The Genetic Architecture Of Left Ventricular Non-Compaction Reveals Both Substantial Overlap With Other Cardiomyopathies And A Distinct Aetiology In A Subset Of Cases

Background Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. We sought to investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. Results We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Individuals with MYH7 truncating variants identified in the UK Biobank and cohorts of healthy volunteers also displayed significantly greater non-compaction compared to matched controls, with 50% meeting the diagnostic criteria for LVNC. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVNC/arrhythmia phenotypes. These results underline the complex genetic landscape of LVNC and inform how genetic testing in LVNC cases should be pursued and interpreted. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement RW received support from an Amsterdam Cardiovascular Sciences fellowship. FM is supported by a post-doctoral research fellowship from the University of Florence. CRB acknowledges the support from the Dutch Heart Foundation (CVON 2018-30 Predict 2), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq. IO acknowledges support from the Italian Ministry of Health (RF-2013-02356787) and from the European Union (Horizon 2020 framework program, GA 777204 — SILICOFCM). EML acknowledges the Netherlands Organization for Scientific Research (VIDI fellowship, 91718361) and the Dutch Heart Foundation (CVON 2017-15 RESCUED). AdM and DPO’R are supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London and the Medical Research Council, UK. AdM also received support from the Academy of Medical Sciences (SGL015/1006) and the Mason Medical Research Trust. DPO’R is also funded by the British Heart Foundation (NH/17/1/32725, RG/19/6/34387). AMR, JSW, PJRB and SAC are funded by the Wellcome Trust (107469/Z/15/Z), NIHR Imperial Biomedical Research Centre, NIHR Royal Brompton Biomedical Research Unit, a Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, UK [HICF-R6-373], the British Heart Foundation (SP/10/10/28431 and RE/18/4/34215) and the Fondation Leducq [11 CVD-01]. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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