Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

中文翻译：

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肥厚型心肌病患者下一代测序数据的再分析：意大利队列中剪接 MYBPC3 变体的贡献。


肥厚型心肌病 （HCM） 是一种遗传性心肌疾病，其特征是临床和遗传异质性。基因检测可以揭示编码肌节蛋白的基因中存在致病变异。然而，在 40-60% 的 HCM 病例中，它会产生不确定或阴性结果，除其他原因外，还包括技术限制，例如无法检测致病性内含子变异。因此，我们旨在通过改进 MYBPC3 中内含子变异的计算机检测来提高 HCM 分子分析的诊断率，这些内含子变异可能逃避通常与标记诊断面板一起使用的算法的检测。我们在 Illumina TruSight Cardio panel 分析中纳入了 142 例结果为阴性的 HCM 先证者，包括 174 个心肌病基因的外显子区。使用现有的生物信息学工具重新分析原始数据。在 3 例患者 （2.1%） 中检测到剪接变异 c.1224-80G>A，这让我们重新考虑他们的分子诊断。这些患者表现出晚发和轻微症状，尽管没有共同的特殊表型特征。总的来说，罕见的剪接 MYBPC3 变异可能在导致 HCM 中发挥作用，应进行系统检测，以在使用多基因面板的基因检测中提供更全面的解决方案。