EP.23A novel LMNA mutation identified in an Argentinian patient with autosomal dominant Emery-Dreifuss muscular dystrophy phenotype

Abstract

LMNA mutations result in a broad array of diseases, named laminopathies. The Emery-Dreifuss muscular dystrophy and the dilated cardiomyopathy with conduction defects phenotypes, result primarily from heterozygous missense mutations in the LMNA gene (often in a dominant negative fashion), whilst truncating mutations resulting in premature termination codon are less common, but also described. We report a 38-year-old man with slowly progressive weakness and wasting in an humeroperoneal distribution beginning in early childhood, accompanied by elbow and achilles tendon contractures. At the age of 37, an implantable cardioverter defibrillator was required as he developed severe cardiac conduction defects. Incipient structural myocardial changes were also evident in the cardiac nuclear magnetic resonance. His family history reveals the existence of a twin sister with similar weakness pattern and contractures, without conduction or structural cardiac abnormalities. Additionally, both his father and paternal uncle suffered from dilated cardiomyopathy, without muscular weakness, and passed away from sudden death at 45 and 67 years of age respectively. Suspecting a Laminopathy a target next generation panel for cardiomyopathy and skeletal muscle disease was performed. A novel pathogenic variant c.210del (p.Ser71Alafs*25), at heterozygous state, was identified in LMNA. This sequence change creates a premature translational stop signal in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic. This variant is not present in population databases, and has not been reported in the literature in individuals with LMNA-related conditions. We present a 38-year-old patient with autosomal dominant Emery-Dreifuss muscular dystrophy phenotype, with strong family history, and a novel truncating variant identified in LMNA. Functional protein studies would contribute to confirm the pathogenicity of this variant.