New insights from a large Moroccan-Jewish family concerning pathogenicity of FLNC nonsense mutation

Introduction

Following two familial cases of sudden-cardiac-death (SCD) in a 14-year old boy and his aunt, age 47, molecular-autopsy revealed a novel truncating mutation in the FLNC gene (FLNC:c.7467_7474delAAGTCCCT).
Mutations in Filamin C have been associated with various types of hereditary cardiomyopathies, with nonsense mutations mainly associated with arrhythmogenic dilated cardiomyopathy (AR-DCM). Current literature reports sudden death prevalence of 13-25% among carriers, with mean age of 42±15 years for first SCD event. This study reports cascade screening of this large Moroccan-Jewish family.

Material and methods

30 members were screened following genetic counseling. Carriers underwent a workup that consisted of an electrocardiogram (ECG), echocardiogram, stress test, 24-hour Holter, and cardiac MRI (CMR) followed by cardiologist consultation.

Results and discussion

16 carriers were discovered of the screened family members; ages ranged between 12 to 88 (mean 52±25). All identified carriers have been asymptomatic to date, 14 underwent clinical workup. ECG showed right-axis deviation in 43% (n=6), with no other pertinent findings. Holter recorded frequent premature ventricular contractions (PVCs) in 50% (n=7) with poly-morphology (n=5). Echo found three carriers with mild left-ventricular (LV) systolic dysfunction (EF 45-55%) and three with mild LV dilatation (indexed LVIDd 3.14 cm/m2). CMR was pathogenic in 9 out of 10 exams: pathologic late-gadolinium-enhancement (LGE) was observed in all studies, mainly in the mid-myocardium, frequently involving the septum and the inferior hinge-point. CMR demonstrated a decline in systolic function of either left or right ventricles (n=4).

Conclusion

This large pedigree presents a a lower penetrance of severe pathogenicity in carriers of a FLNC truncating mutation, in contrast to former descriptions. This may be due to a relatively distal mutation, or the possible co-inheritance of a protective gene or epigenetic modification. Alternatively, the relatively large pedigree compared to previously published smaller families may enable a more accurate assessment of pathogenicity.