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. 2025 Feb 5;15(1):4306.
doi: 10.1038/s41598-025-88465-8.

Whole genome sequencing in early onset advanced heart failure

Erik Linnér  1   2 , Tomasz Czuba  3   4 , Olof Gidlöf  3   4 , Jakob Lundgren  3   5 , Entela Bollano  4   6 , Maria Hellberg  7 , Selvi Celik  3 , Neha Pimpalwar  3 , Philipp Rentzsch  8 , Molly Martorella  9 , Anders Gummesson  4   10 , Olle Melander  11   12 , Sebastian Albinsson  13 , Göran Dellgren  14 , Jan Borén  4 , Anders Jeppsson  4   14 , R Thomas Lumbers  15 , Sonia Shah  16 , Johan Nilsson  17   18 , Pradeep Natarajan  19   20 , Tuuli Lappalainen  8   9 , Malin Levin  4 , Hans Ehrencrona  7   21 , J Gustav Smith  3   5   4   6
Affiliations

Whole genome sequencing in early onset advanced heart failure

Erik Linnér et al. Sci Rep. .

Abstract

The genetic contributions to early onset heart failure (HF) are incompletely understood. Genetic testing in advanced HF patients undergoing heart transplantation (HTx) may yield clinical benefits, but data is limited. We performed deep-coverage whole genome sequencing (WGS) in 102 Swedish HTx recipients. Gene lists were compiled through a systematic literature review. Variants were prioritized for pathogenicity and classified manually. We also compared polygenic HF risk scores to a population-based cohort. We found a pathogenic (LP/P) variant in 34 individuals (34%). Testing yield was highest in hypertrophic (63% LP/P carriers), dilated (40%) and arrhythmogenic right ventricular (33%) cardiomyopathy and lower in ischemic cardiomyopathy (10%). A family history was more common in LP/P variant carriers than in non-carriers but was present in less than half of carriers (44% vs 13%, P < 0.001), whereas age was similar. Polygenic risk scores were similar in HTx recipients and the population cohort. In conclusion, we observed a high prevalence of pathogenic cardiomyopathy gene variants in individuals with early-onset advanced HF, which could not accurately be ruled out by family history and age. In contrast, we did not observe higher polygenic risk scores in early onset advanced HF cases than in the general population.

Keywords: Cardiomyopathies; Genetics; Genomics; Heart failure; Heart transplantation.

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Conflict of interest statement

Declarations. Competing interests: R.T.L reports research grants from Pfizer and consultancy fees from FITFILE and HealthLumen, unrelated to the present work. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Other authors have no conflicts to declare.

Figures

Fig. 1
Fig. 1
Yield of genetic testing in heart transplant recipients. Monogenic contributions to early onset advanced heart failure. (a) Number of individuals in which a pathogenic/likely pathogenic variant (LP/P), variant of uncertain significance with suggestive evidence of pathogenicity (VUS) or no variant of interest (none) were identified based on phenotype. (b) Frequency of family history based on whether a LP/P, VUS or no variant of interest was found. DCM dilated cardiomyopathy (CM), ICM ischemic CM, HCM hypertrophic CM including phenocopies, ACHD adult congenital heart disease, ARVC arrhythmogenic right ventricular CM, RHD rheumatic heart disease.
Fig. 2
Fig. 2
Genes identified from genetic testing of heart transplant recipients. Pathogenic variants in sarcomeric genes were most common in DCM and HCM phenotypes, while variants in desmosomal genes were mainly detected in ARVC. Storage diseases include glycogen storage disease and lysosomal storage disease. All patients with genetic amyloidosis had transthyretin amyloidosis. DCM dilated cardiomyopathy (CM), HCM hypertrophic CM including HCM phenocopies, ARVC arrhythmogenic right ventricular CM, ICM ischemic cardiomyopathy, ACHD adult congenital heart disease.
Fig. 3
Fig. 3
Distribution of polygenic risk score in heart transplant recipients and the general population. Polygenic risk scores are standardized to the corresponding scores of the population-based Malmö Diet and Cancer cohort.
Fig. 4
Fig. 4
Graphical abstract. Yield of whole genome sequencing in patients with early onset advanced heart failure. LP/P likely pathogenic or pathogenic variant, VUS variant of uncertain significance.
See this image and copyright information in PMC

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