Cardiology · 7 h ago
Deep-Intronic MYBPC3 Variant Linked to Hypertrophic Cardiomyopathy
A genetic and functional study identified the deep-intronic MYBPC3 variant c.2308+227G>A in 35 unrelated patients with hypertrophic cardiomyopathy (HCM). Family data and splicing assays support pathogenicity despite a low SpliceAI prediction score.
- Variant found in 35 unrelated HCM probands
- 56 of 81 confirmed carriers met HCM criteria
- Functional assays showed abnormal splicing and truncated proteins
Researchers investigated the previously unreported MYBPC3 variant c.2308+227G>A after identifying it in a cohort of genotype-negative patients with HCM in Salamanca, Spain. The study combined genetic and clinical assessment, family studies, splicing assays and haplotype reconstruction. The variant was found in 35 unrelated probands and 46 relatives from 27 families, yielding 81 confirmed carriers.
Among carriers, 56 (69%) met diagnostic criteria for HCM. Estimated cumulative penetrance by age 60 was 81% in women and 96% in men. The combined logarithm of the odds score across 20 informative families was 5.51, supporting cosegregation. Splicing assays using blood, with confirmation in cardiac tissue, showed that the variant promotes use of pre-existing cryptic splice sites, producing two misspliced mRNAs that encode truncated proteins. SpliceAI had predicted a low likelihood of an effect (Δ score, 0.03).
During follow-up, probands carrying the variant did not differ significantly from cohorts with other pathogenic MYBPC3 variants in heart failure, arrhythmic events, atrial fibrillation or mortality. The findings support considering deep-intronic MYBPC3 variants when genetic testing has not explained HCM. The study does not establish a change to clinical management, and the findings concern a specific variant and cohort.
In practice
For patients with HCM whose genetic cause remains unresolved, this study supports considering deep-intronic MYBPC3 variants that may be missed or deprioritized by standard prediction tools. The specific variant c.2308+227G>A was associated with disease in a cohort and supported by family cosegregation and functional splicing assays. These findings expand the potential genetic explanation for HCM but do not establish a management change; evidence concerns one variant and cohort, and no differences in clinical outcomes versus other pathogenic MYBPC3 variants were observed.
AI-generated clinical interpretation · Not editor-reviewed
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Circulation: Natural Missplicing Events Amplified by an Elusive Deep-Intronic MYBPC3 Variant Cause Hypertrophic Cardiomyopathy ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.