Familial Hypocalciuric Hypercalcemia (FHH) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10125 AP2S1 81479,81479 Order Options and Pricing
CASR 81405,81479
GNA11 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10125Genes x (3)81479 81405, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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.

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for this test are patients with familial hypocalciuric hypercalcemia.

Genes

Official Gene Symbol OMIM ID
AP2S1 602242
CASR 601199
GNA11 139313
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Hannan F. M. et al. 2012. Human Molecular Genetics. 21: 2768-2778. PubMed ID: 22422767
  • Hannan F.M., Thakker R.V. 2013. Best Practice & Research. Clinical Endocrinology & Metabolism. 27: 359-71. PubMed ID: 23856265
  • Hendy G.N. et al. 2014. The Journal of Clinical Endocrinology and Metabolism. 99: E1311-5. PubMed ID: 24731014
  • Human Gene Mutation Database (HGMD).
  • Mannstadt M. et al. 2013. The New England Journal of Medicine. 368: 2532-4. PubMed ID: 23802536
  • Nesbit M.A. et al. 2013. Nature Genetics. 45: 93-7. PubMed ID: 23222959
  • Nesbit M.A. et al. 2013. The New England Journal of Medicine. 368: 2476-86. PubMed ID: 23802516
  • Pollak M.R. et al. 1993. Cell. 75: 1297-303. PubMed ID: 7916660

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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