Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Is a Fully Penetrant, Lethal Arrhythmic Disorder Caused by a Missense Mutation in the TMEM43 Gene

摘要: Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from genetically isolated population. Identification of key recombination events reduced the disease region to 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C→T, S358L), was carried all recombinant ARVD5 ancestral haplotypes affected subjects not found population controls. The mutation occurs highly conserved domain TMEM43 predicted be deleterious. Clinical outcomes 257 151 unaffected compared, penetrance determined. We concluded that at locus lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy 41 years males compared 71 females (relative risk 6.8, 95% CI 1.3–10.9). Heart failure late manifestation survivors. Although little known about function gene, it contains response element for PPARγ (an adipogenic transcription factor), which may explain fibrofatty replacement myocardium, characteristic pathological finding ARVC.