Natural Missplicing Events Amplified by an Elusive Deep-Intronic MYBPC3 Variant Cause Hypertrophic Cardiomyopathy.

MYBPC3 c.2308+227G>A is a pathogenic deep-intronic variant that disrupts MYBPC3 splicing in HCM, with 81 confirmed carriers and 96% male penetrance by age 60.

• Why it matters: Deep-intronic MYBPC3 variants can be missed by DNA testing because prediction tools often deprioritize distant, low-efficiency splice changes. Identifying such “genotype-negative” causes is needed to explain unresolved HCM genetics.
• What they did: In a cohort of genotype-negative HCM patients from Salamanca, Spain, the variant was found in 35 probands and 46 relatives (81 carriers), with cosegregation supported by a combined LOD of 5.51 across 20 families. Splicing assays in blood and cardiac tissue showed cryptic donor c.2308+299 and acceptor c.2309-580 usage, producing two misspliced mRNAs encoding truncated proteins.
• The result: By age 60, cumulative penetrance was estimated at 81% in women and 96% in men, and the missplicing events are the leading unannotated intron 23 splice errors across MYBPC3 precursor mRNA. A shared haplotype among carriers supports an ancient founder effect and implies this variant can explain recurrent, elusive HCM cases.