances neither parent is affected. For example, a proportion of MEN1, CDC73 and RET pathogenic variants occur de novo (i.e., appearing for the first time in the affected individual), whilst in rare instances there may be germline mosaicism, in which the disease-associated mutation occurs in a proportion of one parents' gametes, such that apparently unaffected parents may give rise to multiple affected offspring.…”

“…Furthermore, an increased prevalence of rare germline missense GCM2 variants has been reported in cohorts of patients with sporadic PHPT, although are associated with a low disease penetrance. 27,28,[62][63][64] Recent clinical studies report an increased prevalence of multi-gland parathyroid disease, lesser rates of surgical cure, and increased risk of parathyroid carcinoma in FIHP kindreds harboring GCM2 variants 27,64 The genetic basis of the remaining 80% of FIHP kindreds remains unexplained, although the majority of such kindreds have low numbers of affected individuals, and in some instances may represent the chance occurrence of sporadic disease in multiple family members. Indeed, to date, genetic investigation of such kindreds has not identified other recurrently mutated genes.…”

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism

“…It has been shown that gcm2 -null mice develop parathyroid hypoplasia and hypoparathyroidism ( 11 ), and that homozygous and heterozygous germline inactivating GCM2 pathogenic variants in humans lead to hypoparathyroidism ( 12 , 13 ). Other variants are associated with hyperparathyroidism ( 14 , 15 ), with an overall higher frequency of GCM2 variants in sporadic and familial PHPT than in the general population ( 8 , 16 ). In 2017, Guan et al.…”