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Genetic testing for familial hypoparathyroidism (R153)

Background information

Primary hypoparathyroidism is caused by a group of heterogeneous conditions in which hypocalcaemia and hyperphosphatemia occur as a result of deficient PTH secretion. It may occur as part of a syndrome or in isolation.

GATA3: Pathogenic mutations cause the autosomal dominant condition HDR syndrome. Patients typically present with hypoparathyroidism, deafness and/or renal dysplasia. A significant proportion of cases arise de novo.

AIRE: Pathogenic mutations cause the autosomal recessive condition autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or APS1. Clinical presentation can be highly variable, including isolated hypoparathyroidism; however, a typical presentation would be hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis.

PTH: Very rare. Isolated primary hypoparathyroidism; autosomal recessive and autosomal dominant reported in the literature.

GCM2: Usually autosomal recessive isolated primary hypoparathyroidism (rare reports of dominant inheritance).

CASR: Pathogenic gain of function mutations associated with autosomal dominant hypoparathyroidism / hypocalcaemia (ADH1). CASR mutations may account for ~40-50% of ADH cases and ~55% of patients referrals with isolated hypoparathyroidism / hypocalcaemia (data from our cohort).

GNA11: Pathogenic gain of function mutations associated with autosomal dominant hypocalcaemia type 2 (ADH2). Nesbit et al., 2013, NEJM, report a GNA11 mutation in ~25% of hypocalcaemic (ADH) patients who did not have a CASR mutation.

TBCE: Autosomal recessive. Allelic disorders HRDS (hypoparathyroidism-retardation-dysmorphism syndrome; Sanjad-Sakati syndrome), and KCS1 (Kenny-Caffey syndrome). Presenting complaint is typically hypocalcaemic tetany or convulsions, usually neonatal, (although delayed onset up to seven months is known), with prenatal and postnatal growth failure. There is a Middle Eastern founder variant that accounts for all but one published case.

Testing strategy

Clinically affected probands:

R153.1 - analysis for small variants in the gene panel indicated below

R153.2 - dosage analysis for copy number variants in GATA3

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:

GATA3, AIRE, PTH, GCM2, CASR, GNA11, TBCE

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
Carrier testing in relatives of clinically affected patients with an autosomal recessive condition (mutation known) (R244)