Test Code CASRG CASR Full Gene Sequencing with Deletion/Duplication, Varies

Ordering Guidance

Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Testing for the CASR gene as part of a customized panel is available. For more information, see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

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.

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 whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

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:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Hereditary Renal Genetic Testing Patient Information (T918)

3. If not ordering electronically, complete, print, and send a Renal Diagnostics Test Request (T830) with the specimen.

Secondary ID

618058

Useful For

Providing a genetic evaluation of individuals with a personal or family history of familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, or autosomal dominant hypoparathyroidism (autosomal dominant hypocalcemia)

Establishing a diagnosis of familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, or autosomal dominant hypoparathyroidism (autosomal dominant hypocalcemia)

As a part of the workup for patients with primary hyperparathyroidism, idiopathic hypoparathyroidism, and Bartter syndrome

Disease States

Autosomal dominant hypoparathyroidism
Familial hypocalciuric hypercalcemia
Neonatal severe primary hyperparathyroidism
Idiopathic hypoparathyroidism

Special Instructions

Method Name

Sequence Capture and Next-Generation Sequencing (NGS)

Reporting Name

CASR Full Gene Analysis

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

The extracellular G-protein-coupled calcium-sensing receptor (CASR) is an essential component of calcium homeostasis. CASR is expressed at high levels in the parathyroid glands and kidneys. In the parathyroid glands, an increase in serum calcium 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, kidney calcium excretion is upregulated, and sodium chloride excretion is downregulated.(1) Both activating and inactivating genetic variants have been described in CASR and result in altered calcium sensing and subsequent inappropriate PTH release relative to serum calcium concentration.

Inactivating (loss-of-function) CASR variants result in undersensing of calcium concentrations and consequent PTH overproduction. 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 variants, FHH is due to heterozygous inactivating CASR variants. In FHH, serum calcium levels are mildly-to-moderately elevated, PTH may be normal or only modestly elevated, phosphate is normal or slightly low, and urinary calcium excretion is low for the degree of hypercalcemia.(1) Unlike patients with primary hyperparathyroidism, the majority of FHH patients do not seem to experience adverse long-term effects from hypercalcemia and elevated PTH levels. On the other hand, NSPHT is usually caused by homozygous or compound heterozygous inactivating CASR variants but can occasionally be caused by dominant-negative heterozygous variants.(1) NSPHT presents at birth, or shortly thereafter, with severe hypercalcemia requiring urgent parathyroidectomy.

Activating (gain-of-function) CASR variants lead to oversensing of calcium, resulting in suppression of PTH secretion and consequently hypoparathyroidism and hypocalcemia. This disorder is referred to as autosomal dominant hypocalcemia or autosomal dominant hypoparathyroidism. To date, all activating variants described are functionally dominant and inheritance is therefore autosomal dominant. However, sporadic (no known genetic etiology) cases also occur. Autosomal dominant hypoparathyroidism caused by CASR variants may account for many cases of idiopathic hypoparathyroidism. In addition, while the majority of patients exhibit only hypoparathyroidism, a small subgroup has extreme gain-of-function variants. These individuals may present with additional symptoms that are consistent with type V Bartter syndrome, including hypokalemic metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypomagnesemia.(1-2)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(3) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of variants in coding regions and intron/exon boundaries of the CASR gene, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the CASR gene.

There may be regions of the CASR gene that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences.(Unpublished Mayo method)

The reference transcript for CASR gene is NM_000388.4. Reference transcript numbers may be updated due to transcript reversioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Day(s) Performed