Phenotypic Variability of Filamin C-related Cardiomyopathy: Insights from a Novel Dutch Founder Variant
Heart Rhythm(2023)
摘要
BACKGROUND Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs*23), was recently identified in Dutch patients with DCM.OBJECTIVES The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant.METHODS Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined.RESULTS Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19-67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (,45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribu-tion. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated be-tween 275 and 650 years ago.CONCLUSION The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs*23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart fail-ure and ventricular arrhythmias. The cardiac phenotype is character-ized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function.
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关键词
Dilated Cardiomyopathy
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