This test analyzes the CASR gene, which is associated with the spectrum of CASR-related disorders, including benign familial hypocalciuric hypercalcemia (BFHH), neonatal severe hyperparathyroidism (NSHPT), familial isolated hyperparathyroidism (FIHP), and autosomal dominant hypocalcemia (ADH).
It is important to confirm a diagnosis of CASR and determine the underlying cause of hyperparathyroidism in order to guide specific treatment and management. In individuals with BFHH, parathyroidectomy can be avoided. Although many of the typical signs and symptoms of CASR-related conditions evolve with age, analysis of the CASR gene may confirm a diagnosis of severe neonatal hyperparathyroidism and ADH in infancy or childhood and help guide treatment and management decisions. Identification of a disease-causing variant may also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
Benign familial hypocalciuric hypercalcemia (BFHH)
BFHH is characterized by high levels of calcium in the blood (hypercalcemia) and low levels of calcium in the urine (hypocalciuria), but affected individuals typically have no symptoms related to the condition. Some have enlarged parathyroid glands and slightly elevated levels of parathyroid hormone. This is clinically different from primary hyperparathyroidism and parathyroidectomy can therefore be avoided. Most individuals with this condition are asymptomatic throughout life.
Familial isolated hyperparathyroidism (FIHP)
FIHP is characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). Parathyroid cells may proliferate without control, which occasionally causes enlargement of the parathyroid glands in people with FIHP. Overproduction of parathyroid hormone from these abnormal glands may further stimulate the release of calcium into the blood. The high levels of calcium cause symptoms including kidney stones, gastrointestinal issues, hypertension, and fatigue.
Autosomal dominant hypocalcemia (ADH)
ADH is characterized by hypoparathyroidism and low levels of calcium in the blood (hypocalcemia). Hypocalcemia can cause muscle cramping and seizures, although approximately half of those with this condition have no associated health problems.
Neonatal severe hyperparathyroidism (NSHPT)
NSHPT presents in infants under 6 months of age with parathyroid hyperplasia, causing high levels of parathyroid hormone and hypercalcemia, which can result in skeletal abnormalities and neurological problems.
There is variability of symptoms in individuals who have pathogenic variants in the CASR gene that may be related to a gene dosing effect. However, all pathogenic variants cause nearly a 100% risk for hyperparathyroidism. In general, homozygous or compound heterozygous variants typically cause neonatal severe hyperparathyroidism (NSHPT), an autosomal-recessive disorder with life-threatening hypercalcemia and multiple fractures. Loss-of-function heterozygous variants in CASR cause benign familial hypocalciuric hypocalcemia (BFHH). Gain-of-function heterozygous variants cause FIHP and ADH.
Based on the current literature, up to 90% of individuals with BFHH have a pathogenic variant in CASR. The majority of NSHPT cases are caused by homozygous or compound heterozygous mutations in the CASR gene. A single pathogenic CASR variant has been reported in some individuals with FIHP or ADH.
BFHH, ADH, and FIHP are inherited in an autosomal dominant manner. NSHPT is inherited in an autosomal recessive manner.
In the United States, approximately 100,000 people develop hyperparathyroidism (HPT) each year. HPT is twice as common in women than in men and risk of developing the condition increases with advancing age. Roughly 1 in 500 women over the age of 60 will develop HPT. Approximately 5% of HPT cases are familial. The prevalence of CASR mutations is unknown, although it appears to be rare.
Testing for CASR may be considered for individuals with the following:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|