Whole‐genome sequencing identifies novel candidate pathogenic variants associated with left ventricular non‐compaction in a three‐generation family.

Abbreviations CADD combined annotation dependent depletion FGF fibroblast growth factor LVNC left ventricular non-compaction PCP planar cell polarity RA retinoic acid SNV single-nucleotide variant WGS whole-genome sequencing In this work, we found three novel candidate variants, namely a stop-gain I ZNF107 i (c.G1021T) and two missense variants I CYP26B1 i (c.C364A) and I KIF16B i (c.G1748A), to be the most plausible causes for the left ventricular non-compaction (LVNC) in a three-generation Chinese family. Whole-genome sequencing identifies novel candidate pathogenic variants associated with left ventricular non-compaction in a three-generation family LVNC is a rare genetic cardiomyopathy with two morphological features: a thick bilayered myocardium with prominent ventricular trabeculations and deep intertrabecular recesses in the left ventricular wall.1 Reports on LVNC-related genes are relatively limited, and approximately 42% of LVNC cases are familial, suggesting the existence of unknown mechanisms affecting the explored genetic etiologies of LVNC.2 Fibroblast growth factor (FGF) signaling is likely a contributing factor of LVNC for its pivotal role in compact myocardium proliferation.3 Experiments on mouse embryos showed that some FGF proteins have high expression levels in both the endocardium and epicardium, and their deficiencies lead to a thin myocardium wall and therefore non-compaction.4 Moreover, excessive retinoic acid (RA), a metabolite of vitamin A, can interrupt the activation of the planar cell polarity (PCP) pathway regulating cardiomyocyte polarization.5 As a result, un-polarized cardiomyocytes maintain the original round shape, leading to a non-compacted myocardium. KIF16B encodes a kinesin-like protein mediating FGF signal transduction via regulating the surface presentation of FGFR2. [Extracted from the article]