Invitae Hypoparathyroidism and Hyperparathyroidism Panel

Test description

The Invitae Hypoparathyroidism and Hyperparathyroidism Panel analyzes genes associated with various hereditary causes of parathyroid disease. The parathyroid glands are four small, pea-sized glands located behind the thyroid gland. They regulate and maintain proper calcium levels in the body. Abnormal parathyroid function can cause overactive (hyperparathyroid) or underactive (hypoparathyroid) gland(s). These genes were curated based on the available evidence to date and provide Invitae’s most comprehensive test for individuals and families with symptoms suggestive of parathyroid disease.

Individuals with a pathogenic variant in one of the genes on this panel have a higher risk of developing parathyroid disease. While most of these genes are associated with hereditary causes of hyperparathyroidism, this panel includes CASR and GNA11, which are also associated with hypoparathyroidism. Hypoparathyroidism causes low levels of blood calcium (hypocalcemia) and elevated levels of calcium excreted in the urine (hypercalciuria). Prolonged parathyroid disease can lead to 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 such as certain cancers that are associated with some of the genes on this panel. 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.

*Please note that this panel is only available as part of the Genetic Hypoparathyroidism sponsored testing program. To learn more, please visit invitae.com/hypoparathyroidism.

Genes tested

AP2S1, CASR, CDC73, CDKN1B, GNA11, MEN1, RET

DISORDERS TESTED

  • autosomal dominant hypocalcemia (ADH)
  • CASR-related disorders
  • CDC73-related disorders
  • CDKN1B-related disorders
  • familial hypocalciuric hypercalcemia (FHH)
  • hyperparathyroidism jaw tumor syndrome
  • MEN1-related disorders
  • multiple endocrine neoplasia type 1 (MEN1)
  • multiple endocrine neoplasia type 2A (MEN2A)
  • multiple endocrine neoplasia type 2B (MEN2B
  • multiple endocrine neoplasia type 4 (MEN4)

CLINICAL DESCRIPTION

Parathyroid disease is the result of abnormally functioning parathyroid glands. These are 4 pea-sized glands located behind the thyroid gland. The parathyroid glands produce parathyroid hormone, which regulates the levels of calcium in the body. Parathyroid glands can be overactive leading to hyperparathyroidism, or underactive leading to hypoparathyroidism. It is unclear if parathyroid disease may predispose to cancer.

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). HPT typically causes elevated blood calcium (hypercalcemia) and reduced levels of calcium in the urine (hypocalciuria). Most of the genes on this panel are associated with hereditary predisposition to HPT, with or without other clinical features (see Lifetime Risks section below for details).

The incidence of hypoparathyroidism is less common than hyperparathyroidism at around 70,000 individuals every year, is more common in women than men, and can be acquired or inherited. Hypoparathyroidism is associated with reduced calcium in the blood (hypocalcemia) and elevated levels of calcium in the urine (hypercalciuria). The CASR and GNA11 genes are associated with hereditary forms of hypoparathyroidism as well as HPT. The overall percentage of hereditary parathyroid disease caused by the genes on this panel is currently unclear. Inclusion of multiple genes related to parathyroid disease is expected to increase the clinical sensitivity of this test.

LIFETIME RISKS

Individuals with a pathogenic variant in some of the genes on this panel 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 additional symptoms and cancers may develop, further medical management strategies focused on prevention and early detection may be beneficial. For gene-associated symptoms and cancer risks, see the table below.

