Editing Tetralogy of Fallot (section)

== Cause ==
While the specific causes of TOF have not been fully identified, there are various environmental or genetic factors that have been associated with TOF. So far, around 20% of overall congenital heart defect cases have been due to known causes such as genetic defects and [[teratogens]] which are various factors causing embryo development abnormalities or birth defects.<ref name="Wang_2014">{{cite journal | vauthors = Wang X, Li P, Chen S, Xi L, Guo Y, Guo A, Sun K | title = Influence of genes and the environment in familial congenital heart defects | journal = Molecular Medicine Reports | volume = 9 | issue = 2 | pages = 695–700 | date = February 2014 | pmid = 24337398 | doi = 10.3892/mmr.2013.1847 | doi-access = free }}</ref> However, the other 80% of cases have little known about their cause.<ref name="Wang_2014"/>

Genetic factors linked to TOF include various gene mutations or deletions. Gene deletions associated with TOF include chromosome 22 deletion as well as [[DiGeorge syndrome]].<ref name="Francois_2016">{{cite book| vauthors = Francois LG, Bove EL, Hraška V, Morell VO, Spray TL |title=Surgery of conotruncal anomalies |date=2016 |isbn=9783319230573 |location=Cham |oclc=945874817 }}{{page?|date=October 2024}}</ref>

Specific genes associations with TOF include:

