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Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

1
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
2
Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
*
Author to whom correspondence should be addressed.
Academic Editors: Giuseppe Limongelli and Lia Crotti
Cardiogenetics 2021, 11(2), 73-83; https://doi.org/10.3390/cardiogenetics11020009
Received: 30 March 2021 / Revised: 4 May 2021 / Accepted: 25 May 2021 / Published: 2 June 2021
(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)
Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing. View Full-Text
Keywords: hypertrophic cardiomyopathy; MYBPC3; splice variants; minigene assays hypertrophic cardiomyopathy; MYBPC3; splice variants; minigene assays
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MDPI and ACS Style

Wood, K.A.; Ellingford, J.M.; Eden, J.; Thomas, H.B.; O’Keefe, R.T.; Hopton, C.; Newman, W.G. Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy. Cardiogenetics 2021, 11, 73-83. https://doi.org/10.3390/cardiogenetics11020009

AMA Style

Wood KA, Ellingford JM, Eden J, Thomas HB, O’Keefe RT, Hopton C, Newman WG. Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy. Cardiogenetics. 2021; 11(2):73-83. https://doi.org/10.3390/cardiogenetics11020009

Chicago/Turabian Style

Wood, Katherine A.; Ellingford, Jamie M.; Eden, James; Thomas, Huw B.; O’Keefe, Raymond T.; Hopton, Claire; Newman, William G. 2021. "Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy" Cardiogenetics 11, no. 2: 73-83. https://doi.org/10.3390/cardiogenetics11020009

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