Transcriptome Sequencing of Patients With Hypertrophic Cardiomyopathy Reveals Novel Splice-Altering Variants in MYBPC3.
Full text not available from this repository.Item Type: | Article |
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Status: | Published |
Official URL: | https://doi.org/10.1161/CIRCGEN.120.003202 |
Journal or Publication Title: | Circulation: Genomic and Precision Medicine |
Volume: | 14 |
Number: | 2 |
Date: | 2021 |
Divisions: | Cardio Genomics Molecular Cardiology Bioinformatics and Molecular Genetics |
Depositing User: | General Admin |
Identification Number: | 10.1161/CIRCGEN.120.003202 |
ISSN: | 2574-8300 |
Date Deposited: | 10 Jun 2021 05:52 |
Abstract: | Background: Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could inhibit aberrant mRNA splicing in hiPSC-CMs. Methods: We derived hiPSC-CMs from patients with hypertrophic cardiomyopathy due to MYBPC3 splice-gain variants, or an unresolved genetic cause. We used transcriptome sequencing of hiPSC-CM RNA to identify pathogenic splicing and used AOs to inhibit this splicing. Results: Transcriptome sequencing of hiPSC-CMs confirmed aberrant splicing in 2 people with previously identified MYBPC3 splice-gain variants (c.1090+453C>T and c.1224-52G>A). In a patient with an unresolved genetic cause of hypertrophic cardiomyopathy following genome sequencing, transcriptome sequencing of hiPSC-CMs revealed diverse cryptic exon splicing due to an MYBPC3 c.1928-569G>T variant, and this was confirmed in cardiac tissue from an affected sibling. Antisense oligonucleotide treatment demonstrated almost complete inhibition of cryptic exon splicing in one patient-specific hiPSC-CM line. Conclusions: Transcriptome sequencing of patient specific hiPSC-CMs solved a previously undiagnosed genetic cause of hypertrophic cardiomyopathy and may be a useful adjunct approach to genetic testing. Antisense oligonucleotide inhibition of cryptic exon splicing is a potential future personalized therapeutic option. |
Creators: | Creators Email Holliday, Mira UNSPECIFIED Singer, Emma S. UNSPECIFIED Ross, Samantha B. UNSPECIFIED Lim, Seakcheng UNSPECIFIED Lal, Sean UNSPECIFIED Ingles, Jodie UNSPECIFIED Semsarian, Christopher UNSPECIFIED Bagnall, Richard D. UNSPECIFIED |
Last Modified: | 10 Jun 2021 05:52 |
URI: | https://eprints.centenary.org.au/id/eprint/995 |
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