The Invitae Hyperparathyroidism Panel analyzes genes associated with hereditary hyperparathyroidism (HPT). These genes were curated based on the available evidence to date and provide Invitae’s most comprehensive test for individuals and families with features of HPT.
Individuals with a pathogenic variant in one of these genes have a higher risk of developing parathyroid disease—a disease that can be difficult both to detect and to treat. Prolonged parathyroid disease can also cause other health issues that may result in serious complications. It can be extremely helpful to identify those who are at high risk so that additional screening, surveillance and interventions can be initiated—both for parathyroid disease and for other health issues, including certain cancers. These efforts can result in risk-reduction and early diagnosis, which may increase the chances of successful treatment and survival. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
AP2S1 CASR CDC73 CDKN1B GNA11 MEN1 RET
AP2S1 CASR CDC73 CDKN1B GNA11 MEN1 RET
In the United States, approximately 100,000 people develop hyperparathyroidism (HPT) each year. HPT is twice as common in women than in men, and the risk increases with age. Approximately 1 in 500 women over age 60 will develop HPT. Approximately 5% of HPT cases are familial (inherited). It is unknown if hyperparathyroidism and parathyroid adenomas may predispose to cancer.
The genes on this panel are associated with hereditary predisposition to developing HPT, but the overall percentage of hereditary cases caused by these risk factors is currently unclear. Inclusion of multiple HPT-related genes is expected to increase the clinical sensitivity of this test.
Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated cancer risks, see the table below.
|Gene||Condition||HPT risk||Tumor risk||Other associated cancers/features|
|AP2S1||Familial hypocalciuric hypercalcaemia (FHH)||Elevated (PMID: 26082470, 23222959)||osteomalacia|
|CASR||CASR-related conditions||elevated||hypercalcemia hypocalciuria, hyperplastic parathyroid gland, elevated parathyroid hormone|
|CDC73||hyperparathyroidism jaw tumor syndrome||80% by age 40 (PMID: 20301744)||parathyroid cancer— up to 15% (PMID: 20301744, 22302605)||ossifying jaw tumors, hamartomas, renal cysts, Wilms tumor, uterine fibroids|
|CDKN1B||multiple endocrine neoplasia type 4 (MEN4)||elevated (PMID: 23933118, 23140918)||parathyroid adenomas||pituitary adenomas, pancreatic NETs|
|GNA11||autosomal dominant hypocalcemia (ADH), familial hypocalciuric hypercalcemia (FHH)||Elevated (PMID: 8194446, 23802536, 23802516, 24823460, 26729423)|
|MEN1||multiple endocrine neoplasia type 1 (MEN1)||up to 100% (PMID: 19904212)||parathyroid adenomas||pituitary adenomas, pancreatic NETs, carcinoids, benign thyroid lesions, meningioma, lipoma, adrenocortical carcinoma—1%–13% lifetime risk (PMID: 22084155)|
|RET||multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B)||elevated||parathyroid hyperplasia—20%–30% (PMID: 24899893)||medullary thyroid cancer, pheochromocytomas, distinctive facies (MEN2B), intestinal ganglioneuromas|
Elevated: There is evidence of association, but the penetrance and risk are not well characterized.
Most of the genes on this panel confer an increased risk of developing hyperparathyroidism in an autosomal dominant inheritance pattern. CASR has both autosomal dominant and autosomal recessive inheritance.
Invitae’s hyperparathyroidism panel may be considered for individuals with the following:
Most individuals with hereditary hyperparathyroidism are followed by an endocrinology specialist and medical management is based on a comprehensive assessment.
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|