Researchers ID New Mutations Associated with Early-onset Hypoparathyroidism

A genetic screening of a large Chinese population has revealed 14 new mutations linked to the early development of hypoparathyroidism.

The study, “Genetic screening in a large Chinese cohort of childhood onset hypoparathyroidism by next-generation sequencing combined with TBX1-MLPA,” was published in 
The Journal of Bone and Mineral Research.

Although the most common causes for hypoparathyroidism are damage to, or removal of, the parathyroid glands; in children with non-surgical hypoparathyroidism, genetics can account for the development of this disease.

Mutations in genes that generate instructions for organ development, besides the parathyroid gland, may result in structural and functional defects in such organs. However, mutations that occur in genes that create proteins specific for the development and function of the parathyroid glands tend to cause isolated hypoparathyroidism.

Previous studies have identified more than 10 mutations associated with hypoparathyroidism. However, these studies were small and focused only on one or a few genes. That’s why studies in large groups of people using comprehensive genetic screening are necessary to better understand the possible underlying causes of hypoparathyroidism.

For this study, a team of Chinese researchers used next-generation sequencing (NGS) — a technique that allows sequencing of the entire human genome — to look for genetic alterations in early-onset hypoparathyroidism. This included the detection of TBX1 gene deletions, which have been identified as causing the development of DiGeorge syndrome type 1, a condition that causes parathyroid gland abnormalities.

The team collected clinical data and blood samples from 173 patients who were diagnosed with hypoparathyroidism before reaching age 18. They isolated DNA from blood cells to screen for possible mutations.

Genetic alterations or mutations were found in 27.7% of cases, with 15% of patients carrying a TBX1 mutated gene. Other frequent mutated genes were AIRE (5.2%) CASR (4.6%), GATA3 (2.3%) and FAM111A (0.6%). Overall, the team detected 14 new mutations associated with hypoparathyroidism, none of which had been reported before.

Researchers observed that 26 individuals who carried a TBX1 mutation showed clinical signs of DiGeorge syndrome, such as congenital heart disease, speech alterations, hearing loss, abnormal kidneys, cerebellum atrophy (shrinkage), intellectual disabilities, and alteration of face morphology. Of note, 61.5% of the 26 cases had a milder presentation that had not been originally diagnosed with DiGeorge, highlighting the importance of genetic testing.

Researchers next used a self-designed panel with 15 candidate genes, combined with the presence of the TBX1 mutation, to divide patients into groups of those without mutations (114 cases) and those with mutations (48 cases).

Compared to patients without mutations, patients with mutations showed significantly earlier onset of symptoms (2.8 years vs. 13 years).

“[N]early 42% of patients with mutations had an onset age of less than one year. The proportion of patients with an onset age prior to five years was 60.4% and 7.0% in patients with mutations and those without, respectively,” the researchers wrote.

The team also noted that “up to 60% of hereditary [hypoparathyroidism] patients detected in our study had symptoms prior to five years old, with a mutation detection rate of 66.6%.”

Hypercalciuria (elevated calcium levels in urine and kidneys) was more frequent in patients with mutations (18.8%) than in patients without genetic alterations (2.6%). Additionally, more severe symptoms including epilepsy, intellectual disability, dysmorphic faces, renal complications and hearing loss were more frequent in patients with mutations.

“[W]e propose a genetic screening procedure for hereditary [hypoparathyroidism] based on our results,” the researchers concluded.