Next-generation sequencing in a family with dilated cardiomyopathy identified a dual genetic diagnosis involving a pathogenic FLNC truncating variant and a likely pathogenic LMNA missense variant.
Case Report
This case highlights the clinical importance of comprehensive genetic testing to identify dual genetic diagnoses in cardiomyopathy, which is critical for accurate cascade screening and preventive management.
Abstract We report a three-generation family with a complex genotype associated with dilated and arrhythmogenic cardiomyopathy. A 54-year-old male was referred to the CardioGenetics Clinic after a screening echocardiogram revealed dilated cardiomyopathy (DCM) in the context of a family history that included two sudden cardiac deaths (at 37 and 13 years of age) and an uncle who underwent heart transplantation at 65 years after progressive biventricular systolic dysfunction and atrial fibrillation. Due to the severity of the phenotype, he was designated as the proband for genetic testing. Next-generation sequencing using a broad cardiomyopathy/arrhythmia panel identified a pathogenic truncating variant in the FLNC gene (c. 6976CT, p. Arg2326*) NM₀01458. 4 (ACMG/ACGS 2019: PVS1, PS4ₛup, PM2, PP1ₛtr) and a likely pathogenic missense variant in the LMNA gene (c. 1071CA, p. Asp357Glu) NM₁70707. 4, not previously reported in the literature or population databases (ACMG/ACGS 2019: PM1, PM2, PP1ₛup, PP2, PM5, BP4). Segregation analysis identified three family members as carriers of the FLNC variant. Their phenotype included left ventricular dilation, late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging, and arrhythmic events (syncope). Based on these findings, two were proposed for implantable cardioverter-defibrillator (ICD) implantation. Regarding the LMNA variant, three carriers were identified. All had rhythm disturbances on electrocardiogram (atrial fibrillation, first-degree atrioventricular block, or right bundle branch block), and two showed septal LGE. The individual with first-degree AV block underwent ICD implantation. Additionally, five asymptomatic carriers of either variant were enrolled in regular cardiac surveillance. This family illustrates the rare but clinically significant occurrence of dual genetic diagnoses in cardiomyopathy and highlights two critical pitfalls: the selection of the family member for initial testing and the over-application of ACMG BP5 criteria, that can both compromise cascade screening, risk stratification, and timely preventive management. Comprehensive evaluation of all plausible variants in major cardiomyopathy genes remains essential to avoid under-recognition of clinically relevant findings and to ensure accurate genetic counseling.
Santos et al. (Sun,) conducted a case report in Dilated and arrhythmogenic cardiomyopathy. Next-generation sequencing was evaluated on Identification of pathogenic genetic variants. Next-generation sequencing in a family with dilated cardiomyopathy identified a dual genetic diagnosis involving a pathogenic FLNC truncating variant and a likely pathogenic LMNA missense variant.