HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot

Abstract

As the most prevalent form of birth defect in humans worldwide, congenital heart disease (CHD) is responsible for substantial morbidity and is still the leading cause of birth defect-related demises. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD, and mutations in multiple genes, especially in those coding for cardiac core transcription factors, have been causally linked to various CHDs. Nevertheless, CHD is a genetically heterogeneous disease and the genetic determinants underpinning CHD in an overwhelming majority of patients remain elusive. In the current study, genomic DNA was extracted from venous blood samples of 165 unrelated patients with CHD, and the coding exons and splicing junction sites of the HAND1 gene, which encodes a basic helix-loop-helix transcription factor essential for cardiovascular development, were sequenced. As a result, a novel heterozygous mutation, p.R118C, was identified in a patient with tetralogy of Fallot (TOF). The missense mutation, which was absent in 600 referential chromosomes, altered the amino acid that was completely conserved evolutionarily. Biological assays with a dual-luciferase reporter assay system revealed that the R118C-mutant HAND1 protein had significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation of a downstream target gene between HAND1 and GATA4, another cardiac core transcription factor associated with TOF. To our knowledge, this is the first report on the association of a HAND1 loss-of-function mutation with enhanced susceptibility to TOF in humans. The findings provide novel insight into the molecular etiology underlying TOF, suggesting potential implications for the improved prophylactic and therapeutic strategies for TOF.

Intronic Polymorphisms in Gene of Second Heart Field as Risk Factors for Human Congenital Heart Disease in a Chinese Population

“…Minor alleles in the remaining five SNPs (TBX1: rs41298006 G>A, FGF10: rs75629618 C>T, FGF10: rs10461755 G>A, FGF10: rs75632187 A>G, and FGF10: rs12518964 G>A) could only increase the risk of SV. The previous studies focused on SNPs in exons and the promotor regions associated with CHDs (Wang et al, 2014a(Wang et al, , 2017Sun et al, 2016;Huang et al, 2017;Li and Yang, 2017;Li et al, , 2018bLu et al, 2018;Qiao et al, 2018). However, SNPs in introns also play a role in CHD.…”

“…The knockout of these genes could lead to different types of CHDs in mice (Dai, 2002;Cai et al, 2003;Dodou, 2004;Phan et al, 2005;Takeuchi, 2005;Vong et al, 2006;Tsuchihashi et al, 2011). Further studies revealed that the mutations in SHF genes played important roles in human CHDs (Huang et al, 2017;Wang et al, 2017;Li et al, 2018a;Xu et al, 2018;Zhang et al, 2018).…”

HAND factors regulate cardiac lineage commitment and differentiation from human pluripotent stem cells

“…Furthermore, pathogenic mutations of HAND1 were related to left ventricular hypoplasia and ventricular septum defects [ 38 – 40 ], while HAND2 deficiency contributed to ventricular septum defects and double outlet right ventricle [ 41 ]. In severe CHDs, such as tetralogy of Fallot, mutations of HAND1 / 2 have been identified as well [ 42 , 43 ]. Nevertheless, the roles of HAND in human early cardiac lineage commitment and differentiation are not completely clarified and need further investigation.…”

Comparison of DNA methylation patterns across tissue types in infants with tetralogy of Fallot

“…Prior work has suggested that the etiology of TOF is multifactorial and associated with chromosomal anomalies such as Trisomies 13, 18, 21, and microdeletion of 22q11.2 (Nguyen & Jay, 2014; Radhakrishna et al, 2018; Vergara et al, 2006). Mutations in certain genes have also been found to be associated with TOF such as JAG1, NKX2‐5, HAND1 , and GATA4 (Bauer et al, 2010; Esposito et al, 2011; Nemer et al, 2006; Wang et al, 2017). These genes encode transcription factors that are important in the regulation of embryologic heart development (Rauch et al, 2010; Vecoli, Pulignani, Foffa, & Andreassi, 2014).…”

“…To estimate sample‐to‐sample variability, we compared the degree of dissimilarity between samples of the same tissue type in multiple patients. In addition, we compared gene‐specific DNA methylation profiles across these same tissue types for a representative group of 10 genes previously associated cardiac development: DKK2 (Phillips, Mukhopadhyay, Poscablo, & Westphal, 2011), GATA4 (Garg et al, 2003), HAND1 (Wang et al, 2017), JAG1 (Eldadah et al, 2001), NKX2‐5 (Goldmuntz, Geiger, & Benson, 2001), NOTCH4 (Zhu et al, 2020), SCO2 (Grunert et al, 2016), TBX5 (Sheng et al, 2014), TBX20 (Gong et al, 2019), and WNT7A (Abraham et al, 2022).…”