Background:TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing.Methods:Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children’s Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed.Results:Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children’s Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance.Conclusions:Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.

中文翻译：

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氨基酸水平信噪比分析有助于预测偶然发现的 TTN 编码肌联蛋白截短变体的致病性


背景： TTN是人体中最大的基因，编码 TTN（肌联蛋白），这是一种在骨骼肌和心肌中发挥关键结构、发育和调节作用的蛋白质。 TTN变异体，特别是截短变异体 (TTNtvs)，与心肌病的致病性有关。尽管存在这种联系，但表面上健康的普通人群也承受着沉重的 TTNtv 负担。这使得偶然发现的 TTNtv 的诊断解释变得复杂，随着临床外显子组测序的扩展，TTNtv 的数量越来越多。方法：偶然发现的 TTNtv 是从临床外显子组测序的大型参考数据库（贝勒遗传学）获得的，并与基因组聚合中的罕见群体变异进行比较数据库和文献中队列研究的心肌病相关变异。对德克萨斯儿童医院接受心肌病评估的 TTNtv 阳性儿童子集进行回顾性评估，了解心肌病的临床特征。进行氨基酸水平的信噪比分析。结果：在A带和N端I带内鉴定出病理热点，与外显子高剪接百分比区域密切相关。附带 TTNtvs 和人口 TTNtvs 并未局限于这些地区。根据当前美国医学遗传学和基因组学学院的标准，结合德克萨斯儿童医院病例的信噪比分析，对变异进行了重新分类。那些被重新分类为可能致病性或致病性的人比那些被重新分类为意义不明的变异的人更有可能在超声心动图上有心肌病的证据。 结论：偶然发现的 TTNtv 在临床外显子组测序转诊中很常见。 当纳入当前的美国医学遗传学和基因组学学院指南时，TTN A 带内的病理热点可能为确定变异致病性提供信息。