Please use this identifier to cite or link to this item: https://doi.org/10.1161/CIRCGEN.119.002823
Title: Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients
Authors: Pua, Chee Jian 
Tham, Nevin
Chin, Calvin WL 
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 WK
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 JR
Tan, Patrick
Foo, Roger
Yip, James WL
Wong, Raymond CC
Chan, Wan Xian 
Pereira, Alexandre C
Tang, Hak Chiaw
Jamuar, Saumya Shekhar
Ware, James S
Seidman, Jonathan G
Seidman, Christine E
Cook, Stuart A 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Genetics & Heredity
Cardiovascular System & Cardiology
cardiomyopathies
hypertrophy
population
troponin I
troponin T
SARCOMERE FUNCTION
FOUNDER MUTATION
ASSOCIATION
GUIDELINES
Issue Date: 1-Oct-2020
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Citation: Pua, Chee Jian, Tham, Nevin, Chin, Calvin WL, 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 WK, 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 JR, Tan, Patrick, Foo, Roger, Yip, James WL, Wong, Raymond CC, Chan, Wan Xian, Pereira, Alexandre C, Tang, Hak Chiaw, Jamuar, Saumya Shekhar, Ware, James S, Seidman, Jonathan G, Seidman, Christine E, Cook, Stuart A (2020-10-01). Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients. CIRCULATION-GENOMIC AND PRECISION MEDICINE 13 (5) : 424-434. ScholarBank@NUS Repository. https://doi.org/10.1161/CIRCGEN.119.002823
Abstract: © 2020 Lippincott Williams and Wilkins. All rights reserved. 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.
Source Title: CIRCULATION-GENOMIC AND PRECISION MEDICINE
URI: https://scholarbank.nus.edu.sg/handle/10635/205911
ISSN: 25748300
DOI: 10.1161/CIRCGEN.119.002823
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