TBX5-encoded T-box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death.

dc.contributor.author

Markunas, Alexandra M

dc.contributor.author

Manivannan, Perathu KR

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Ezekian, Jordan E

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Agarwal, Agnim

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Eisner, William

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Alsina, Katherina

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Allen, Hugh D

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Wray, Gregory A

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Kim, Jeffrey J

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Wehrens, Xander HT

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Landstrom, Andrew P

dc.date.accessioned

2021-03-01T14:21:55Z

dc.date.available

2021-03-01T14:21:55Z

dc.date.issued

2021-03

dc.date.updated

2021-03-01T14:21:54Z

dc.description.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.

dc.identifier.issn

1552-4825

dc.identifier.issn

1552-4833

dc.identifier.uri

https://hdl.handle.net/10161/22400

dc.language

eng

dc.publisher

Wiley

dc.relation.ispartof

American journal of medical genetics. Part A

dc.relation.isversionof

10.1002/ajmg.a.62037

dc.subject

T-box transcription factor 5

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TBX5

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long QT syndrome

dc.title

TBX5-encoded T-box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death.

dc.type

Journal article

duke.contributor.orcid

Wray, Gregory A|0000-0001-5634-5081

duke.contributor.orcid

Landstrom, Andrew P|0000-0002-1878-9631

pubs.begin-page

923

pubs.end-page

929

pubs.issue

3

pubs.organisational-group

Trinity College of Arts & Sciences

pubs.organisational-group

Biology

pubs.organisational-group

Evolutionary Anthropology

pubs.organisational-group

Duke Innovation & Entrepreneurship

pubs.organisational-group

Duke

pubs.organisational-group

Initiatives

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Institutes and Provost's Academic Units

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School of Medicine

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Cell Biology

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Pediatrics, Cardiology

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Basic Science Departments

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Pediatrics

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Clinical Science Departments

pubs.publication-status

Accepted

pubs.volume

185

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