Abstract 17287: Novel Variants in Nexilin are Associated with Left Ventricular Noncompaction Cardiomyopathy
Introduction: Left ventricular noncompaction (LVNC) is characterized by prominent and excessive trabeculations with deep recesses in the left ventricular wall and is mainly caused by dominant mutations in genes encoding sarcomere proteins. Advances in molecular diagnostics using next-generation sequencing (NGS) have led to the discovery of large numbers of genetic variants of uncertain significance (VUS) requiring further validation to determine pathogenicity. Here we report novel variants in nexilin (NEXN), a Z-disc protein that binds F-actin, likely associated with LVNC.
Methods and Results: NGS identified a novel NEXN variant p.C667Y in a newborn presenting with LVNC with severe LV dysfunction. The phenotype was first recognized in utero. Interestingly, LV function significantly improved over the first year of life. Family screening identified LVNC in the 4-year old sister as well as the 31year old father. Additionally a cohort of 92 isolated and non-isolated LVNC patients was screened and a stop codon mutation p.E575stop was found in a proband. He also carries a known MYBPC3 mutation.
NEXN wild-type and the p.C667Y variant were overexpressed in multiple striated muscle cell lines. Immunocytochemistry determined the localization and stability of the mutant protein. While NEXN wild-type co-localized with F-actin, variant p.C667Y formed aggregates throughout the cell cytoplasm. The lack of co-localization indicated protein disruption and loss of filament integrity. To determine the effects of this variant on heart development and physiology in vivo mRNA produced from either wild-type or variant p.C667Y was injected in zebrafish embryos. A trend of higher mortality rates and increased cardiac edema at 48- and 72 hours post-fertilization were detected in mutant embryos compared to wild-type. Further experiments will determine the phenotype in fish, localization and z-disc structure of mutant NEXN proteins in the developmental zebrafish heart.
Conclusions: Two novel NEXN variants p.C667Y and p.E575stop have been identified in patients with LVNC. In vivo and in vitro validation experiments showed evidence for pathogenicity of the p.C667Y variant. NEXN is a rare novel disease gene for LVNC.
Author Disclosures: T. Yuen: None. K. Borle: None. K. Wenzel: None. P. Eileen: None. V. French: None. A. Brodehl: None. J. Lauzon: None. P. Sharma: None. S. Klaassen: None. B. Gerull: None.
- © 2014 by American Heart Association, Inc.