FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Dilated cardiomyopathy (DCM) is a significant cause of heart failure, often with a familial genetic basis.
• Current genetic knowledge explains only half of DCM cases, highlighting the need for new gene discovery.
• Identifying novel DCM-associated genes is crucial for understanding disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To discover novel genes responsible for dilated cardiomyopathy (DCM).
• To investigate the underlying pathological mechanisms of DCM using zebrafish as a model.
• To analyze the function of identified gene variants in a relevant biological system.

Main Methods:

• Whole exome sequencing (WES) was performed on families with unexplained arrhythmogenic DCM.
• Bioinformatic filtering and cosegregation analysis were used to identify pathogenic variants.
• Functional assays and zebrafish morpholino knockdown models were employed to study disease mechanisms.

Main Results:

• Two novel splicing variants in the filamin C (FLNC) gene were identified in affected individuals across three families.
• Reduced FLNC protein levels in cardiac tissue suggested a haploinsufficiency model.
• Zebrafish knockdown of the FLNC ortholog resulted in cardiac dysfunction and abnormal ultrastructure.

Conclusions:

• Novel FLNC splicing variants are identified as a likely cause of DCM in the studied families.
• Evidence supports a gene haploinsufficiency mechanism in FLNC-associated DCM.
• Zebrafish models provide in vivo validation of the pathogenic mechanism for DCM.