Heterozygous Mutations in TBX1 As a Cause of Isolated Hypoparathyroidism

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2018 Aug 24

PMID 30137364

Citations 8

Authors

Dong Li

Christopher T Gordon

Myriam Oufadem

Jeanne Amiel

Harsh S Kanwar

Marina Bakay

Tiancheng Wang

Hakon Hakonarson

Michael A Levine

Affiliations

Soon will be listed here.

Abstract

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.

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