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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.

NHSE funded test referrals should meet the relevant NHSE eligibility criteria (pdf).

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)

Target reporting times

Turnaround times for genetic / genomic testing

Sample requirements and referral information

All referrals should ideally be accompanied by a completed pre-referral form.

Clinical guidance and advice is available to referring consultants from:

Professor Rajesh Thakker, Professor of Medicine
OCDEM, Churchill Hospital

Email: rajesh.thakker@ndm.ox.ac.uk

Requesting specialties:

  • Endocrinology
  • Clinical Genetics

Specimen requirements and referring samples

Price list for non NHSE referrals (pdf)

Contact us

Oxford Genetics Laboratories - Contact us

Last reviewed:02 August 2021