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Genetic testing for familial hypocalciuric hypercalcaemia

Background information

Familial benign hypocalciuric hypercalcaemia is an autosomal dominant disorder of extracellular calcium homeostasis, characterised by lifelong hypercalcaemia with inappropriately low urinary calcium excretion (mean urinary calcium:creatinine clearance ratio <0.01).

Identification of pathogenic variants in the genes responsible for FHH can confirm the diagnosis based on clinical / biochemical presentation. This can assist in directing patient management and whether surgical intervention is required.

It is a genetically heterogeneous condition where the types are clinically indistinguishable.

To date the following genes have been identified as causative of FHH:

CASR: Pathogenic loss of function mutations in the CASR gene account for FHH type1 (FHH1). ~65% of individuals with definite FHH are reported to have a pathogenic variant in this gene.

GNA11: pathogenic variants in this gene are causative of FHH type 2 (FHH2). Nesbit et al., 2013, NEJM, identified pathogenic GNA11 variants in >10% CASR and AP2S1 mutation negative FHH patients (although the cohort tested was small; prospective testing in clinical cohorts indicates variants in GNA11 to be a very rare cause of FHH).

AP2S1: The molecular basis of FHH type 3 (FHH3) has been identified as mutation of codon p.Arg15 of the AP2S1 gene. >20% of CASR negative FHH patients have this mutation (Nesbit et al., Jan 2013, Nature Genetics).

Testing strategy

Clinically affected probands:

Analysis for small variants in the gene panel indicated below

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, GNA11, AP2S1 (targetted codon 15 only)

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