Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients.,Circulation: Genomic and Precision Medicine

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Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients.
Circulation: Genomic and Precision Medicine ( IF 6.0 ) Pub Date : 2020-08-20 , DOI: 10.1161/circgen.119.002823
Chee Jian Pua _{1,

2} , Nevin Tham ₁ , Calvin W L Chin _{1,

3} , Roddy Walsh ₄ , Chiea Chuen Khor ₅ , Christopher N Toepfer _{6,

7} , Giuliana G Repetti ₆ , Amanda C Garfinkel ₆ , Jourdan F Ewoldt ₈ , Paige Cloonan ₈ , Christopher S Chen ₈ , Shi Qi Lim ₁ , Jiashen Cai ₃ , Li Yang Loo ₂ , Siew Ching Kong ₁ , Charleston W K Chiang _{9,

10} , Nicola Whiffin _{11,

12} , Antonio de Marvao _{11,

12} , Pei Min Lio ₁ , An An Hii ₁ , Cheng Xi Yang ₁ , Thu Thao Le ₁ , Yasmin Bylstra ₁₃ , Weng Khong Lim ₁₃ , Jing Xian Teo ₁₃ , Kallyandra Padilha _{6,

14} , Gabriela V Silva _{6,

14} , Bangfen Pan ₁₅ , Risha Govind _{11,

12} , Rachel J Buchan _{11,

12} , Paul J R Barton _{11,

12} , Patrick Tan _{5,

13} , Roger Foo _{5,

15} , James W L Yip ₁₆ , Raymond C C Wong ₁₆ , Wan Xian Chan ₁₆ , Alexandre C Pereira _{6,

14} , Hak Chiaw Tang ₁ , Saumya Shekhar Jamuar _{3,

12,

17,

18} , James S Ware _{11,

12} , Jonathan G Seidman ₆ , Christine E Seidman _{6,

19} , Stuart A Cook _{1,

3,

11,

12}

Affiliation

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.).
Yong Loo Lin School of Medicine, National University Singapore (C.J.P., L.Y.L.).
Duke-National University of Singapore Medical School (C.W.L.C., J.C., S.S.J., S.A.C.).
Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (R.W.).
Genome Institute of Singapore (C.C.K., P.T., R.F.).
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.).
Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.N.T.).
Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.).
Center for Genetic Epidemiology, University of Southern California (C.W.K.C.).
Center for Neurobehavioral Genetics, University of California, Los Angeles (C.W.K.C.).
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.).
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.).
SingHealth/Duke-NUS Precision Medicine Inst, Singapore (Y.B., W.K.L., J.X.T., P.T., S.S.J.).
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor)-University of São Paulo Medical School, Brazil (K.P., G.V.S., A.C.P.).
Cardiovascular Research Institute, National University Health System, Singapore (B.P., R.F.).
Cardiology Department, National University Heart Centre, Singapore (J.W.L.Y., R.C.C.W., W.X.C.).
KK Women's and Children's Hospital, Singapore (S.S.J.).
SingHealth Duke-NUS Genomic Medicine Centre, Singapore (S.S.J.).
Cardiovascular Division, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA (C.E.S.).

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 (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, P=0.0057, genome aggregation database-East Asian AF=0.0062, P=0.0086; TNNT2:p.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 (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, 0.35–0.86]) 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, 0.83–0.97]) support the likely pathogenicity of TNNT2:p.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.

更新日期：2020-10-20

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