{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:29:09Z","timestamp":1785770949237,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial\u2013mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy\u2013Tetralogy\u2013Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype\u2013phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology.<\/jats:p>","DOI":"10.3390\/genes17020181","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tetralogy of Fallot: Genetic, Epigenetic and Clinical Insights into a Multifactorial Congenital Heart Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6991-8516","authenticated-orcid":false,"given":"Maria Felicia","family":"Gagliardi","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Surgery, Milano-Bicocca University, 20126 Milan, Italy"},{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-7800","authenticated-orcid":false,"given":"Emanuele","family":"Micaglio","sequence":"additional","affiliation":[{"name":"Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Micheletti","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Gabriela","family":"Negura","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-8436","authenticated-orcid":false,"given":"Francesca","family":"Bevilacqua","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Guglielmi","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Pasqualin","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"},{"name":"Postgraduate School in Radiodiagnostics, University of Milan, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Giamberti","sequence":"additional","affiliation":[{"name":"Congenital Cardiac Surgery Unit, IRCCS Policlinico San Donato, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Chessa","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, 20097 Milan, Italy"},{"name":"Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","unstructured":"Horenstein, M.S., Diaz-Frias, J., and Guillaume, M. 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