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

Journal article

C. Pua, Nevin Tham, C. Chin, R. Walsh, C. Khor, Christopher N Toepfer, Giuliana G. Repetti, Amanda C Garfinkel, Jourdan F Ewoldt, Paige E. Cloonan, Christopher S. Chen, Shiqi Lim, Jiashen Cai, L. Loo, S. Kong, Charleston W. K. Chiang, N. Whiffin, A. de Marvao, P. Lio, A. Hii, Chengxi Yang, T. Le, Yasmin Bylstra, W. K. Lim, J. X. Teo, Kallyandra Padilha, G. Venturini, B. Pan, Risha Govind, R. Buchan, P. Barton, P. Tan, Roger Foo, J. Yip, R. Wong, W. Chan, A. Pereira, H. Tang, S. Jamuar, J. Ware, J. Seidman, C. Seidman, S. Cook
Circulation Genomic and Precision Medicine, 2020

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Pua, C., Tham, N., Chin, C., Walsh, R., Khor, C., Toepfer, C. N., … Cook, S. (2020). Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients. Circulation Genomic and Precision Medicine.

Chicago/Turabian Click to copy
Pua, C., Nevin Tham, C. Chin, R. Walsh, C. Khor, Christopher N Toepfer, Giuliana G. Repetti, et al. “Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients.” Circulation Genomic and Precision Medicine (2020).

MLA Click to copy
Pua, C., et al. “Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients.” Circulation Genomic and Precision Medicine, 2020.

BibTeX Click to copy

@article{c2020a,
  title = {Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients},
  year = {2020},
  journal = {Circulation Genomic and Precision Medicine},
  author = {Pua, C. and Tham, Nevin and Chin, C. and Walsh, R. and Khor, C. and Toepfer, Christopher N and Repetti, Giuliana G. and Garfinkel, Amanda C and Ewoldt, Jourdan F and Cloonan, Paige E. and Chen, Christopher S. and Lim, Shiqi and Cai, Jiashen and Loo, L. and Kong, S. and Chiang, Charleston W. K. and Whiffin, N. and de Marvao, A. and Lio, P. and Hii, A. and Yang, Chengxi and Le, T. and Bylstra, Yasmin and Lim, W. K. and Teo, J. X. and Padilha, Kallyandra and Venturini, G. and Pan, B. and Govind, Risha and Buchan, R. and Barton, P. and Tan, P. and Foo, Roger and Yip, J. and Wong, R. and Chan, W. and Pereira, A. and Tang, H. and Jamuar, S. and Ware, J. and Seidman, J. and Seidman, C. and Cook, S.}
}

Abstract

Supplemental Digital Content is available in the text. 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.