TBX5-Encoded T-Box Transcription Factor 5 Variant T223M Is Associated With Long QT Syndrome and Pediatric Sudden Cardiac Death

Authors

Alexandra M Markunas
Perathu K R Manivannan
Jordan E Ezekian
Agnim Agarwal
William Eisner
Katherina Alsina
Hugh D Allen
Gregory A Wray
Jeffrey J Kim
Xander H T Wehrens
Andrew P Landstrom

Publication Date

3-1-2021

Journal

American Journal of Medical Genetics Part A

DOI

10.1002/ajmg.a.62037

PMID

33369127

PMCID

PMC7945047

PubMedCentral® Posted Date

3-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adult, Amino Acid Sequence, Amino Acid Substitution, Atrial Natriuretic Factor, Child, Child, Preschool, Death, Sudden, Cardiac, Electrocardiography, Female, Humans, Long QT Syndrome, Male, Middle Aged, Models, Molecular, Mutation, Missense, Pedigree, Point Mutation, Promoter Regions, Genetic, Protein Conformation, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid, T-Box Domain Proteins, Exome Sequencing

Abstract

Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, SIFT, SNAP2, and PredictSNP prediction tools. The variant was located in a highly conserved region of TBX5 predicted to be part of the DNA-binding interface. A luciferase assay identified a 57.5% reduction in the ability of TBX5-T223M to drive expression at the atrial natriuretic factor promotor compared to wildtype TBX5 in vitro. We conclude that the variant is pathogenic in this family, and we put TBX5 forward as a disease susceptibility allele for genotype-negative LQTS. The identification of this familial variant may serve as a basis for the identification of previously unknown mechanisms of LQTS with broader implications for cardiac electrophysiology.

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