Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy
| Autor: | Katherine A. Wood, Jamie M. Ellingford, James Eden, Huw B. Thomas, Raymond T. O’Keefe, Claire Hopton, William G. Newman |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Cardiogenetics, Vol 11, Iss 2, Pp 73-83 (2021) |
| Druh dokumentu: | article |
| ISSN: | 2035-8148 2035-8253 |
| DOI: | 10.3390/cardiogenetics11020009 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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