{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T03:19:59Z","timestamp":1792984799966,"version":"4.5.0"},"reference-count":77,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2019,2,15]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of \u226520. The clustering of variants in 2 genes,\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      and\n                      <jats:italic>FLT4<\/jats:italic>\n                      , surpassed thresholds for genome-wide significance (assigned as\n                      <jats:italic>P<\/jats:italic>\n                      &lt;5\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ) after correction for multiple comparisons.\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%\u20136.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling.\n                      <jats:italic>FLT4<\/jats:italic>\n                      variants were found in 2.4% (95% CI, 1.6%\u20133.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      ,\n                      <jats:italic>FLT4<\/jats:italic>\n                      and the well-established TOF gene,\n                      <jats:italic>TBX1<\/jats:italic>\n                      , we identified potential association with variants in several other candidates, including\n                      <jats:italic>RYR1<\/jats:italic>\n                      ,\n                      <jats:italic>ZFPM1<\/jats:italic>\n                      ,\n                      <jats:italic>CAMTA2<\/jats:italic>\n                      ,\n                      <jats:italic>DLX6<\/jats:italic>\n                      , and\n                      <jats:italic>PCM1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by\n                      <jats:italic>FLT4<\/jats:italic>\n                      . Together, variants in these genes are found in almost 7% of TOF patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.118.313250","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T08:44:17Z","timestamp":1547714657000},"page":"553-563","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":181,"title":["Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot"],"prefix":"10.1161","volume":"124","author":[{"given":"Donna J.","family":"Page","sequence":"first","affiliation":[{"name":"From the Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom (D.J.P., S.G.W., R.M.M., E.F., B.D.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu 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Manchester Academic Health Science Centre, University of Manchester, United Kingdom (D.J.P., S.G.W., R.M.M., E.F., B.D.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisavet","family":"Fotiou","sequence":"additional","affiliation":[{"name":"From the Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom (D.J.P., S.G.W., R.M.M., E.F., B.D.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J.","family":"Cordell","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (M.J.M., H.J.C., L.S., A.T., 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