{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:57:22Z","timestamp":1790413042486,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic\/likely pathogenic: 18%,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001) but an excess of variants of uncertain significance (24%,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001), as compared to Whites (pathogenic\/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055,\n              <jats:italic>P<\/jats:italic>\n              =0.0057, genome aggregation database-East Asian AF=0.0062,\n              <jats:italic>P<\/jats:italic>\n              =0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001, genome aggregation database-East Asian AF=0.0009,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35\u20130.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83\u20130.97]) support the likely pathogenicity of TNNT2:p.R286H.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in\n              <jats:italic>TNNT2<\/jats:italic>\n              or\n              <jats:italic>TNNI3<\/jats:italic>\n              but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002823","type":"journal-article","created":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T15:38:27Z","timestamp":1597937907000},"page":"424-434","source":"Crossref","is-referenced-by-count":38,"title":["Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in\n            <i>TNNI3<\/i>\n            and\n            <i>TNNT2<\/i>\n            That Are Common in Chinese Patients"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4683-3043","authenticated-orcid":true,"given":"Chee Jian","family":"Pua","sequence":"first","affiliation":[{"name":"National Heart Centre Singapore (C.J.P., N.T., C.W.L.C., S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."},{"name":"Yong Loo Lin School of Medicine, National University Singapore (C.J.P., L.Y.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin","family":"Tham","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore (C.J.P., N.T., C.W.L.C., S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9867-4390","authenticated-orcid":true,"given":"Calvin W.L.","family":"Chin","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore (C.J.P., N.T., C.W.L.C., S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."},{"name":"Duke-National University of Singapore Medical School (C.W.L.C., J.C., S.S.J., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5092-8825","authenticated-orcid":true,"given":"Roddy","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiea Chuen","family":"Khor","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (C.C.K., P.T., R.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-2030","authenticated-orcid":true,"given":"Christopher N.","family":"Toepfer","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA (C.N.T., G.G.R., A.C.G., K.P., G.V.S., A.C.P., J.G.S., C.E.S.)."},{"name":"Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.N.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9172-6787","authenticated-orcid":true,"given":"Giuliana G.","family":"Repetti","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA (C.N.T., G.G.R., A.C.G., K.P., G.V.S., A.C.P., J.G.S., C.E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda C.","family":"Garfinkel","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA (C.N.T., G.G.R., A.C.G., K.P., G.V.S., A.C.P., J.G.S., C.E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jourdan F.","family":"Ewoldt","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Cloonan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Boston University, MA 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S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charleston W.K.","family":"Chiang","sequence":"additional","affiliation":[{"name":"Center for Genetic Epidemiology, University of Southern California (C.W.K.C.)."},{"name":"Center for Neurobehavioral Genetics, University of California, Los Angeles (C.W.K.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Whiffin","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Royal Brompton Hospital, London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.)."},{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-5887","authenticated-orcid":true,"given":"Antonio","family":"de Marvao","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Royal Brompton Hospital, London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.)."},{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (N.W., A.d.M., R.G., R.J.B., P.J.R.B., J.S.W., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei Min","family":"Lio","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore (C.J.P., N.T., C.W.L.C., S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An An","family":"Hii","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore (C.J.P., N.T., C.W.L.C., S.Q.L., S.C.K., P.M.L., A.A.H., C.X.Y., T.T.L., H.C.T., S.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"National 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