Familial Hypocalciuric Hypercalcemia (FHH) Panel

Familial hypocalciuric hypercalcemia (FHH) is a heritable disorder of mineral homeostasis characterized by lifelong elevation of serum calcium concentrations (Pollak et al. 1993; Nesbit et al. 2013). 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) by genetic profiling.

Familial hypocalciuric hypercalcemia (FHH) is inherited in an autosomal dominant manner and consists of three variants (FHH1, FHH2 and FHH3) depending on the causative gene.

Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function CASR pathogenic variants, accounting for around 65% of FHH patients (Pollak et al. 1993). CASR has 6 coding exons that encode the calcium-sensing receptor, a G-protein-coupled receptor (GPCR), which is essential in extracellular calcium homeostasis and regulation of salt-water metabolism (Hannan et al. 2013). Genetic defects located throughout the CASR gene include missense, nonsense, splicing site variants, and small deletion/insertions, while large deletions and insertions are very rare (Human Gene Mutation Database). The majority (>50%) of pathogenic variants associated with hypercalcemic and hypocalcemic disorders are located in the extracellular domain (ECD) of CaSR (Hannan et al. 2012).

Familial hypocalciuric hypercalcemia type 2 (FHH2) is caused by inactivating GNA11 pathogenic variants (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 to changes in extracellular calcium concentrations. Genetic defects found so far in the GNA11 gene include missense mutations and small deletions. No large deletions have been reported (Human Gene Mutation Database).

Familial hypocalciuric hypercalcemia type 3 (FHH3) is caused by AP2S1 pathogenic variants (Nesbit et al. 2013). AP2S1 has 5 coding exons that encode the σ-2 subunit of the adaptor-related protein complex 2 (AP2), which is a central component of clathrin-coated vesicles (CCVs) pivotal in clathrin-mediated endocytosis. Genetic defects found to date in the AP2S1 gene are all missense substitutions only occurring at codon p.Arg15 (Nesbit et al. 2013; Hendy et al. 2014).

CASR pathogenic variants are detected in around 65% of FHH patients (Hannan et al. 2013).

Heterozygous AP2S1 missense variants were found in 13% to 20% of unrelated FHH patients who were negative for CASR pathogenic variants (Nesbit et al. 2013; Hendy et al. 2014).

Detection rate of pathogenic variants in the GNA11 gene in a large cohort of patients with FHH2 is unknown in the literature because documented GNA11 pathogenic variants have been reported only in limited cases (Mannstadt et al. 2013; Nesbit et al. 2013).

In reported in FHH patients, large deletions and duplications were rarely found in CASR while no deletions and duplications have been reported in GNA11 and AP2S1.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).