Novel Truncating Variant c.1222DupC in RBM20 Causes Cardiomyopathy Consistent With Haploinsufficiency

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Splicing Factor Research

Background:

• RNA binding motif protein 20 (RBM20) is crucial for cardiac gene splicing.
• Pathogenic RBM20 variants cause familial dilated cardiomyopathy (DCM) via target gene missplicing.

Purpose of the Study:

• To investigate a novel RBM20 variant (c.1222DupC) identified in a DCM patient.
• To determine the functional impact of this variant on RBM20 activity and cardiac function.

Main Methods:

• Expressed the variant RBM20 in cellular models (neonatal rat cardiomyocytes, HEK293 cells).
• Generated and differentiated RBM20-c.1222DupC human induced pluripotent stem cells (hiPSC-CMs).
• Performed splicing assays, Western blotting, RNA sequencing, and calcium transient analysis.

Main Results:

• The RBM20-c.1222DupC variant is a heterozygous truncating variant causing premature termination.
• In vitro and in hiPSC-CMs, the variant led to loss of RBM20 activity, reduced protein levels, and widespread splicing defects in known RBM20 targets.
• Increased calcium transients were observed in hiPSC-CMs with the variant.

Conclusions:

• RBM20 c.1222DupC is a novel truncating variant causing DCM.
• The mechanism involves haploinsufficiency leading to splicing abnormalities and impaired cardiac calcium handling.