Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy
Genetic variants in <i>MYBPC3</i> are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in <i>MYBPC3</i> affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the patho...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Cardiogenetics |
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| Online Access: | https://www.mdpi.com/2035-8148/11/2/9 |
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| author | Katherine A. Wood Jamie M. Ellingford James Eden Huw B. Thomas Raymond T. O’Keefe Claire Hopton William G. Newman |
| author_facet | Katherine A. Wood Jamie M. Ellingford James Eden Huw B. Thomas Raymond T. O’Keefe Claire Hopton William G. Newman |
| author_sort | Katherine A. Wood |
| collection | DOAJ |
| description | Genetic variants in <i>MYBPC3</i> are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in <i>MYBPC3</i> 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 <i>MYBPC3</i> variants and analyse the impact of variants on splicing using <i>in vitro</i> 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 <i>MYBPC3</i> 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 <i>MYBPC3</i> splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing. |
| first_indexed | 2024-03-10T10:46:46Z |
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| institution | Directory Open Access Journal |
| issn | 2035-8253 2035-8148 |
| language | English |
| last_indexed | 2024-03-10T10:46:46Z |
| publishDate | 2021-06-01 |
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| series | Cardiogenetics |
| spelling | doaj.art-5c46b773a2b144039d74397e5dc7663c2023-11-21T22:31:43ZengMDPI AGCardiogenetics2035-82532035-81482021-06-01112738310.3390/cardiogenetics11020009Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic CardiomyopathyKatherine A. Wood0Jamie M. Ellingford1James Eden2Huw B. Thomas3Raymond T. O’Keefe4Claire Hopton5William G. Newman6Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKManchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UKDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UKGenetic variants in <i>MYBPC3</i> are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in <i>MYBPC3</i> 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 <i>MYBPC3</i> variants and analyse the impact of variants on splicing using <i>in vitro</i> 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 <i>MYBPC3</i> 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 <i>MYBPC3</i> splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing.https://www.mdpi.com/2035-8148/11/2/9hypertrophic cardiomyopathy<i>MYBPC3</i>splice variantsminigene assays |
| spellingShingle | Katherine A. Wood Jamie M. Ellingford James Eden Huw B. Thomas Raymond T. O’Keefe Claire Hopton William G. Newman Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy Cardiogenetics hypertrophic cardiomyopathy <i>MYBPC3</i> splice variants minigene assays |
| title | Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy |
| title_full | Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy |
| title_fullStr | Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy |
| title_full_unstemmed | Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy |
| title_short | Pathogenic Intronic Splice-Affecting Variants in <i>MYBPC3</i> in Three Patients with Hypertrophic Cardiomyopathy |
| title_sort | pathogenic intronic splice affecting variants in i mybpc3 i in three patients with hypertrophic cardiomyopathy |
| topic | hypertrophic cardiomyopathy <i>MYBPC3</i> splice variants minigene assays |
| url | https://www.mdpi.com/2035-8148/11/2/9 |
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