遗传性心脏病中的大型新一代测序基因面板：致病变异和意义未明变异的检出率
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.
作者信息
van Lint F H M, Mook O R F, Alders M, Bikker H, Lekanne Dit Deprez R H, Christiaans I
机构信息
Department of Clinical Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
出版信息
Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.
BACKGROUND
Genetic heterogeneity is common in inherited cardiac diseases. Next-generation sequencing gene panels are therefore suitable for genetic diagnosis. We describe the results of implementation of cardiomyopathy and arrhythmia gene panels in clinical care.
METHODS
We present detection rates for variants with unknown (class 3), likely (class 4), and certain (class 5) pathogenicity in cardiogenetic gene panels since their introduction into diagnostics.
RESULTS
In 936 patients tested on the arrhythmia panel, likely pathogenic and pathogenic variants were detected in 8.8% (4.6% class 5; 4.2% class 4), and one or multiple class 3 variants in 34.8%. In 1970 patients tested on the cardiomyopathy panel, likely pathogenic and pathogenic variants were detected in 19.8% (12.0% class 5; 7.9% class 4), and one or multiple class 3 variants in 40.8%. Detection rates of all different classes of variants increased with the increasing number of genes on the cardiomyopathy gene panel. Multiple variants were detected in 11.7% and 28.5% of patients on the arrhythmia and cardiomyopathy panels respectively. In more recent larger versions of the cardiomyopathy gene panel the detection rate of likely pathogenic and pathogenic variants only slightly increased, but was associated with a large increase of class 3 variants.
CONCLUSION
Overall detection rates (class 3, 4, and 5 variants) in a diagnostic setting are 44% and 61% for the arrhythmia and cardiomyopathy gene panel respectively, with only a small minority of likely pathogenic and pathogenic variants (8.8% and 19.8% respectively). Larger gene panels can increase the detection rate of likely pathogenic and pathogenic variants, but mainly increase the frequency of variants of unknown pathogenicity.
背景
遗传异质性在遗传性心脏病中很常见。因此，新一代测序基因panel适用于基因诊断。我们描述了心肌病和心律失常基因panel在临床护理中的实施结果。
方法
我们展示了心脏发生基因panel自引入诊断以来，具有未知（3类）、可能（4类）和确定（5类）致病性的变异的检测率。
结果
在936例接受心律失常panel检测的患者中，检测到可能致病和致病的变异的比例为8.8%（5类为4.6%；4类为4.2%），检测到一个或多个3类变异的比例为34.8%。在1970例接受心肌病panel检测的患者中，检测到可能致病和致病的变异的比例为19.8%（5类为12.0%；4类为7.9%），检测到一个或多个3类变异的比例为40.8%。随着心肌病基因panel上基因数量的增加，所有不同类别的变异的检测率均升高。在心律失常和心肌病panel上分别有11.7%和28.5%的患者检测到多个变异。在心肌病基因panel的更新的更大版本中，可能致病和致病的变异的检测率仅略有增加，但与3类变异的大幅增加相关。
结论
在诊断环境中，心律失常和心肌病基因panel的总体检测率（3类、4类和5类变异）分别为44%和61%，只有一小部分可能致病和致病的变异（分别为8.8%和19.8%）。更大的基因panel可以提高可能致病和致病的变异的检测率，但主要增加了未知致病性变异的频率。
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