Novel TBX1 Gene Mutation Caused Family’s Hypoparathyroidism, Deafness, Case Study Says

A novel mutation in the TBX1 gene caused hypoparathyroidism and deafness in a man and his three children, a case study reports.

The study, “A Novel TBX1 Variant Causing Hypoparathyroidism and Deafness,” was published in the Journal of the Endocrine Society.

Hypoparathyroidism is caused by low levels of the parathyroid hormone (PTH) in the body. Normally, PTH production is produced when calcium levels in the blood are low. Accordingly, one of the consequences of low PTH levels is a marked decrease of calcium in the blood.

Most hypoparathyroidism cases occur in patients who have undergone neck surgery (post-surgical hypoparathyroidism) due to permanent damage to the parathyroid glands, the structures responsible for producing PTH.

But the condition may also be caused by genetic mutations, such as those seen in people with DiGeorge syndrome, who are missing a small part of chromosome 22.

TBX1 is one of the genes deleted in DiGeorge syndrome patients, with increasing evidence suggesting that the lack of this gene may explain the majority of their symptoms. The gene codes for a protein that has key regulatory functions during development.

In their case report, researchers in Saudi Arabia described a family of four — a 39-year-old man with two sons (5 and 12), and a daughter (14) — who showed symptoms of hypoparathyroidism and hypocalcemia (low calcium). Additional features included facial asymmetry, nasal speech, and deafness.

The lack of renal (kidney) involvement in all four cases made HDR syndrome (also known as Barakat syndrome) unlikely. HDR is a rare, genetic syndrome characterized by hypoparathyroidism, deafness, and kidney disease. The absence of cardiac complications and recurrent infections made DiGeorge syndrome also unlikely.

Therefore, the researchers suspected “a novel syndrome or a known syndrome with a novel presentation.”

They performed a whole genome sequencing — a technique that identifies the entire human genome — and uncovered a novel heterozygous TBX1 mutation, located in exon 9 of one of three forms of TBX1. Exons are the parts of genes that contain information for the production of proteins. Heterozygous mutations refer to changes in one of the two gene copies inherited from the parents.

This mutation is predicted to affect the normal function of TBX1 and likely explains the disease features in the family, the researchers said.

“We report a family of four members who presented with congenital hypoparathyroidism, facial dysmorphism, normal intelligence, deafness, and no cardiac involvement,” the researchers wrote.

“Whole genome sequencing revealed a paternally-inherited novel heterozygous variant, … which we think is responsible for the phenotype [manifestations] within the family,” they added.