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Identification of TBX2 and TBX3 variants in patients with conotruncal heart defects by target sequencing

Huilin Xie1, Erge Zhang1, Nanchao Hong1

  • 1Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.

Human Genomics
|September 19, 2018
PubMed
Abstract

Insights

Genetic variants in TBX2 and TBX3 genes are linked to conotruncal heart defects (CTDs). This study identifies specific TBX2 and TBX3 variants contributing to CTD development in a large patient cohort.

Area of Science:

  • Genetics
  • Developmental Biology
  • Cardiology

Background:

  • Conotruncal heart defects (CTDs) are complex congenital heart malformations arising from outflow tract abnormalities.
  • The precise genetic underpinnings of CTDs are not fully understood, though TBX2 and TBX3 dysfunction is implicated.
  • Investigating TBX2 and TBX3 variants is crucial for understanding CTD pathogenesis.

Purpose of the Study:

  • To screen for and genetically analyze variants in TBX2 and TBX3 genes in a large cohort of CTD patients.
  • To investigate the functional impact of identified TBX2 and TBX3 variants on gene expression and downstream targets.
  • To establish a genetic association between TBX2/TBX3 variants and CTD etiology.

Main Methods:

  • Target sequencing was employed to identify TBX2 and TBX3 variants in 588 CTD patients and 300 healthy controls.
  • Expression levels of TBX2 and TBX3 variants at mRNA and protein levels were analyzed.
  • Functional assays were performed to assess the transcriptional activity of variant proteins on downstream genes like PEA3 and MEF2C.

Main Results:

  • Specific TBX2 variants (p.R608W, p.R616Q) and TBX3 variants (p.A192T, p.A562V) were identified in CTD patients but not in controls.
  • These identified variants exhibited altered mRNA and protein expression compared to wild-type.
  • Functional analysis showed impaired transcriptional regulation of downstream targets PEA3 (for TBX2 variants) and MEF2C (for TBX3 variants).

Conclusions:

  • The identified variants of TBX2 (R608W, R616Q) and TBX3 (A192T, A562V) are associated with the etiology of CTDs.
  • This study provides the first large-scale population-based evidence linking TBX2 and TBX3 variants to CTDs.
  • These findings highlight the critical role of TBX2 and TBX3 in normal heart development and CTD pathogenesis.
Keywords:
Conotruncal heart defectsTBX2TBX3Target sequencingVariant

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