Despite new strategies, such as evaluating deep intronic variants and new genes in whole‐genome‐sequencing studies, the diagnostic yield of genetic testing in hypertrophic cardiomyopathy (HCM) is still around 50%. FHOD3 has emerged as a novel disease‐causing gene for this phenotype, but the relevance and clinical implication of copy‐number variations (CNVs) have not been determined. In this study, CNVs were evaluated using a comparative depth‐of‐coverage strategy by next‐generation sequencing (NGS) in 5493 HCM probands and 2973 disease‐controls. We detected three symmetrical deletions in FHOD3 that involved exons 15 and 16 in three HCM families (no CNVs were detected in the control group). These exons are part of the diaphanous inhibitory domain of FHOD3 protein, considered a cluster of mutations for HCM. The clinical characteristics of the affected carriers were consistent with those reported in FHOD3 in previous studies. This study highlights the importance of performing CNV analysis systematically in NGS genetic testing panels for HCM, and reinforces the relevance of the FHOD3 gene in the disease.

中文翻译：

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下一代测序检测到的FHOD3特定外显子的缺失与肥厚型心肌病有关。

尽管有新的策略，例如在全基因组测序研究中评估深度内含子变体和新基因，但肥厚型心肌病（HCM）的基因检测的诊断率仍约为50％。FHOD3已成为该表型的新型致病基因，但尚未确定拷贝数变异（CNV）的相关性和临床意义。在这项研究中，通过比较测序的深度策略，通过5493 HCM先证者和2973疾病控制者的下一代测序（NGS）评估了CNV。我们在FHOD3中检测到三个对称缺失涉及三个HCM家族的15号和16号外显子（对照组中未检测到CNV）。这些外显子是FHOD3蛋白透明抑制域的一部分，被认为是HCM突变的簇。受影响的携带者的临床特征与先前研究中FHOD3中报道的那些一致。这项研究强调了在HCM的NGS基因检测小组中系统进行CNV分析的重要性，并加强了FHOD3基因在疾病中的相关性。