TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant

Anne Kathrine Møller Nielsen, Anna Maria Dehn, Vibeke Hjortdal, Lars Allan Larsen*

*Corresponding author for this work

Research output: Contribution to journalReviewResearchpeer-review

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Abstract

T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.

Original languageEnglish
Article number104920
JournalEuropean Journal of Medical Genetics
Volume68
Number of pages6
ISSN1769-7212
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Keywords

  • Cardiovascular
  • Genetics
  • Holt-Oram syndrome
  • TBX5

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