Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

Antonio de Marvao; Kathryn A McGurk; Sean L Zheng; Marjola Thanaj; Wenjia Bai; Jinming Duan; Carlo Biffi; Francesco Mazzarotto; Ben Statton; Timothy J W Dawes; Nicolò Savioli; Brian P Halliday; Xiao Xu; Rachel J Buchan; A John Baksi; Marina Quinlan; Paweł Tokarczuk; Upasana Tayal; Catherine Francis; Nicola Whiffin; Pantazis I Theotokis; Xiaolei Zhang; Mikyung Jang; Alaine Berry; Antonis Pantazis; Paul J R Barton; Daniel Rueckert; Sanjay K Prasad; Roddy Walsh; Carolyn Y Ho; Stuart A Cook; James S Ware; Declan P O'Regan

doi:10.1016/j.jacc.2021.07.017

Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

Antonio de Marvao, Kathryn A McGurk, Sean L Zheng, Marjola Thanaj, Wenjia Bai, Jinming Duan, Carlo Biffi, Francesco Mazzarotto, Ben Statton, Timothy J W Dawes, Nicolò Savioli, Brian P Halliday, Xiao Xu, Rachel J Buchan, A John Baksi, Marina Quinlan, Paweł Tokarczuk, Upasana Tayal, Catherine Francis, Nicola WhiffinPantazis I Theotokis, Xiaolei Zhang, Mikyung Jang, Alaine Berry, Antonis Pantazis, Paul J R Barton, Daniel Rueckert, Sanjay K Prasad, Roddy Walsh, Carolyn Y Ho, Stuart A Cook, James S Ware, Declan P O'Regan

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Abstract

Background
Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Objectives
The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.

Methods
This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

Results
The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).

Conclusions
In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

Original language	English
Pages (from-to)	1097-1110
Journal	Journal of the American College of Cardiology
Volume	78
Issue number	11
Early online date	6 Sept 2021
DOIs	https://doi.org/10.1016/j.jacc.2021.07.017
Publication status	Published - 14 Sept 2021

Keywords

cardiovascular magnetic resonance
deep learning
genetics
hypertrophic cardiomyopathy
penetrance

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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de Marvao, A., McGurk, K. A., Zheng, S. L., Thanaj, M., Bai, W., Duan, J., Biffi, C., Mazzarotto, F., Statton, B., Dawes, T. J. W., Savioli, N., Halliday, B. P., Xu, X., Buchan, R. J., Baksi, A. J., Quinlan, M., Tokarczuk, P., Tayal, U., Francis, C., ... O'Regan, D. P. (2021). Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy. Journal of the American College of Cardiology, 78(11), 1097-1110. Advance online publication. https://doi.org/10.1016/j.jacc.2021.07.017

@article{abd72b606f5d41798cd1c967463880a7,

title = "Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy",

abstract = "BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.ObjectivesThe goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.MethodsThis study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).ConclusionsIn this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.",

keywords = "cardiovascular magnetic resonance, deep learning, genetics, hypertrophic cardiomyopathy, penetrance",

author = "{de Marvao}, Antonio and McGurk, {Kathryn A} and Zheng, {Sean L} and Marjola Thanaj and Wenjia Bai and Jinming Duan and Carlo Biffi and Francesco Mazzarotto and Ben Statton and Dawes, {Timothy J W} and Nicol{\`o} Savioli and Halliday, {Brian P} and Xiao Xu and Buchan, {Rachel J} and Baksi, {A John} and Marina Quinlan and Pawe{\l} Tokarczuk and Upasana Tayal and Catherine Francis and Nicola Whiffin and Theotokis, {Pantazis I} and Xiaolei Zhang and Mikyung Jang and Alaine Berry and Antonis Pantazis and Barton, {Paul J R} and Daniel Rueckert and Prasad, {Sanjay K} and Roddy Walsh and Ho, {Carolyn Y} and Cook, {Stuart A} and Ware, {James S} and O'Regan, {Declan P}",

year = "2021",

month = sep,

day = "14",

doi = "10.1016/j.jacc.2021.07.017",

language = "English",

volume = "78",

pages = "1097--1110",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

number = "11",

}

de Marvao, A, McGurk, KA, Zheng, SL, Thanaj, M, Bai, W, Duan, J, Biffi, C, Mazzarotto, F, Statton, B, Dawes, TJW, Savioli, N, Halliday, BP, Xu, X, Buchan, RJ, Baksi, AJ, Quinlan, M, Tokarczuk, P, Tayal, U, Francis, C, Whiffin, N, Theotokis, PI, Zhang, X, Jang, M, Berry, A, Pantazis, A, Barton, PJR, Rueckert, D, Prasad, SK, Walsh, R, Ho, CY, Cook, SA, Ware, JS & O'Regan, DP 2021, 'Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy', Journal of the American College of Cardiology, vol. 78, no. 11, pp. 1097-1110. https://doi.org/10.1016/j.jacc.2021.07.017

TY - JOUR

T1 - Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

AU - de Marvao, Antonio

AU - McGurk, Kathryn A

AU - Zheng, Sean L

AU - Thanaj, Marjola

AU - Bai, Wenjia

AU - Duan, Jinming

AU - Biffi, Carlo

AU - Mazzarotto, Francesco

AU - Statton, Ben

AU - Dawes, Timothy J W

AU - Savioli, Nicolò

AU - Halliday, Brian P

AU - Xu, Xiao

AU - Buchan, Rachel J

AU - Baksi, A John

AU - Quinlan, Marina

AU - Tokarczuk, Paweł

AU - Tayal, Upasana

AU - Francis, Catherine

AU - Whiffin, Nicola

AU - Theotokis, Pantazis I

AU - Zhang, Xiaolei

AU - Jang, Mikyung

AU - Berry, Alaine

AU - Pantazis, Antonis

AU - Barton, Paul J R

AU - Rueckert, Daniel

AU - Prasad, Sanjay K

AU - Walsh, Roddy

AU - Ho, Carolyn Y

AU - Cook, Stuart A

AU - Ware, James S

AU - O'Regan, Declan P

PY - 2021/9/14

Y1 - 2021/9/14

N2 - BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.ObjectivesThe goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.MethodsThis study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).ConclusionsIn this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

AB - BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.ObjectivesThe goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.MethodsThis study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).ConclusionsIn this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

KW - cardiovascular magnetic resonance

KW - deep learning

KW - genetics

KW - hypertrophic cardiomyopathy

KW - penetrance

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U2 - 10.1016/j.jacc.2021.07.017

DO - 10.1016/j.jacc.2021.07.017

M3 - Article

C2 - 34503678

SN - 0735-1097

VL - 78

SP - 1097

EP - 1110

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 11

ER -

Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

Abstract

Keywords

ASJC Scopus subject areas

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