The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing
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DOI：
10.1038/gim.2013.204
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发表时间：
2014-08-01
影响因子：
8.8
通讯作者：
Funke, Birgit H.
中科院分区：
文献类型：
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作者：
Pugh, Trevor J.;Kelly, Melissa A.;Funke, Birgit H.
目的：扩张型心肌病的特点是大量的基因座、等位基因和临床异质性，需要在临床重叠疾病中检测许多基因。很少有研究对足够的个体进行测序；因此，个体基因的贡献和致病变异谱仍然很不明确。我们分析了5年来在分子诊断实验室检测的766例扩张型心肌病患者。方法：采用从5个基因到46个基因的基因面板对患者进行检测，其中121例采用涵盖46个基因的多发性心肌病下一代面板进行检测。使用我们当前的临床级评分系统重新评估所有变异，以消除困扰许多旧分析的假阳性疾病关联。结果：高达37%的扩张型心肌病患者携带20个基因中的一个临床相关变异，其中titin （TTN）是最大的贡献者（高达14%）。致心律失常的右室心肌病基因Desmoplakin （DSP）贡献了2.4%，说明了多疾病检测的实用性。随着基因面板大小的增加，临床敏感性从10%增加到37%。然而，不确定病例的数量也从4.6%增加到51%。结论：我们的数据说明了广泛基因面板对遗传和临床异质性疾病的效用，但也突出了分子诊断向全基因组检测发展的挑战。
Purpose: Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory.Methods: Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses.Results: Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%.Conclusion: Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.