Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy.
Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy.
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DOI：
10.3390/jpm12050733
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发表时间：
2022-04-30
影响因子：
--
通讯作者：
Landstrom AP
中科院分区：
文献类型：
--
作者：
Kurzlechner LM;Jones EG;Berkman AM;Tadros HJ;Rosenfeld JA;Yang Y;Tunuguntla H;Allen HD;Kim JJ;Landstrom AP
背景：肥厚型心肌病(HCM)是最常见的遗传性心肌病，易导致猝死。大多数儿童肥厚型心肌炎患者存在一种已知的肉瘤基因的致病变异。随着临床环境中外显子组测序的增加，HCM相关基因的偶然变异被发现的频率越来越高。偶然变异的诊断性解释对于加强临床患者管理至关重要。我们试图使用氨基酸水平的信噪比(S：N)分析来建立肉瘤HCM相关基因的致病热点，并完善2015年美国医学遗传学学会(ACMG)的标准来预测偶发变异致病。方法和结果：从临床ES转诊数据库(Bayler Genetics)获得HCM基因的偶然变异(MYBPC3、MYH7、MYL2、MYL3、ACTC1、TPM1、TNNT2、TNNI3和TNNC1)，并与罕见群体变异(GnomAD)和来自HCM文献队列研究的变异进行比较。德克萨斯儿童医院对ES队列的一个子集进行了临床评估。我们比较了编码区域特定氨基酸位置的ES和HCM变异与gnomAD中罕见的变异(MAF<；0.0001)的频率。在基因和氨基酸水平上计算S：N的比值以确定致病热点。采用ACMG标准对ES队列变异进行重新分类，并与PM1标准进行S：N相关分析，减轻了不确定意义变异的负担。在临床验证队列中，大多数有心肌病或家族史的先证者存在可能的致病或致病变异。结论：HCM相关基因的偶然变异在临床ES转诊患者中很常见，尽管大多数与疾病无关。利用氨基酸水平的S：N作为临床工具，可以通过识别病原热点来提高ACMG标准的诊断判别能力。
Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencing (ES) in clinical settings, incidental variants in HCM-associated genes are being identified more frequently. Diagnostic interpretation of incidental variants is crucial to enhance clinical patient management. We sought to use amino acid-level signal-to-noise (S:N) analysis to establish pathogenic hotspots in sarcomeric HCM-associated genes as well as to refine the 2015 American College of Medical Genetics (ACMG) criteria to predict incidental variant pathogenicity. Methods and Results: Incidental variants in HCM genes (MYBPC3, MYH7, MYL2, MYL3, ACTC1, TPM1, TNNT2, TNNI3, and TNNC1) were obtained from a clinical ES referral database (Baylor Genetics) and compared to rare population variants (gnomAD) and variants from HCM literature cohort studies. A subset of the ES cohort was clinically evaluated at Texas Children’s Hospital. We compared the frequency of ES and HCM variants at specific amino acid locations in coding regions to rare variants (MAF < 0.0001) in gnomAD. S:N ratios were calculated at the gene- and amino acid-level to identify pathogenic hotspots. ES cohort variants were re-classified using ACMG criteria with S:N analysis as a correlate for PM1 criteria, which reduced the burden of variants of uncertain significance. In the clinical validation cohort, the majority of probands with cardiomyopathy or family history hosted likely pathogenic or pathogenic variants. Conclusions: Incidental variants in HCM-associated genes were common among clinical ES referrals, although the majority were not disease-associated. Leveraging amino acid-level S:N as a clinical tool may improve the diagnostic discriminatory ability of ACMG criteria by identifying pathogenic hotspots.
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影响因子：
39.3
作者：
Elliott, Perry M.;Anastasakis, Aris;Watkins, Hugh
通讯作者：
Watkins, Hugh
DOI：
10.1038/gim.2017.218
发表时间：
2018-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kelly MA;Caleshu C;Morales A;Buchan J;Wolf Z;Harrison SM;Cook S;Dillon MW;Garcia J;Haverfield E;Jongbloed JDH;Macaya D;Manrai A;Orland K;Richard G;Spoonamore K;Thomas M;Thomson K;Vincent LM;Walsh R;Watkins H;Whiffin N;Ingles J;van Tintelen JP;Semsarian C;Ware JS;Hershberger R;Funke B
通讯作者：
Funke B
DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1161/hcg.0000000000000086
发表时间：
2021-10
期刊：
Circulation. Genomic and precision medicine
影响因子：
--
作者：
Landstrom AP;Kim JJ;Gelb BD;Helm BM;Kannankeril PJ;Semsarian C;Sturm AC;Tristani-Firouzi M;Ware SM;American Heart Association Council on Genomic and Precision Medicine; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Lifestyle and Cardiometabolic Health
通讯作者：
American Heart Association Council on Genomic and Precision Medicine; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Lifestyle and Cardiometabolic Health
影响因子：
7.4
作者：
Musunuru, Kiran;Hershberger, Ray E.;Sturm, Amy C.
通讯作者：
Sturm, Amy C.