Genetic Insights into Non-syndromic Tetralogy of Fallot

Overview

Journal Front Physiol

Date 2022 Oct 24

PMID 36277185

Authors

Nouf J Althali

Kathryn E Hentges

Affiliations

Soon will be listed here.

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.

Citing Articles

Gene Variants Predispose Individuals to Tetralogy of Fallot.

Feng Z, Huang X, Gao Y, Gao H, Na W, Tan C Phenomics. 2025; 4(6):548-561.

PMID: 40061823 PMC: 11889330. DOI: 10.1007/s43657-024-00175-9.

Detection of Genetic Variations in Children with Tetralogy of Fallot Using Whole Exome Sequencing Technology Integrated Bioinformatics Analysis.

Abdullahi K, Ali A, Adan M, Shu Q Genet Test Mol Biomarkers. 2024; 28(12):474-484.

PMID: 39653367 PMC: 11659463. DOI: 10.1089/gtmb.2024.0350.

Valvulopathies and Genetics: Where are We?.

Coll M, Fernandez-Falgueras A, Iglesias A, Brugada R Rev Cardiovasc Med. 2024; 25(2):40.

PMID: 39077344 PMC: 11263169. DOI: 10.31083/j.rcm2502040.

Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot.

Li Y, Tian M, Zhou Z, Tu J, Zhang R, Huang Y Pediatr Res. 2024; .

PMID: 38951655 DOI: 10.1038/s41390-024-03328-8.

Genetic insights into Tetralogy of Fallot: Oh MYH(6).

Mital R, Lozier J, Mead T Pediatr Res. 2024; 96(2):297-298.

PMID: 38600301 PMC: 11343695. DOI: 10.1038/s41390-024-03195-3.

References

Clark C, Zhang B, Lee B, Evans S, Lassar A, Lee K . Evolutionary conservation of Nkx2.5 autoregulation in the second heart field. Dev Biol. 2012; 374(1):198-209. PMC: 3549048. DOI: 10.1016/j.ydbio.2012.11.007. View

Oechslin E, Attenhofer Jost C, Rojas J, Kaufmann P, Jenni R . Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol. 2000; 36(2):493-500. DOI: 10.1016/s0735-1097(00)00755-5. View

Topf A, Griffin H, Glen E, Soemedi R, Brown D, Hall D . Functionally significant, rare transcription factor variants in tetralogy of Fallot. PLoS One. 2014; 9(8):e95453. PMC: 4122343. DOI: 10.1371/journal.pone.0095453. View

Ho C, Day S, Ashley E, Michels M, Pereira A, Jacoby D . Response by Ho et al to Letter Regarding Article, "Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)". Circulation. 2019; 139(12):1559-1560. PMC: 6445361. DOI: 10.1161/CIRCULATIONAHA.118.039069. View

Dentice M, Cordeddu V, Rosica A, Ferrara A, Santarpia L, Salvatore D . Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006; 91(4):1428-33. DOI: 10.1210/jc.2005-1350. View

Goldmuntz E, Clark B, Mitchell L, Jawad A, Cuneo B, Reed L . Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998; 32(2):492-8. DOI: 10.1016/s0735-1097(98)00259-9. View

Jiang J, Li R, Wang J, Liu X, Xu Y, Fang W . Prevalence and spectrum of GATA5 mutations associated with congenital heart disease. Int J Cardiol. 2012; 165(3):570-3. DOI: 10.1016/j.ijcard.2012.09.039. View

Benson D, Silberbach G, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S . Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999; 104(11):1567-73. PMC: 409866. DOI: 10.1172/JCI8154. View

Luxan G, DAmato G, MacGrogan D, de la Pompa J . Endocardial Notch Signaling in Cardiac Development and Disease. Circ Res. 2015; 118(1):e1-e18. DOI: 10.1161/CIRCRESAHA.115.305350. View

10.

Chung I, Rajakumar G . Genetics of Congenital Heart Defects: The NKX2-5 Gene, a Key Player. Genes (Basel). 2016; 7(2). PMC: 4773750. DOI: 10.3390/genes7020006. View

11.

Sun H, Zhang S, Wang J, Zhou X, Zhang H, Yang H . Expanding the phenotype associated with SMARCC2 variants: a fetus with tetralogy of Fallot. BMC Med Genomics. 2022; 15(1):40. PMC: 8895577. DOI: 10.1186/s12920-022-01185-0. View

12.

McElhinney D, Krantz I, Bason L, Piccoli D, Emerick K, Spinner N . Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation. 2002; 106(20):2567-74. DOI: 10.1161/01.cir.0000037221.45902.69. View

13.

Goldmuntz E . The epidemiology and genetics of congenital heart disease. Clin Perinatol. 2001; 28(1):1-10. DOI: 10.1016/s0095-5108(05)70067-1. View

14.

Skoric-Milosavljevic D, Lahrouchi N, Bosada F, Dombrowsky G, Williams S, Lesurf R . Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot. Genet Med. 2021; 23(10):1952-1960. PMC: 8486653. DOI: 10.1038/s41436-021-01212-y. View

15.

Pinsker B, Serfas J, Krasuski R . Burden and Impact of Arrhythmias in Repaired Tetralogy of Fallot. Curr Cardiol Rep. 2022; 24(3):225-234. DOI: 10.1007/s11886-022-01638-z. View

16.

Eldadah Z, Hamosh A, Biery N, Montgomery R, Duke M, Elkins R . Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Hum Mol Genet. 2001; 10(2):163-9. DOI: 10.1093/hmg/10.2.163. View

17.

Qian Y, Xiao D, Guo X, Chen H, Hao L, Ma X . Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation. J Transl Med. 2017; 15(1):69. PMC: 5379520. DOI: 10.1186/s12967-017-1173-0. View

18.

Lyons I, Parsons L, Hartley L, Li R, Andrews J, Robb L . Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 1995; 9(13):1654-66. DOI: 10.1101/gad.9.13.1654. View

19.

Tomita-Mitchell A, Maslen C, Morris C, Garg V, Goldmuntz E . GATA4 sequence variants in patients with congenital heart disease. J Med Genet. 2007; 44(12):779-83. PMC: 2652815. DOI: 10.1136/jmg.2007.052183. View

20.

Goodship J, Hall D, Topf A, Mamasoula C, Griffin H, Rahman T . A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot. Circ Cardiovasc Genet. 2012; 5(3):287-92. PMC: 4643453. DOI: 10.1161/CIRCGENETICS.111.962035. View