Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy-Reference-Cited by-同舟云学术

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy

Published:2023-12 Issue:6 Volume:16 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Curran Lara¹²^ORCID,de Marvao Antonio³⁴⁵^ORCID,Inglese Paolo³^ORCID,McGurk Kathryn A.¹³^ORCID,Schiratti Pierre-Raphaël³,Clement Adam³^ORCID,Zheng Sean L.¹³,Li Surui⁶³,Pua Chee Jian⁷^ORCID,Shah Mit³,Jafari Mina^ORCID,Theotokis Pantazis¹³^ORCID,Buchan Rachel J.¹²³,Jurgens Sean J.⁸⁹^ORCID,Raphael Claire E.¹²¹⁰^ORCID,Baksi Arun John¹²,Pantazis Antonis¹²,Halliday Brian P.¹²,Pennell Dudley J.¹²^ORCID,Bai Wenjia⁶¹¹^ORCID,Chin Calvin W.L.⁷¹²¹³,Tadros Rafik¹⁴¹⁵,Bezzina Connie R.⁸^ORCID,Watkins Hugh¹⁶^ORCID,Cook Stuart A.⁴⁷^ORCID,Prasad Sanjay K.¹²^ORCID,Ware James S.¹²³,O’Regan Declan P.³

Affiliation:

1. National Heart and Lung Institute (L.C., K.A.M., S.L.Z., P.T., R.J.B., C.E.R., A.J.B., A.P., B.P.H., D.J.P., S.K.P., J.S.W.)

2. Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust (L.C., R.J.B., C.E.R., A.J.B., A.P., B.P.H., D.J.P., S.K.P., J.S.W.).

3. Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (A.d.M., P.I., K.A.M., P.-R.S., A.C., S.L.Z., S.L., M.S., M.J., P.T., R.J.B., S.A.C., J.S.W., D.P.O.).

4. Department of Women and Children’s Health (A.d.M.).

5. British Heart Foundation Centre of Research Excellence, School of Cardiovascular & Metabolic Medicine and Sciences, King’s College London, United Kingdom (A.d.M.).

6. Biomedical Image Analysis Group, Department of Computing (S.L., W.B.)

7. National Heart Research Institute Singapore, Singapore, PRC (C.J.P., C.W.L.C., S.A.C.).

8. Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands (S.J.J., C.R.B.).

9. Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.J.J.).

10. Mayo Clinic Rochester, MN (C.E.R.).

11. Department of Brain Sciences, Imperial College London, London, United Kingdom (W.B.).

12. Department of Cardiology, National Heart Center Singapore, Singapore, PRC (C.W.L.C.).

13. Cardiovascular Sciences ACP, Duke NUS Medical School, Singapore (C.W.L.C.).

14. Cardiovascular Genetics Centre, Montreal Heart Institute (R.T.).

15. Faculty of Medicine, Université de Montréal, QC, Canada (R.T.).

16. Radcliffe Department of Medicine, University of Oxford, United Kingdom (H.W.).

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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