Elevated: There is evidence of association, but the penetrance and risk are not well characterize

GENE

CONDITION

HPT RISK

TUMOR RISK

OTHER ASSOCIATED FEATURES

AP2S1 Familial hypocalciuric hypercalcaemia (FHH) Elevated (PMID: 26082470, 23222959) osteomalacia
CASR CASR-related conditions (familial hypocalciuric hypercalcemia (FHH), dominant hypocalcemia (ADH), ADH with Bartter syndrome neonatal severe hyperparathyroidism (NSHPT)) Elevated hyperparathyroidism, hypercalcemia, hypocalciuria, hyperplastic parathyroid gland, elevated parathyroid hormone, hypoparathyroidism, hypocalcemia, hypercalciuria
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) hyperparathyroidism, elevated parathyroid hormone, hypercalcemia, hypocalciuria, hypoparathyroidism, hypocalcemia, hypercalciuria
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

Inheritance

Most of the genes on this panel confer an increased risk of developing hyperparathyroidism and/or hypoparathyroidism in an autosomal dominant inheritance pattern. CASR has both autosomal dominant and autosomal recessive inheritance.

CONSIDERATIONS FOR TESTING

Invitae’s hypoparathyroidism and hyperparathyroidism panel may be considered for individuals with the following:

  • hypoparathyroidism
  • hyperparathyroidism
  • early onset hyperparathyroidism
  • a family history of hypercalcemia or hypocalcemia
  • ossifying fibroma(s) of the maxilla or mandible
  • parathyroid carcinoma

References

1. Falchetti, A, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet. Med. 2009; 11(12):825-35. doi: 10.1097/GIM.0b013e3181be5c97. PMID: 19904212

2. Marquard, J, Eng, C. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1257/ PMID: 20301434

3. Wang, TT, et al. Two cases of multiple ossifying fibromas in the jaws. Diagn Pathol. 2014; 9:75. doi: 10.1186/1746-1596-9-75. PMID: 24678936

4. Thakker, RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 2014; 386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. PMID: 23933118

5. Pannett, AA, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003; 58(5):639-46. doi: 10.1046/j.1365-2265.2003.01765.x. PMID: 12699448

6. Vergés, B, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 2002; 87(2):457-65. doi: 10.1210/jcem.87.2.8145. PMID: 11836268

7. Gorvin, CM, et al. A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2). J. Bone Miner. Res. 2016; 31(6):1200-6. PMID: 26729423

8. Li, D, et al. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J. Clin. Endocrinol. Metab. 2014; 99(9):E1774-83. PMID: 24823460

9. Mannstadt, M, et al. Germline mutations affecting Gα11 in hypoparathyroidism. N. Engl. J. Med. 2013; 368(26):2532-4. PMID: 23802536

10. Schulz, KD. [Metastases in breast carcinoma]. Dtsch. Med. Wochenschr. 1994; 119(20):750. PMID: 8194446

11. Hannan, FM, et al. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects. Hum. Mol. Genet. 2015; 24(18):5079-92. PMID: 26082470

12. Nesbit, MA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 2013; 45(1):93-7. PMID: 23222959

13. Thakker, RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S272-4. PMID: 23565397

14. Villablanca, A, et al. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur. J. Endocrinol. 2002; 147(3):313-22. PMID: 12213668

15. Asgharian, B, et al. Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. J. Clin. Endocrinol. Metab. 2004; 89(11):5328-36. doi: 10.1210/jc.2004-0218. PMID: 15531478

16. Miedlich, S, et al. Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?. Eur. J. Endocrinol. 2001; 145(2):155-60. PMID: 11454510

17. Norton, JA, et al. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015; 24(4):795-832. PMID: 26363542

18. Shibata, Y, et al. Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation. Endocr. J. 2015; 62(7):627-32. doi: 10.1507/endocrj.EJ15-0057. PMID: 25959515

19. Kutcher, MR, et al. Hyperparathyroidism-jaw tumor syndrome. Head Neck. 2013; 35(6):E175-7. PMID: 22302605

20. Pasquali, D, et al. Multiple endocrine neoplasia, the old and the new: a mini review. G Chir. 2012; 33(11-12):370-3. PMID: 23140918

21. Guarnieri, V, et al. Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J. Clin. Endocrinol. Metab. 2006; 91(8):2827-32. PMID: 16720667

22. Choi, KH, et al. Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C. Korean J Pediatr. 2015; 58(4):148-53. PMID: 25932037

