Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.
Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.
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氨基酸水平的信噪分析有助于预测偶然发现的ttn编码的Titin截断变异的致病性。
DOI：
10.1161/circgen.120.003131
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Landstrom AP
中科院分区：
文献类型：
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作者：
Connell PS;Berkman AM;Souder BM;Pirozzi EJ;Lovin JJ;Rosenfeld JA;Liu P;Tunuguntla H;Allen HD;Denfield SW;Kim JJ;Landstrom AP
TTN是人体最大的基因，编码TTN，TTN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的变异，特别是截断变异(TTNtvs)，已被认为与心肌病(CM)的致病有关。尽管有这种联系，但在表面上健康的普通人群中，TTNtv的负担也很高。这使偶然发现的TTNtv的诊断解释变得复杂，由于扩大的临床外显子组测序(ES)，TTNtv的丰度越来越高。偶然鉴定的TTNtv是从临床ES(贝勒遗传学)的大型转介数据库中获得的，并与文献中队列研究中来自gnomAD和CM相关变体的罕见人群变体进行了比较。在德克萨斯儿童医院(TCH)对TTNTV阳性儿童进行了心肌病评估，回顾了心肌病的临床特征。进行氨基酸水平的信噪比分析(S：N)。病理热点位于A-带和N-末端I-带，与外显子高剪接率(PSI)密切相关。偶发TTNtv和人口TTNtv未定位于这些地区。根据ACMG的现行标准，结合S对TCH病例的分析，对TCH的变异进行重新分类。那些被重新归类为可能致病或致病的患者在超声心动图上更有可能有CM的证据，而不是那些被重新归类为意义未知的变异。偶然发现的TTNtv在临床ES转诊中很常见。如果将TTN A带内的病理热点纳入ACMG的现行指南，可能有助于确定不同的致病性。
TTN, the largest gene in the human body, encodes titin (TTN), 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 (CM). 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 (ES). Incidentally identified TTNtvs were obtained from a large referral database of clinical ES (Baylor Genetics) and compared to rare population variants from gnomAD and CM-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children’s Hospital (TCH) were retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis (S:N) was performed. Pathologic hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent spliced in (PSI) of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were re-classified based on current ACMG criteria with incorporation of S:N analysis among TCH cases. Those re-classified as likely pathogenic or pathogenic were more likely to have evidence of CM on echocardiography than those re-classified as variants of unknown significance. Incidentally found TTNtvs are common among clinical ES referrals. Pathologic hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current ACMG guidelines.