The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases

摘要: Abstract Background Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and subject of considerable conjecture as to whether it represents distinct pathology or secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. We sought investigate genetic architecture LVNC identifying genes variant classes robustly disease comparing these genetically Methods performed rare association analysis using six different cohorts comprising 840 cases together 125,748 gnomAD population controls compared results similar analyses dilated cardiomyopathy (DCM) hypertrophic (HCM) cases. Results observed substantial overlap enriched DCM/HCM, indicating that many belongs spectrum more established cardiomyopathies, representing phenotypic variation patients DCM- HCM-causing variants. In contrast, five were uniquely cases, which truncating variants MYH7, ACTN2 PRDM16 may represent aetiology. MYH7 are generally considered non-pathogenic but detected 2% 0.1% controls, including cluster around single splice region. Individuals identified UK Biobank healthy volunteers also displayed significantly greater matched 50% meeting diagnostic criteria for LVNC. Additionally, structural (exon deletions) RYR2 missense transmembrane region HCN4 confirming prior reports regarding combined arrhythmia phenotypes. Conclusions demonstrated can clarify relationship between highlighted DCM/HCM joint LVNC/arrhythmia These underline complex landscape inform how testing should be pursued interpreted.