23. Vezzoli, G, et al. Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J. Nephrol. 2006; 19(4):525-8. PMID: 17048213

24. Watanabe, S, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet. 2002; 360(9334):692-4. PMID: 12241879

25. Frank-Raue, K, et al. Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2011; 75(1):50-5. PMID: 21521328

26. Roizen, J, Levine, MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012; 75(9):425-34. PMID: 22989537

27. Nagase, T, et al. A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. J. Clin. Endocrinol. Metab. 2002; 87(6):2681-7. PMID: 12050233

28. Gatta-Cherifi, B, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database. Eur. J. Endocrinol. 2012; 166(2):269-79. doi: 10.1530/EJE-11-0679. PMID: 22084155

29. Egbuna, OI, Brown, EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol. 2008; 22(1):129-48. PMID: 18328986

30. Ellard, S, et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin. Endocrinol. (Oxf). 2005; 62(2):169-75. doi: 10.1111/j.1365-2265.2005.02190.x. PMID: 15670192

31. Moline, J, Eng, C. Multiple endocrine neoplasia type 2: an overview. Genet. Med. 2011; 13(9):755-64. PMID: 21552134

32. Nesbit, MA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N. Engl. J. Med. 2013; 368(26):2476-2486. PMID: 23802516

33. Hyde SM, et al. CDC73-Related Disorders. 2008 Dec 31. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK3789/ PMID: 20301744

34. Brandi, ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 2001; 86(12):5658-71. doi: 10.1210/jcem.86.12.8070. PMID: 11739416

35. Carpten, JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 2002; 32(4):676-80. PMID: 12434154

36. Wang, O, et al. Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PLoS ONE. 2012; 7(9):e45567. PMID: 23029104

37. Bricaire, L, et al. Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2013; 98(2):E403-8. PMID: 23293331

38. Parfitt, J, et al. Tumor suppressor gene mutation in a patient with a history of hyperparathyroidism-jaw tumor syndrome and healed generalized osteitis fibrosa cystica: a case report and genetic pathophysiology review. J. Oral Maxillofac. Surg. 2015; 73(1):194.e1-9. doi: 10.1016/j.joms.2014.09.008. PMID: 25511968

39. Iacobone, M, et al. Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred. Langenbecks Arch Surg. 2009; 394(5):817-25. doi: 10.1007/s00423-009-0511-y. PMID: 19529956

40. Thakker, RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 2012; 97(9):2990-3011. doi: 10.1210/jc.2012-1230. PMID: 22723327

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43. Warner, J, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004; 41(3):155-60. PMID: 14985373

44. Thim, SB, et al. Activating calcium-sensing receptor gene variants in children: a case study of infant hypocalcaemia and literature review. Acta Paediatr. 2014; 103(11):1117-25. PMID: 25039540

46. Bradley, KJ, et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 2005; 257(1):18-26. doi: 10.1111/j.1365-2796.2004.01421.x. PMID: 15606373

MANAGEMENT GUIDELINES

Most individuals with hereditary hyperparathyroidism and hypoparathyroidism are followed by an endocrinology specialist and medical management is based on a comprehensive assessment.

Assay

Assay and technical information

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).

Based on review of current medical guidelines and peer-reviewed publications, 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. Any variants that fall outside these regions are not analyzed unless otherwise noted. 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.

The Invitae Expanded Skeletal Dysplasias Panel includes sequence analysis and deletion/duplication analysis of all genes with the exception of the following limitations:

GENE

TRANSCRIPT REFERENCE

SEQUENCING ANALYSIS

DELETION/DUPLICATION ANALYSIS

AP2S1 NM_004069.4 YES YES
CASR NM_000388.3 YES YES
CDC73 NM_024529.4 YES YES
CDKN1B NM_004064.4 YES YES
GNA11 NM_002067.4 YES YES
MEN1 NM_130799.2 YES YES
RET NM_020975.4 YES YES