* [[JAG1]] codes for ligands within the Notch family of proteins and is highly expressed in the developing heart.<ref name="pmid11152664">{{cite journal | vauthors = Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, Dietz HC | title = Familial Tetralogy of Fallot caused by mutation in the jagged1 gene | journal = Human Molecular Genetics | volume = 10 | issue = 2 | pages = 163–169 | date = January 2001 | pmid = 11152664 | doi = 10.1093/hmg/10.2.163 | doi-access = free }}</ref> Mutations of the JAG1 gene can lead to abnormal heart development associated with TOF.<ref name="pmid11152664" />
* [[Nkx2-5|NKX2-5]] codes for cardiac morphogenesis regulators to allow for proper heart development.<ref>{{cite journal | vauthors = Chung IM, Rajakumar G | title = Genetics of Congenital Heart Defects: The NKX2-5 Gene, a Key Player | journal = Genes | volume = 7 | issue = 2 | page = 6 | date = January 2016 | pmid = 26805889 | pmc = 4773750 | doi = 10.3390/genes7020006 | doi-access = free }}</ref> Defects in this gene typically causes septal defects and has been associated with around 4% of all TOF cases.<ref name="pmid11714651">{{cite journal | vauthors = Goldmuntz E, Geiger E, Benson DW | title = NKX2.5 mutations in patients with tetralogy of fallot | journal = Circulation | volume = 104 | issue = 21 | pages = 2565–2568 | date = November 2001 | pmid = 11714651 | doi = 10.1161/hc4601.098427 | doi-access = free }}</ref>
* [[ZFPM2]] is another cardiac regulator involved in regulation of GATA4.<ref name="pmid14517948">{{cite journal | vauthors = Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, Amati F, Gianni D, Tandoi C, Marino B, Crossley M, Dallapiccola B | display-authors = 6 | title = Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot | journal = Human Mutation | volume = 22 | issue = 5 | pages = 372–377 | date = November 2003 | pmid = 14517948 | doi = 10.1002/humu.10261 | s2cid = 21531781 }}</ref> Mutations of the ZFPM2 gene lead to reduced GATA production and have been seen in some TOF cases.<ref name="pmid14517948" />
* [[VEGF]] a well-known endothelial growth factor involved in the vascularization of the heart.<ref name="pmid15937089">{{cite journal | vauthors = Lambrechts D, Devriendt K, Driscoll DA, Goldmuntz E, Gewillig M, Vlietinck R, Collen D, Carmeliet P | display-authors = 6 | title = Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study | journal = Journal of Medical Genetics | volume = 42 | issue = 6 | pages = 519–522 | date = June 2005 | pmid = 15937089 | pmc = 1736071 | doi = 10.1136/jmg.2004.026443 }}</ref> Decreased VEGF expression has been shown to be a modifier of TOF.<ref name="pmid15937089" />
* [[Notch 1|NOTCH1]] is involved in the vascularization of tissues and is the most common site of genetic variations involved with TOF, accounting for 7% of all TOF cases.<ref name="Page_2019">{{cite journal | vauthors = Page DJ, Miossec MJ, Williams SG, Monaghan RM, Fotiou E, Cordell HJ, Sutcliffe L, Topf A, Bourgey M, Bourque G, Eveleigh R, Dunwoodie SL, Winlaw DS, Bhattacharya S, Breckpot J, Devriendt K, Gewillig M, Brook JD, Setchfield KJ, Bu'Lock FA, O'Sullivan J, Stuart G, Bezzina CR, Mulder BJ, Postma AV, Bentham JR, Baron M, Bhaskar SS, Black GC, Newman WG, Hentges KE, Lathrop GM, Santibanez-Koref M, Keavney BD | display-authors = 6 | title = Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot | journal = Circulation Research | volume = 124 | issue = 4 | pages = 553–563 | date = February 2019 | pmid = 30582441 | pmc = 6377791 | doi = 10.1161/CIRCRESAHA.118.313250 }}</ref>
* [[TBX1]] expresses progenitors involved with the development of the right ventricle.<ref name="Griffin_2010">{{cite journal | vauthors = Griffin HR, Töpf A, Glen E, Zweier C, Stuart AG, Parsons J, Peart I, Deanfield J, O'Sullivan J, Rauch A, Scambler P, Burn J, Cordell HJ, Keavney B, Goodship JA | display-authors = 6 | title = Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants | journal = Heart | volume = 96 | issue = 20 | pages = 1651–1655 | date = October 2010 | pmid = 20937753 | pmc = 2976076 | doi = 10.1136/hrt.2010.200121 }}</ref> Chromosome 22q11 deletions also deleting TBX1 gene have been seen in 17% TOF cases.<ref name="Griffin_2010" />
* [[FLT4]] gene expression leads to Vascular endothelial growth factor receptor 3 ([[VEGFR-3]]) which helps vascularization.<ref name="Page_2019"/> Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases.<ref name="Page_2019" />
* [[FOXC2]] is another gene involved in embryonic development of the cardiac system.<ref name="Morgenthau_2018">{{cite journal | vauthors = Morgenthau A, Frishman WH | title = Genetic Origins of Tetralogy of Fallot | journal = Cardiology in Review | volume = 26 | issue = 2 | pages = 86–92 | date = Mar–Apr 2018 | pmid = 29045289 | doi = 10.1097/CRD.0000000000000170 | s2cid = 46781422 }}</ref> Mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and TOF.<ref name="Morgenthau_2018" />
* [[GATA4]] aids in cardiac development by helping increase the production of cardiomyocytes.<ref>{{cite journal | vauthors = Zhou P, He A, Pu WT | title = Chapter five - Regulation of GATA4 Transcriptional Activity in Cardiovascular Development and Disease | journal = Current Topics in Developmental Biology | volume = 100 | pages = 143–169 | date = January 2012 | pmid = 22449843 | doi = 10.1016/B978-0-12-387786-4.00005-1 | publisher = Academic Press | series = Heart Development | veditors = Bruneau BG }}</ref> Mutations of this gene have been seen in various familial TOF cases often lasting 2–3 generations.<ref name="Morgenthau_2018" />
*[[FLNA]] is a protein coded by the gene of the same name that crosslinks [[actin filaments]] into networks in [[cytoplasm]] and helps anchor membrane proteins for the actin [[cytoskeleton]]. Mutations of this gene were seen to cause TOF in some patients.<ref>{{cite journal | vauthors = Kalayinia S, Maleki M, Mahdavi M, Mahdieh N | title = Whole-Exome Sequencing Reveals a Novel Mutation of FLNA Gene in an Iranian Family with Nonsyndromic Tetralogy of Fallot | journal = Laboratory Medicine | volume = 52 | issue = 6 | pages = 614–618 | date = November 2021 | pmid = 33942857 | doi = 10.1093/labmed/lmab018 }}</ref>
The Environmental Factors that have been studied to potentially be associated with TOF include:

