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Genetic testing for familial hyperparathyroidism (R151)

Background information

Primary hyperparathyroidism (PHPT) is characterised by hypercalcaemia and inappropriately high levels of parathyroid hormone (PTH). It is most commonly associated with sporadic parathyroid adenomas but can be seen in association with hereditary conditions.

Hereditary / familial PHPT may occur either as part of a syndrome, for example multiple endocrine neoplasia type I (MEN1) or as an isolated endocrinopathy with similarly affected family members - familial isolated hyperparathyroidism (FIHP).

Testing strategy

Clinically affected probands

R151.1 - analysis for small variants in the gene panel indicated below

Dosage analysis for copy number variants in CDC73, MEN1 and CDKN1B is also typically included

Individual gene analysis is available to non NHSE referrals where clinically indicated

Genes tested

Genes analysed are in accordance with the 'green' high evidence of clinical association gene list in panel app - CASR, CDC73, CDKN1B, MEN1, RET (exons 5, 8, 10, 11 and 13-16), AP2S1 (targeted codon 15 only)

GCM2 (codons p.379_395) is also available (Amber gene) - activating mutations have been reported in the CCID region of GCM2 (codons p.379_395), penetrance has not been determined (Guan et al 2016 Am J Hum Genet 99:1-11)

As significance of this gene in hyperparathyroidism families is unclear, this is not currently routinely included in the funded NHS tests, but may be reported on a research basis if identified

Targeted analysis for known / previously reported familial variants:

Presymptomatic testing in clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)
Diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
Segregation studies in affected family members to aid variant interpretation (R375)
Prenatal diagnosis is not typically requested