Test ID: CASRZ CASR Gene, Full Gene Analysis, Varies
Reporting Name
CASR Gene, Full Gene AnalysisUseful 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
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.
Interpretation
Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.
Special Instructions
Report Available
14 to 20 daysDay(s) Performed
Varies
Clinical Reference
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-423
2. Hendy GN, D'Souza-Li L, Yang B, et al: Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hypocalciuric hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000 Oct;16(4):281-296. The authors maintain a CASR polymorphism/mutation database available at www.casrdb.mcgill.ca/
3. Lienhardt A, Bai M, Lgarde JP, et al: Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 2001 Nov;86(1):5313-5323
4. Hu J, Spiegel AM: Naturally occurring mutations of the extracellular Ca2+ -sensing receptor: implications for its structure and function. Trends Endocrinol Metab 2003 Aug;14(6):282-288
5. Naesens M, Steels P, Verberckmoes R, et al: Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol 2004;96(3):65-78
6. Egbuna OI, Brown EM: Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008;22:129-148
Method Name
Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis
Specimen Type
VariesShipping Instructions
Specimen preferred to arrive within 96 hours of draw.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Specimen 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.
Specimen Minimum Volume
1 mL
Specimen Stability Information
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Ambient (preferred) | ||
Frozen | |||
Refrigerated |
Reference Values
An interpretive report will be provided
Test Classification
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81405-CASR (calcium-sensing receptor) (eg, hypocalcemia), full gene sequence
LOINC Code Information
Test ID | Test Order Name | Order LOINC Value |
---|---|---|
CASRZ | CASR Gene, Full Gene Analysis | 82534-9 |
Result ID | Test Result Name | Result LOINC Value |
---|---|---|
37446 | Result Summary | 50397-9 |
37447 | Result | 82939-0 |
37448 | Interpretation | 69047-9 |
37449 | Additional Information | 48767-8 |
37450 | Specimen | 31208-2 |
37451 | Source | 31208-2 |
37452 | Released By | 18771-6 |
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Calcium Sensing Receptor (CASR) Gene Testing Patient Information (T551) in Special Instructions
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