Five patients with disorders of calcium metabolism presented with GCM2 gene variants

Abstract

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.

Figure 1

Pedigree of 5 families with variants in the GCM2 gene. The novel variant is marked in bold. Index case are indicated by the arrows. Squares denote male family members, circles female family members, and solid symbols symptomatic subjects.

Figure 2

Schematic representation of the GCM2 gene, representing the position of 3 missense variants and one short duplication. Variant marked in bold has not been reported to date. TAD1 transcriptional activation domain 1, TAD2 transcriptional activation domain 2, CCID C-terminal conserved inhibitory domain.