Endocrine Abstracts

Hypoparathyroidism may occur as: a hereditary syndromic disorder (e.g. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED), Hypoparathyroidism Sensorineural Deafness and Renal Disease (HDR), Autosomal Dominant Hypoparathyroidism type 1 (ADH1), or ADH type 2 (ADH2), which are due to mutations of autoimmune regulator (AIRE), GATA binding protein 3 (GATA3), calcium-sensing receptor (CASR) and G-protein subunit alpha 11 (GNA11)); or a non-syndromic isolated endocrinopathy, due to mutations of glial cells missing homolog 2 (GCM2), and parathyroid hormone (PTH) genes. The functions of these genes are as follows: AIRE encodes a transcription factor controlling immune tolerance; GATA3 is a transcription factor regulating parathyroid development; CASR is a G-protein coupled receptor (GPCR) regulating extra-cellular calcium homeostasis; G-protein subunit alpha-11 is a CaSR signalling modulator; GCM2 is a parathyroid-specific transcription factor regulating development; and PTH is a regulator of extracellular calcium homeostasis. Identifying the genetic cause may facilitate the diagnosis and screening for associated endocrine and non-endocrine disorders, and genetic counselling. Historically, individual genes were screened in order of their frequencies of occurrence. However, in our experience, sequential testing of multiple genes, which was often required, can result in a delay in diagnosis and multiple patient-healthcare encounters. We have therefore evaluated the use of a panel of 6 genes: AIRE, GATA3, CASR, GNA11, GCM2 and PTH, implicated in hypoparathyroidism. Gene panel testing was undertaken on 63 unrelated patients and ˜40% of these had abnormalities comprising mutations (n=22) and unknown variants (n=4). Of the 22 mutations, 36% (n=8), 23% (n=5), 18% (n=4), 14% (n=3), 5% (n=1) and 5% (n=1) had mutations in CASR, GNA11, GCM2, AIRE, PTH and GATA3 respectively; the frequencies involving each of the genes were not significantly different (χ²-test). This demonstrates the utility of panel gene testing over individual gene testing to provide rapid clinical diagnoses that will benefit patients, clinicians and healthcare services.