Your browser doesn't support javascript.
loading
Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients.
Pua, Chee Jian; Tham, Nevin; Chin, Calvin W L; Walsh, Roddy; Khor, Chiea Chuen; Toepfer, Christopher N; Repetti, Giuliana G; Garfinkel, Amanda C; Ewoldt, Jourdan F; Cloonan, Paige; Chen, Christopher S; Lim, Shi Qi; Cai, Jiashen; Loo, Li Yang; Kong, Siew Ching; Chiang, Charleston W K; Whiffin, Nicola; de Marvao, Antonio; Lio, Pei Min; Hii, An An; Yang, Cheng Xi; Le, Thu Thao; Bylstra, Yasmin; Lim, Weng Khong; Teo, Jing Xian; Padilha, Kallyandra; Silva, Gabriela V; Pan, Bangfen; Govind, Risha; Buchan, Rachel J; Barton, Paul J R; Tan, Patrick; Foo, Roger; Yip, James W L; Wong, Raymond C C; Chan, Wan Xian; Pereira, Alexandre C; Tang, Hak Chiaw; Jamuar, Saumya Shekhar; Ware, James S; Seidman, Jonathan G; Seidman, Christine E; Cook, Stuart A.
Afiliação
  • Pua CJ; 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.).
  • Tham N; Yong Loo Lin School of Medicine, National University Singapore (C.J.P., L.Y.L.).
  • Chin CWL; 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.).
  • Walsh R; 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.).
  • Khor CC; Duke-National University of Singapore Medical School (C.W.L.C., J.C., S.S.J., S.A.C.).
  • Toepfer CN; Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (R.W.).
  • Repetti GG; Genome Institute of Singapore (C.C.K., P.T., R.F.).
  • Garfinkel AC; 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.).
  • Ewoldt JF; Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.N.T.).
  • Cloonan P; 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.).
  • Chen CS; 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.).
  • Lim SQ; Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.).
  • Cai J; Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.).
  • Loo LY; Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.).
  • Kong SC; 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.).
  • Chiang CWK; Duke-National University of Singapore Medical School (C.W.L.C., J.C., S.S.J., S.A.C.).
  • Whiffin N; Yong Loo Lin School of Medicine, National University Singapore (C.J.P., L.Y.L.).
  • de Marvao A; 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.).
  • Lio PM; Center for Genetic Epidemiology, University of Southern California (C.W.K.C.).
  • Hii AA; Center for Neurobehavioral Genetics, University of California, Los Angeles (C.W.K.C.).
  • Yang CX; 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.).
  • Le TT; 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.).
  • Bylstra Y; 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.).
  • Lim WK; 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.).
  • Teo JX; 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.).
  • Padilha K; 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.).
  • Silva GV; 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.).
  • Pan B; 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.).
  • Govind R; SingHealth/Duke-NUS Precision Medicine Inst, Singapore (Y.B., W.K.L., J.X.T., P.T., S.S.J.).
  • Buchan RJ; SingHealth/Duke-NUS Precision Medicine Inst, Singapore (Y.B., W.K.L., J.X.T., P.T., S.S.J.).
  • Barton PJR; SingHealth/Duke-NUS Precision Medicine Inst, Singapore (Y.B., W.K.L., J.X.T., P.T., S.S.J.).
  • Tan P; 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.).
  • Foo R; Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor)-University of São Paulo Medical School, Brazil (K.P., G.V.S., A.C.P.).
  • Yip JWL; 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.).
  • Wong RCC; Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor)-University of São Paulo Medical School, Brazil (K.P., G.V.S., A.C.P.).
  • Chan WX; Cardiovascular Research Institute, National University Health System, Singapore (B.P., R.F.).
  • Pereira AC; 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.).
  • Tang HC; 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.).
  • Jamuar SS; 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.).
  • Ware JS; 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.).
  • Seidman JG; 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.).
  • Seidman CE; 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.).
  • Cook SA; Genome Institute of Singapore (C.C.K., P.T., R.F.).
Circ Genom Precis Med ; 13(5): 424-434, 2020 10.
Article em En | MEDLINE | ID: mdl-32815737
ABSTRACT

BACKGROUND:

To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.

METHODS:

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.

RESULTS:

Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic 18%, P<0.0001) but an excess of variants of uncertain significance (24%, P<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 (TNNI3p.R79C, disease allele frequency [AF]=0.018; TNNT2p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3p.R79C, Singaporean controls AF=0.0055, P=0.0057, genome aggregation database-East Asian AF=0.0062, P=0.0086; TNNT2p.R286H, Singaporean controls AF=0.0017, P<0.0001, genome aggregation database-East Asian AF=0.0009, P<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3p.R79C, 0.7%; TNNT2p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3p.R79C is considered variant of uncertain significance. Mutant TNNT2p.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, 0.83-0.97]) support the likely pathogenicity of TNNT2p.R286H.

CONCLUSIONS:

As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiomiopatia Hipertrófica / Troponina I / Troponina T / Povo Asiático Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged País/Região como assunto: Asia Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiomiopatia Hipertrófica / Troponina I / Troponina T / Povo Asiático Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged País/Região como assunto: Asia Idioma: En Ano de publicação: 2020 Tipo de documento: Article