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TBX5 ‐encoded T‐box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death
Author(s) -
Markunas Alexandra M.,
Manivannan Perathu K. R.,
Ezekian Jordan E.,
Agarwal Agnim,
Eisner William,
Alsina Katherina,
Allen Hugh D.,
Wray Gregory A.,
Kim Jeffrey J.,
Wehrens Xander H. T.,
Landstrom Andrew P.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62037
Subject(s) - long qt syndrome , missense mutation , nav1.5 , genetics , sudden death , qt interval , biology , sudden cardiac death , genotype , exome sequencing , allele , bioinformatics , gene , medicine , phenotype , sodium channel , chemistry , organic chemistry , sodium
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.