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

Autor:	Holliday M; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney., Singer ES; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney., Ross SB; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney., Lim S; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney., Lal S; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney., Ingles J; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia (J.I., C.S.)., Semsarian C; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia (J.I., C.S.)., Bagnall RD; Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.; Faculty of Medicine and Health (M.H., E.S.S., S.B.R., S.L., J.I., C.S., R.D.B.), The University of Sydney.
Jazyk:	angličtina
Zdroj:	Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2021 Apr; Vol. 14 (2), pp. e003202. Date of Electronic Publication: 2021 Mar 03.
DOI:	10.1161/CIRCGEN.120.003202
Abstrakt:	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.
Databáze:	MEDLINE
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