Genetic Architecture, Developmental Mechanisms and Genomic Applications in Left Ventricular Non-Compaction Cardiomyopathy (LVNC)

Left ventricular noncompaction cardiomyopathy (LVNC) is characterised by a two-layered ventricular wall with prominent trabeculations and deep recesses adjacent to a thinned compact layer. The phenotype spans from incidental findings to severe heart failure and malignant arrhythmias. More than 190 genes belonging to sarcomeric, cytoskeletal, mitochondrial, transcriptional and signalling pathways have been implicated, although only a subset reaches high gene disease validity in contemporary frameworks. Objectives: (i) Delineate the validated genetic landscape of LVNC; (ii) integrate developmental biology with cardiac genomics; (iii) translate genotype knowledge into diagnostic, prognostic and therapeutic guidance; (iv) outline a research agenda for precision cardiology. Methods: A narrative, pathway-oriented review of human and experimental studies (2000–July 2024). Results: Thirty-two genes meet definitive/strong validity thresholds and cluster in five biological networks. Oligogenic constellations account for ~4% of probands in recent cohorts. Imaging correlates (especially quantitative trabecular complexity and diffuse fibrosis metrics) provide complementary risk information. Conclusions: LVNC represents a convergence phenotype triggered by perturbations across developmental and structural networks; clinical management benefits from integrated genomics–imaging workflows and mechanism-informed trial design.