Heterozygous Mutations in TBX1 as a Cause of Isolated Hypoparathyroidism

J Clin Endocrinol Metab. 2018 Nov 1;103(11):4023-4032. doi: 10.1210/jc.2018-01260.


Context: Most cases of autosomal dominant isolated hypoparathyroidism are caused by gain-of-function mutations in CASR or GNA11 or dominant negative mutations in GCM2 or PTH.

Objective: To identify the genetic etiology for dominantly transmitted isolated hypoparathyroidism in two multigenerational families with 14 affected family members.

Methods: We performed whole exome sequencing of DNA from two families and examined the consequences of mutations by minigene splicing assay.

Results: We discovered disease-causing mutations in both families. A splice-altering mutation in TBX1 (c.1009+1G>C) leading to skipping of exon 8 (101 bp) was identified in 10 affected family members and five unaffected subjects of family A, indicating reduced penetrance for this point mutation. In a second family from France (family B), we identified another splice-altering mutation (c.1009+2T>C) adjacent to the mutation identified in family A that results in skipping of the same exon; two subjects in family B had isolated hypoparathyroidism, whereas a third subject manifested the clinical triad of the 22q11.2 deletion syndrome, indicative of variable expressivity.

Conclusions: We report evidence that heterozygous TBX1 mutations can cause isolated hypoparathyroidism. This study adds knowledge to the increasingly expanding list of causative and candidate genes in isolated hypoparathyroidism.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • DiGeorge Syndrome / blood
  • DiGeorge Syndrome / diagnosis
  • DiGeorge Syndrome / genetics*
  • Exons / genetics
  • Female
  • Heterozygote
  • Humans
  • Hypercalciuria / blood
  • Hypercalciuria / diagnosis
  • Hypercalciuria / genetics*
  • Hypocalcemia / blood
  • Hypocalcemia / diagnosis
  • Hypocalcemia / genetics*
  • Hypoparathyroidism / blood
  • Hypoparathyroidism / congenital*
  • Hypoparathyroidism / diagnosis
  • Hypoparathyroidism / genetics
  • Infant
  • Male
  • Mutation
  • Pedigree
  • Penetrance
  • RNA Splice Sites / genetics
  • T-Box Domain Proteins / genetics*
  • Whole Exome Sequencing


  • RNA Splice Sites
  • T-Box Domain Proteins
  • TBX1 protein, human

Supplementary concepts

  • Hypercalciuric Hypocalcemia, Familial