{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T05:06:22Z","timestamp":1779512782357,"version":"3.53.1"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"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>Background\/Objectives: Congenital heart malformations (CHDs) are not rare diseases, and, in many cases, their pathogenic mechanisms are well established. Several conotruncal defects are associated with genetic syndromes such as DiGeorge syndrome and RASopathies, reflecting shared developmental pathways affecting cardiac outflow tract formation. However, even common CHDs may occur within complex syndromic contexts, making early diagnosis essential for optimal management. This review aims to provide a unifying framework linking ciliary dysfunction to CHD phenotypes. Methods: We performed an integrative narrative review of genetic, experimental, and developmental studies focusing on the role of primary and motile cilia in cardiac morphogenesis. Particular attention was given to signaling pathways regulated by cilia and their contribution to disease phenotypes. Results: Emerging evidence indicates that primary and motile cilia act as central regulators of cardiac development, integrating morphogen gradients and mechanical cues into transcriptional programs. Dysfunctions in ciliary structure or signaling are increasingly recognized as important contributors to selected complex CHD phenotypes, particularly in syndromic forms and laterality-associated defects. This cilia-centered model may help explain part of the phenotypic heterogeneity observed in CHD and highlights shared mechanisms across distinct clinical entities. Conclusions: Understanding cilia-dependent mechanisms provides a unifying conceptual framework linking genetic defects to disrupted morphogenesis. This perspective may refine disease interpretation and support future development of precision diagnostics and pathway-informed therapeutic strategies in CHD.<\/jats:p>","DOI":"10.3390\/genes17050584","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:45:34Z","timestamp":1779291934000},"page":"584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ciliopathies in Complex Congenital Heart Disease: Molecular Genetics, Embryologic Mechanisms and Clinical Implications"],"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, San Donato Milanese, 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, San Donato Milanese, 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, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9501-8425","authenticated-orcid":false,"given":"Andrea","family":"Giordano","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baldassare Maria","family":"Alonzo","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, San Donato Milanese, 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, San Donato Milanese, 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, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Giamberti","sequence":"additional","affiliation":[{"name":"Congenital Cardiac Surgery Unit, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7432-4815","authenticated-orcid":false,"given":"Massimo","family":"Chessa","sequence":"additional","affiliation":[{"name":"Pediatric and Adult Congenital Heart Centre, IRCCS Policlinico San Donato, San Donato Milanese, 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":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e653","DOI":"10.1161\/CIR.0000000000000606","article-title":"Genetic basis for congenital heart disease: Revisited: A scientific statement from the American Heart Association","volume":"138","author":"Pierpont","year":"2018","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.jacc.2016.11.060","article-title":"Advances in the genetics of congenital heart disease","volume":"69","author":"Blue","year":"2017","journal-title":"J. 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