Hypercalcemic and Hypocalcemic Disorders via the GNA11 Gene

Familial hypocalciuric hypercalcemia (FHH) is a heritable disorder of mineral homeostasis characterized by lifelong elevation of serum calcium concentrations. FHH patients are usually asymptomatic and the disorder is generally considered benign. Clinical features of FHH include hypermagnesemia and low urinary calcium excretion. FHH patients have normal or mildly elevated circulating parathyroid hormone (PTH) level. In uncommon symptomatic cases, some adult patients have chondrocalcinosis and pancreatitis while some children may develop neonatal severe hyperparathyroidism (NSHPT). The age of FHH onset is mostly in infancy, but severe FHH can present in either childhood or early adulthood. FHH is a genetically heterogeneous disorder and consists of three variants: FHH1, FHH2 and FHH3. FHH2 is caused by dominant inactivating GNA11 mutations.

Autosomal dominant hypocalcemia (ADH) is characterized by mild to moderate hypocalcemia. ADH patients are generally asymptomatic, but some patients may have neuromuscular symptoms such as paresthesia, carpopedal spasm and seizures. Other common features of ADH include hyperphosphatemia, hypomagnesemia and relative hypercalciuria. ADH consists of two variants: ADH1 and ADH2. ADH2 is caused by dominant activating GNA11 mutations (Mannstadt et al. 2013; Nesbit et al. 2013).

GNA11 has 7 coding exons that encode the subunit alpha-11 of a G-protein member. Patients with defects in this protein exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. Genetic defects found so far in the GNA11 gene include missense mutations and small deletions. No large deletions or insertions have been reported in GNA11 for hypercalcemia or hypocalcemia (Human Gene Mutation Database).

Familial hypocalciuric hypercalcemia type 2 (FHH2) is an autosomal dominant disorder caused by inactivating GNA11 mutations (Mannstadt et al. 2013; Nesbit et al. 2013). The other two FHH-causative genes are CASR (FHH1) and AP2S1 (FHH3) (Nesbit et al. 2013; Hannan et al. 2013). CASR mutations were detected in around 65% of FHH patients.

Autosomal dominant hypocalcemia type 2 is an autosomal dominant disorder caused by activating GNA11 mutations (Mannstadt et al. 2013; Nesbit et al. 2013). The other known ADH-causative gene is CASR (Hannan et al. 2013).

Detection rate of pathogenic variants in the GNA11 gene in a large cohort of patients with familial hypocalciuric hypercalcemia type 2 or autosomal dominant hypocalcemia type 2 is unknown in the literature because documented GNA11 pathogenic variants have been reported only in limited cases.

This test provides full coverage of all coding exons of the GNA11 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).