{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:08:13Z","timestamp":1778634493296,"version":"3.51.4"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the\n              <jats:italic>PTPN11<\/jats:italic>\n              gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52;\n              <jats:italic>P<\/jats:italic>\n              =2.9\u00d710\n              <jats:sup>\u22126<\/jats:sup>\n              ) in the total cohort of TOF cases and controls; this remained highly significant after Bonferroni correction for 207 analyses (corrected\n              <jats:italic>P<\/jats:italic>\n              =0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Common variation in the linkage disequilibrium block including the\n              <jats:italic>PTPN11<\/jats:italic>\n              gene contributes to the risk of nonsyndromic TOF. Rare mutations in\n              <jats:italic>PTPN11<\/jats:italic>\n              are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras\/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in\n              <jats:italic>PTPN11<\/jats:italic>\n              function in sporadic, nonsyndromic congenital heart disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.111.962035","type":"journal-article","created":{"date-parts":[[2012,4,14]],"date-time":"2012-04-14T04:59:45Z","timestamp":1334379585000},"page":"287-292","source":"Crossref","is-referenced-by-count":34,"title":["A Common Variant in the\n            <i>PTPN11<\/i>\n            Gene Contributes to the Risk of Tetralogy of Fallot"],"prefix":"10.1161","volume":"5","author":[{"given":"Judith A.","family":"Goodship","sequence":"first","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darroch","family":"Hall","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Topf","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrysovalanto","family":"Mamasoula","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Griffin","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thahira J.","family":"Rahman","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise","family":"Glen","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huay","family":"Tan","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Palomino Doza","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline L.","family":"Relton","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"Bentham","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoumo","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Cosgrove","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Brook","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Granados-Riveron","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances A.","family":"Bu'Lock","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Graham","family":"Stuart","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Parsons","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather J.","family":"Cordell","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard","family":"Keavney","sequence":"additional","affiliation":[{"name":"From the Institute of Genetic Medicine (J.A.G., D.H., A.T., C.M., H.G., T.J.R., E.G., H.T., J.P.D., C.L.R., H.J.C., B.K.), Newcastle University, Newcastle upon Tyne; Department of Cardiovascular Medicine (J.B., S.B., C.C.), Oxford University, Oxford; Institute of Genetics (D.B., J.G.-R.), Nottingham University, Nottingham; University Hospitals of Leicester NHS Trust (F.A.B.L.), Leicester; Newcastle upon Tyne Hospitals NHS Foundation Trust (J.O.S.), Newcastle upon Tyne; Bristol Royal Hospital for..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.107.3.e32"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.2.163"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.9.2.179"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)06486-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc4601.098427"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2010.200121"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00040-5"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1710"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.027631"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.35.5.413"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000899"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.10252"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1159\/000119108"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2010.00579.x"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00420-0"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9410"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22030"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.415"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr589"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcm094"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010855"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.467"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng2068"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0807917"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.582"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.468"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2010.30"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00197421"},{"key":"e_1_3_4_31_2","first-page":"2062","article-title":"Crystal structure of the tyrosine phosphatase SHP-2","volume":"112","author":"Hof P","year":"2011","unstructured":"Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. 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