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HelpTest ID CASRZ CASR Gene, Full Gene Analysis
Useful For
Establishing a diagnosis of familial hypocalciuric hypercalcemia
As part of the workup of some patients with primary hyperparathyroidism
Establishing a diagnosis of neonatal severe primary hyperparathyroidism
Establishing a diagnosis of autosomal dominant hypoparathyroidism
As part of the workup of idiopathic hypoparathyroidism
As part of the workup of patients with Bartter syndrome
Special Instructions
Method Name
Polymerase Chain Reaction (PCR) Followed by DNA Sequence
Analysis
(PCR is utilized pursuant to a license agreement with Roche
Molecular Systems, Inc.)
Reporting Name
CASR Gene, Full Gene AnalysisSpecimen Type
VariesSpecimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube.
Additional Information: Specimen preferred to arrive within 96 hours of collection.
Forms:
1. Calcium Sensing Receptor (CASR) Gene Testing Patient Information (T551) in Special Instructions
2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.
Specimen Minimum Volume
1 mL
Specimen Stability Information
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Ambient (preferred) | |
| Frozen | ||
| Refrigerated | ||
Clinical Information
The extracellular G-protein-coupled calcium-sensing receptor (CASR) is an essential component of calcium homeostasis. CASR is expressed at particularly high levels in the parathyroid glands and kidneys. It forms stable homodimeric cell-membrane complexes, which signal upon binding of extracellular calcium ions (Ca[++]). In the parathyroid glands, this results in downregulation of gene expression of the main short-term regulator of calcium homeostasis, parathyroid hormone (PTH), as well as diminished secretion of already synthesized PTH. At the same time, renal calcium excretion is upregulated and sodium chloride excretion is downregulated. Ca(++) binding to CASR is highly cooperative within the physiological Ca(++) concentration range, leading to a steep dose-response curve, which results in tight control of serum calcium levels.
To date, over 100 different alterations in the CASR gene have been described. Many of these cause diseases of abnormal serum calcium regulation. Inactivating mutations result in undersensing of Ca(++) concentrations and consequent PTH overproduction and secretion. This leads to either familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSPHT), depending on the severity of the functional impairment.
Except for a very small percentage of cases with no apparent CASR mutations, FHH is due to heterozygous inactivating CASR mutations. Serum calcium levels are mildly-to-moderately elevated. PTH is within the reference range or modestly elevated, phosphate is normal or slightly low, and urinary calcium excretion is low for the degree of hypercalcemia. Unlike patients with primary hyperparathyroidism (PHT), which can be difficult to distinguish from FHH, the majority of FHH patients do not seem to suffer any adverse long-term effects from hypercalcemia and elevated PTH levels. They should, therefore, generally not undergo parathyroidectomy.
NSPHT is usually due to homozygous or compound heterozygous inactivating CASR mutations, but can occasionally be caused by dominant-negative heterozygous mutations. The condition presents at birth, or shortly thereafter, with severe hypercalcemia requiring urgent parathyroidectomy.
Activating mutations lead to oversensing of Ca(++), resulting in suppression of PTH secretion and consequently hypoparathyroidism. All activating mutations described are functionally dominant and disease inheritance is therefore autosomal dominant. However, sporadic cases also occur. Autosomal dominant hypoparathyroidism caused by CASR mutations may account for many cases of idiopathic hypoparathyroidism. Disease severity depends on the degree of gain of function, spanning the spectrum from mild hypoparathyroidism, which is diagnosed incidentally, to severe and early onset disease. In addition, while the majority of patients suffer only from hypoparathyroidism, a small subgroup with extreme gain of function mutations suffer from concomitant inhibition of renal sodium chloride transport. These individuals may present with additional symptoms of hypokalemic metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypomagnesemia, consistent with type V Bartter syndrome.
Reference Values
An interpretive report will be provided
Cautions
Some individuals who have involvement of the CASR gene may have a pathogenic variant that is not identified by the methods performed (eg, large genomic deletions, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of positive carrier status or affected status of neonatal severe primary hyperparathyroidism (NSPHY), hypocalciuric hypercalcemia (FHH), or autosomal dominant hypoparathyroidism (ADH). For predictive testing of asymptomatic individuals, it is important to first document the presence of a pathogenic gene variant in an affected family member.
Test results should be interpreted in context of clinical findings, family history, and other laboratory data.
Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
In some cases, DNA variants of undetermined significance may be identified. Rarely, sequence variants in primer- or probe-binding sites can result in false-negative test results. If results obtained do not match the clinical findings, additional testing should be considered.
Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common benign variants identified for this patient are available upon request.
Very rarely, patients with typical biochemical findings of FHH, with or without a supporting family history, will have no CASR mutations. In 2 such families, linkage to chromosome 19 has been established, suggesting that a small percentage of FHH cases are caused by mutations in other genes, possibly related to CASR downstream signaling.
Up to 20% of patients with clinically typical autosomal dominant hypoparathyroidism may also lack demonstrable CASR mutations.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Day(s) Performed
Performed weekly, varies
Report Available
14 daysPerforming Laboratory
Mayo Medical Laboratories in Rochester
CPT Code Information
81405-CASR (calcium-sensing receptor) (eg, hypocalcemia), full gene sequence