AP2S1, CASR, CDC73, CDKN1B, GNA11, MEN1 AND RET GENE ANALYSIS IN FAMILIAL ISOLATED HYPERPARATHYROIDISM AND FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA
Primary hyperparathyroidism is characterised by hypercalcaemia, inappropriately high parathyroid hormone (PTH) levels and isolated parathyroid tumours. Hereditary primary hyperparathyroidism may develop as a solitary endocrinopathy or as part of the Multiple Endocrine Neoplasia type 1 (MEN1) or hereditary hyperparathyroidism-jaw tumour (HPT-JT) syndromes.
MEN1 disease-causing variants have been reported in 20-57% of families with familial isolated hyperparathyroidism (Villablanca et al 2002 Eur J Endocrinol 147:313-322; Pannett et al 2003 Clin Endocrinol 58:639-646). Inactivating variants of CDC73 (formerly known as HRPT2), account for approximately 14% of familial isolated hyperparathyroidism cases and 50% of HPT-JT cases (Cascon et al 2011 Genes Chromosomes and Cancer 50:922-929). Inactivating variants in the CASR gene cause primary hyperparathyroidism and Familial hypocalciuric hypercalcaemia (FHH). Variants in CASR account for approximately 15-18% of Familial Isolated Hyperparathyroidism cases (Warner et al 2004 J Med Genet 41:155-160).
Familial Hypocalciuric Hypercalcaemia (FHH) is an autosomal dominant disorder characterised by elevated serum calcium concentrations with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level.
FHH type 1 is caused by disease-causing variants in the CASR gene, FHH type 2 is caused by disease-causing variants in the GNA11 gene and FHH type 3 is caused by disease-causing variants in the AP2S1 gene. Pathogenic variants in AP2S1, CASR and GNA11 genes account for more than 75% cases of Familial Hypocalciuric Hypercalcaemia (Alberto et al 2018 Best Pract Res Clin Endocrinol Metab 32:781-790).
The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.
NHSE test directory code: R151 Familial hyperparathyroidism or Familial Hypocalciuric Hypercalcaemia. Testing criteria can be found on this webpage: https://www.england.nhs.uk/publication/national-genomic-test-directories/.
AMEND is a registered charity offering support for patients with MEN types 1 and 2, and associated sporadic growths. Click here to view their website.