Transcriptome Sequencing of Patients With Hypertrophic Cardiomyopathy Reveals Novel Splice-Altering Variants in MYBPC3

Transcriptome Sequencing of Patients With Hypertrophic Cardiomyopathy Reveals Novel Splice-Altering Variants in MYBPC3.

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Item Type: Article
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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