{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:31:33Z","timestamp":1792737093733,"version":"4.5.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"41","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,10,10]]},"abstract":"<jats:p>\n                    Tetralogy of Fallot (TOF), the most common severe cyanotic congenital heart disease, has unclear genetic causes. Through next-generation sequencing in 131 patients with nonsyndromic TOF, we identified an increased burden of rare deleterious variants in ciliary genes and cilium pathway and observed a multigenic inheritance pattern, with an odds ratio (OR) of 1.672 [95% confidence interval (CI),\u00a01.120 to 2.547;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.0104] for more than two deleterious variants and a cumulative OR of 3.158 (95% CI,\u00a01.381 to 6.371;\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.0038) for six variants. Functional validation in single- and double-heterozygous mouse models carrying these variants recapitulated TOF-like phenotypes and impaired normal cilia structure and function, particularly disrupting Hedgehog signaling in cardiomyocytes, and down-regulating key transcription factors\n                    <jats:italic toggle=\"yes\">Gata4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Nkx2-5<\/jats:italic>\n                    . Together, our study provides compelling evidence linking ciliary gene variants to a heightened risk of TOF in Han Chinese, offering valuable genetic insights into the etiology and pathogenesis of nonsyndromic TOF and supporting a multigenic inheritance model for the disease.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adt0836","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:59:09Z","timestamp":1760119149000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Loss-of-function variants in ciliary genes confer high risk for tetralogy of Fallot"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5817-3965","authenticated-orcid":true,"given":"Yan","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211100, 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