O’Neill, Matthew J. and Chen, Suet Nee and Rumping, Lynne and Johnson, Renee and van Slegtenhorst, Marjon and Glazer, Andrew M. and Yang, Tao and Solus, Joseph F. and Laudeman, Julie and Mitchell, Devyn W. and Vanags, Loren R. and Kroncke, Brett M. and Anderson, Katherine and Gao, Shanshan and Verdonschot, Job A.J. and Brunner, Han and Hellebrekers, Debby and Taylor, Matthew R.G. and Roden, Dan M. and Wessels, Marja W. and Lekanne Dit Deprez, Ronald H. and Fatkin, Diane and Mestroni, Luisa and Shoemaker, M. Benjamin (2023) Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant. Heart Rhythm, 20 (8). pp.1158-1166. ISSN 15475271
Full text not available from this repository.Abstract
BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. METHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity. RESULTS: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity. 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 Apr 2024 02:25 |
| Last Modified: | 03 Apr 2024 02:25 |
| URI: | http://eprints.victorchang.edu.au/id/eprint/1442 |
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