Imperial College London
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DrAntonioSimoes Monteiro de Marvao

Faculty of Medicine, Institute of Clinical Sciences

Honorary Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 1510antonio.de-marvao

 
 
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Location

 

Robert Steiner MRI UnitHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Pua:2020:10.1161/CIRCGEN.119.002823,
author = {Pua, CJ and Tham, N and Chin, CW and Walsh, R and Khor, CC and Toepfer, CN and Repetti, GG and Garfinkel, AC and Ewoldt, JF and Cloonan, P and Chen, CS and Lim, SQ and Cai, J and Loo, LY and Kong, SC and Chiang, CWK and Whiffin, N and de, Marvao A and Lio, PM and Hii, AA and Yang, CX and Le, TT and Bylstra, Y and Lim, WK and Teo, JX and Padilha, K and Venturini, G and Pan, B and Govind, R and Buchan, RJ and Barton, PJ and Tan, P and Foo, R and Yip, JWL and Wong, RCC and Chan, WX and Pereira, AC and Tang, HC and Jamuar, SS and Ware, JS and Seidman, JG and Seidman, CE and Cook, SA},
doi = {10.1161/CIRCGEN.119.002823},
journal = {Circ Genom Precis Med},
title = {Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients.},
url = {http://dx.doi.org/10.1161/CIRCGEN.119.002823},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies. Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 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, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA 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 to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3:p.R79C is considered a VUS. Mutant TNNT2:p.R286H iPSC-CMs 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 to Caucasians, 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-Caucasian
AU  - Pua,CJ
AU  - Tham,N
AU  - Chin,CW
AU  - Walsh,R
AU  - Khor,CC
AU  - Toepfer,CN
AU  - Repetti,GG
AU  - Garfinkel,AC
AU  - Ewoldt,JF
AU  - Cloonan,P
AU  - Chen,CS
AU  - Lim,SQ
AU  - Cai,J
AU  - Loo,LY
AU  - Kong,SC
AU  - Chiang,CWK
AU  - Whiffin,N
AU  - de,Marvao A
AU  - Lio,PM
AU  - Hii,AA
AU  - Yang,CX
AU  - Le,TT
AU  - Bylstra,Y
AU  - Lim,WK
AU  - Teo,JX
AU  - Padilha,K
AU  - Venturini,G
AU  - Pan,B
AU  - Govind,R
AU  - Buchan,RJ
AU  - Barton,PJ
AU  - Tan,P
AU  - Foo,R
AU  - Yip,JWL
AU  - Wong,RCC
AU  - Chan,WX
AU  - Pereira,AC
AU  - Tang,HC
AU  - Jamuar,SS
AU  - Ware,JS
AU  - Seidman,JG
AU  - Seidman,CE
AU  - Cook,SA
DO  - 10.1161/CIRCGEN.119.002823
PY  - 2020///
TI  - Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients.
T2  - Circ Genom Precis Med
UR  - http://dx.doi.org/10.1161/CIRCGEN.119.002823
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32815737
ER  -
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