Heart failure & cardiomyopathies
Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant
Authors' conclusion
Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic.
Study context
- Population
- Heterozygotes for the filamin C (FLNC) intronic variant of uncertain significance (VUS) c.970–4A>G (9 individuals, 4 kindreds)4 kindreds
- Participants
- 9 participants
Methodological detailsmulticentre, 5 tertiary centres, iPSC-CM functional studies
- Multicentre
- 5 tertiary centres
- iPSC-CM functional studies
Main finding
As reported in the abstract
- Spectrum of phenotypes, from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation
- Variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon
- Nonsense-mediated decay (NMD) inhibition upregulated aberrantly spliced transcripts (quantitative polymerase chain reaction (qPCR) and RNA-sequencing)
- Proband-derived iPSC-CMs: irregular spontaneous action potentials, increased action potential duration, increased sodium late current
- Multiple ACMG pathogenicity criteria fulfilled
Original publication
Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant. Heart Rhythm. Published 9 May 2023. doi:10.
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