* Maternal Alcohol consumption: During [[embryonic development]], many of the body’s processing and filtration systems are not fully developed.<ref name="Zhu_2015">{{cite journal | vauthors = Zhu Y, Romitti PA, Caspers Conway KM, Shen DH, Sun L, Browne ML, Botto LD, Lin AE, Druschel CM | display-authors = 6 | title = Maternal periconceptional alcohol consumption and congenital heart defects | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 103 | issue = 7 | pages = 617–629 | date = July 2015 | pmid = 26118863 | pmc = 7668305 | doi = 10.1002/bdra.23352 }}</ref> Fetal body is unable to process alcohol as well as adults which can lead to improper development, including [[cardiogenesis]].<ref name="Zhu_2015" /> While no conclusive evidence has been found between effects of alcohol consumption and TOF, maternal alcohol consumption has been seen in various patients with TOF.<ref name="Zhu_2015" />
*Maternal smoking: Maternal smoking has been associated with various fetal complications such as premature delivery and low birth weight which can lead to TOF.<ref name="Wang_2014"/> In the famous Baltimore-Washington Study, it was reported that smoking more than one pack per day while pregnant was associated with two specific cardiac deflects, both part of TOF: pulmonary stenosis and transposition with VSD.<ref name="Wang_2014" />
*Maternal diabetes: Maternal diabetes, [[Diabetes mellitus|diabetes Mellitus]], and [[gestational diabetes]] are well-known risk factors of fetal CHD, including TOF.<ref name="Priest_2015">{{cite journal | vauthors = Priest JR, Yang W, Reaven G, Knowles JW, Shaw GM | title = Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring | journal = JAMA Pediatrics | volume = 169 | issue = 12 | pages = 1112–1116 | date = December 2015 | pmid = 26457543 | doi = 10.1001/jamapediatrics.2015.2831 | pmc = 4996656 }}</ref> Maternal diabetes has been shown to increase the risk of cardiovascular deformations, namely the transposition of great arteries, one of the four deformations in TOF.<ref>{{Cite journal |vauthors=Petropoulos AC |publisher=BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health |date=2004-03-01 |title=Congenital heart disease and maternal diabetes |url=https://adc.bmj.com/content/89/3/211 |journal=Archives of Disease in Childhood |language=en |volume=89 |issue=3 |pages=211 |issn=0003-9888 |access-date=2021-11-17 |archive-date=2021-11-17 |archive-url=https://web.archive.org/web/20211117174646/https://adc.bmj.com/content/89/3/211 |url-status=live }}</ref> Studies have also looked at whether diabetes increases the risk of malformation or poor sugar regulation and have found that sugar regulation does not significantly affect cardiac malformations.<ref name="Priest_2015" /> Retrospective studies have shown that diabetic mothers with good glucose control still retained the elevated CHD risk.<ref name="Priest_2015" />
*Rubella: Rubella is characterized as mild, contagious viral disease with often unnoticed consequences.<ref name="Yazigi_2017">{{cite journal | vauthors = Yazigi A, De Pecoulas AE, Vauloup-Fellous C, Grangeot-Keros L, Ayoubi JM, Picone O | title = Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature | journal = The Journal of Maternal-Fetal & Neonatal Medicine | volume = 30 | issue = 3 | pages = 274–278 | date = February 2017 | pmid = 27002428 | doi = 10.3109/14767058.2016.1169526 | s2cid = 43897118 }}</ref> Infection with rubella during the first trimester has been seen to cause various fetal malformations, including TOF.<ref name="Yazigi_2017" />
*Maternal Age: Older maternal age, especially after 35 can have various pregnancy risks due to existing co-morbidities such as hypertension, diabetes, hypothyroidism, and consanguinity.<ref name="Hashim_2020">{{cite journal | vauthors = Hashim ST, Alamri RA, Bakraa R, Rawas R, Farahat F, Waggass R | title = The Association Between Maternal Age and the Prevalence of Congenital Heart Disease in Newborns from 2016 to 2018 in Single Cardiac Center in Jeddah, Saudi Arabia | journal = Cureus | volume = 12 | issue = 3 | page = e7463 | date = March 2020 | pmid = 32351842 | pmc = 7188012 | doi = 10.7759/cureus.7463 | doi-access = free }}</ref> These risk factors can effect fetal development and lead to various fetal conditions such as CHD (including TOF), Down Syndrome and Autism.<ref name="Hashim_2020" />

[[Embryology]] studies show that [[anterior]] malalignment of the [[aorticopulmonary septum]] results in the clinical combination of a [[ventricular septal defect]] (VSD), [[Pulmonary Stenosis|pulmonary stenosis]], and an [[overriding aorta]].<ref name="Munoz_2010" />{{rp|200}} [[Right ventricular hypertrophy]] develops progressively from resistance to blood flow through the [[Ventricle (heart)|right ventricular]] outflow tract.<ref name="Curr2016" />