Genetic insights into non-syndromic Tetralogy of Fallot

Abstract

Congenital heart defects (CHD) include structural abnormalities of the heart or/and great vessels that are present at birth. CHD affects around 1% of all newborns worldwide. Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital cardiac abnormality, affecting three out of every 10,000 live infants with a prevalence rate of 5–10% of all congenital cardiac defects. The four hallmark characteristics of TOF are: right ventricular hypertrophy, pulmonary stenosis, ventricular septal defect, and overriding aorta. Approximately 20% of cases of TOF are associated with a known disease or chromosomal abnormality, with the remaining 80% of TOF cases being non-syndromic, with no known aetiology. Relatively few TOF patients have been studied, and little is known about critical causative genes for non-syndromic TOF. However, rare genetic variants have been identified as significant risk factors for CHD, and are likely to cause some cases of TOF. Therefore, this review aims to provide an update on well-characterized genes and the most recent variants identified for non-syndromic TOF.

Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot

“…No variant was identified in more than two probands. Of the genes mutated in two probands, WASHC5 , CLUH and CHD7 were identified to be expressed in the heart, of which WASCH5 and CHD7 have previously been identified to be related to CHD pathogenesis, including syndromic cases of TOF ( 8 , 11 , 14 , 31 , 63 – 65 ). Our findings further the case that these genes are also important in non-syndromic TOF.…”

“…Identification of the pathogenic origins of TOF have thus far focused on single driver genes, primarily by pedigree studies ( 7 , 8 ). Conversely, animal model studies have elucidated important pathogenic pathways that may be driven by polygenic or environmental perturbations.…”

Functions of cilia in cardiac development and disease

“…Heart development is a complex process that requires precise spatiotemporal gene expression to orchestrate the accurate formation of a four‐chambered organ with a connected circulatory system (Bruneau, 2013 ; Buijtendijk et al., 2020 ; Houyel & Meilhac, 2021 ). Errors during these precisely controlled processes can lead to structural malformations known as congenital heart defects (CHDs; Althali & Hentges, 2022 ; Morton et al., 2022 ; Samsa et al., 2015 ). CHDs are present in nearly 1% of live births, thereby making CHDs the most common birth defect (Althali & Hentges, 2022 ; van der Linde et al., 2011 ).…”

“…Errors during these precisely controlled processes can lead to structural malformations known as congenital heart defects (CHDs; Althali & Hentges, 2022 ; Morton et al., 2022 ; Samsa et al., 2015 ). CHDs are present in nearly 1% of live births, thereby making CHDs the most common birth defect (Althali & Hentges, 2022 ; van der Linde et al., 2011 ). Several genetic and non‐genetic factors contribute to the development of CHD (S. S. Patel & Burns, 2013 ; Peng et al., 2019 ; Shiaulou Yuan et al., 2013 ).…”

Novel hub genes and regulatory network related to ferroptosis in tetralogy of Fallot

“…TOF is characterized by four typical features, namely, ventricular septal defect, overriding aorta, pulmonary artery stenosis, and right ventricular hypertrophy ( 2 ). This condition is classified as a conotruncal defect and is believed to result from incomplete separation between the truncus arteriosus and the bulbus arteriosus during early embryonic development ( 3 ). However, the precise molecular mechanisms underlying the pathogenesis of TOF remain not fully understood.…”