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.