Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms

Abstract

Abstract Background FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype–phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants. Methods We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants. Results In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential. Conclusion For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.

Keywords

• FLNC variant
• Cardiomyopathies
• Early-onset
• Splicing defects