Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients-Reference-Cited by-同舟云学术

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Published:2020-10 Issue:5 Volume:13 Page:424-434
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Pua Chee Jian¹²^ORCID,Tham Nevin¹,Chin Calvin W.L.¹³^ORCID,Walsh Roddy⁴^ORCID,Khor Chiea Chuen⁵,Toepfer Christopher N.⁶⁷^ORCID,Repetti Giuliana G.⁶^ORCID,Garfinkel Amanda C.⁶,Ewoldt Jourdan F.⁸,Cloonan Paige⁸,Chen Christopher S.⁸,Lim Shi Qi¹,Cai Jiashen³^ORCID,Loo Li Yang²,Kong Siew Ching¹,Chiang Charleston W.K.⁹¹⁰,Whiffin Nicola¹¹¹²,de Marvao Antonio¹¹¹²^ORCID,Lio Pei Min¹,Hii An An¹,Yang Cheng Xi¹,Le Thu Thao¹,Bylstra Yasmin¹³,Lim Weng Khong¹³,Teo Jing Xian¹³,Padilha Kallyandra⁶¹⁴,Silva Gabriela V.⁶¹⁴,Pan Bangfen¹⁵,Govind Risha¹¹¹²^ORCID,Buchan Rachel J.¹¹¹²^ORCID,Barton Paul J.R.¹¹¹²^ORCID,Tan Patrick⁵¹³,Foo Roger⁵¹⁵^ORCID,Yip James W.L.¹⁶,Wong Raymond C.C.¹⁶,Chan Wan Xian¹⁶,Pereira Alexandre C.⁶¹⁴,Tang Hak Chiaw¹,Jamuar Saumya Shekhar³¹²¹⁷¹⁸,Ware James S.¹¹¹²^ORCID,Seidman Jonathan G.⁶^ORCID,Seidman Christine E.⁶¹⁹^ORCID,Cook Stuart A.¹³¹¹¹²^ORCID

Affiliation:

1. 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.).

2. Yong Loo Lin School of Medicine, National University Singapore (C.J.P., L.Y.L.).

3. Duke-National University of Singapore Medical School (C.W.L.C., J.C., S.S.J., S.A.C.).

4. Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (R.W.).

5. Genome Institute of Singapore (C.C.K., P.T., R.F.).

6. 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.).

7. Radcliffe Department of Medicine, University of Oxford, United Kingdom (C.N.T.).

8. Department of Biomedical Engineering, Boston University, MA (J.F.E., P.C., C.S.C.).

9. Center for Genetic Epidemiology, University of Southern California (C.W.K.C.).

10. Center for Neurobehavioral Genetics, University of California, Los Angeles (C.W.K.C.).

11. 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.).

12. 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.).

13. SingHealth/Duke-NUS Precision Medicine Inst, Singapore (Y.B., W.K.L., J.X.T., P.T., S.S.J.).

14. Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor)-University of São Paulo Medical School, Brazil (K.P., G.V.S., A.C.P.).

15. Cardiovascular Research Institute, National University Health System, Singapore (B.P., R.F.).

16. Cardiology Department, National University Heart Centre, Singapore (J.W.L.Y., R.C.C.W., W.X.C.).

17. KK Women’s and Children’s Hospital, Singapore (S.S.J.).

18. SingHealth Duke-NUS Genomic Medicine Centre, Singapore (S.S.J.).

19. Cardiovascular Division, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA (C.E.S.).

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 (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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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