A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve.

Wei-Feng Jiang,Xin-Hua Wang,Xu Liu,Ying-Jia Xu,Xing-Biao Qiu,Yi-Qing Yang,Shao-Hui Wu,Cui-Mei Zhao

doi:10.1590/1678-4685-gmb-2020-0142

Wei-Feng Jiang, Xin-Hua Wang + Show 6 more

Open Access

https://doi.org/10.1590/1678-4685-gmb-2020-0142

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Abstract

TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 index patients with both CHD and AF, a novel heterozygous variation, NM_000192.3: c.577G>T; p.(Gly193*), was identified in one index patient with CHD and AF as well as bicuspid aortic valve (BAV), with an allele frequency of approximately 0.28%. Genetic analysis of the proband’s pedigree showed that the variation co-segregated with the diseases. The pathogenic variation was not detected in 292 unrelated healthy subjects. Functional analysis by using a dual-luciferase reporter assay system showed that the Gly193*-mutant TBX5 protein failed to transcriptionally activate its target genes MYH6 and NPPA. Moreover, the mutation nullified the synergistic transactivation between TBX5 and GATA4 as well as NKX2-5. Additionally, whole-exome sequencing analysis showed no other genes contributing to the diseases. This investigation firstly links a pathogenic variant in the TBX5 gene to familial CHD and AF as well as BAV, suggesting that CHD and AF as well as BAV share a common developmental basis in a subset of patients.

Highlights

As the most prevalent type of human birth defect, congenital heart defect (CHD) occurs in about 1% of all live neonates, accounting for nearly a third of all forms of developmental abnormalities (Benjamin et al, 2019; OliveiraBrancati et al, 2020)
A total of 178 unrelated cases suffering from CHD and atrial fibrillation (AF) (105 males, with a mean age of 33 years at initial diagnosis of AF) were clinically analyzed in contrast to a total of 292 unrelated control people (173 males, with a mean age of 33 years)
There was no significant difference between case and control groups in gender, age or ethnicity

Summary

Introduction

As the most prevalent type of human birth defect, congenital heart defect (CHD) occurs in about 1% of all live neonates, accounting for nearly a third of all forms of developmental abnormalities (Benjamin et al, 2019; OliveiraBrancati et al, 2020). Cardiogenesis undergoes a highly complex biological process, and both environmental and genetic pathogenic factors can perturb this finely regulated process, leading to CHD (Patel and Burns, 2013; Pierpont et al, 2018; Shabana et al, 2020). The genetic determinants underlying CHD in a large proportion of cases remain to be unveiled

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