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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
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| Series: | Cardiogenetics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2035-8148/11/2/9 |
| Summary: | 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. |
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| ISSN: | 2035-8253 2035-8148 |