García-Molina Esperanza, Sabater-Molina María, López-Cuenca David, Olmo María C, Pérez Inmaculada, Muñoz Esparza Carmen, Gimeno Blanes Juan R
Cardiogenetics Laboratory, Inherited Cardiac Disease Unit, IMIB University Hospital Virgen de la Arrixaca Murcia (Spain).
Department of Genetic and Microbiology, Murcia University Murcia, Spain.
Am J Transl Res. 2019 Mar 15;11(3):1724-1735. eCollection 2019.
With the development of deep sequencing, a significant proportion of mutations already listed in studies have inconclusive pathogenicity. We aim to establish the proportion of cases in which familial studies are possible and cosegregation analysis is informative. We also compare cosegregation analysis with in silico software and a proposed pathogenicity score. 204 consecutive positive tests were reviewed. 4 different in silico software programs were used. Spaendonck-Zwarts' pathogenicity score was also calculated. A total of 73 of the missense variants could be classified by the score as being likely or definitively pathogenic. A high percentage of nonsense variants were found in desmosomal genes and missense variants in sarcomeric genes. 36.3% of the missense variants in our cohort classified as very likely or definitively pathogenic were novel. Cosegregation analysis was positive in 19.5% and could be discarded in 15.6%. There was a significant discrepancy between the in silico tools used in the setting of inherited heart disease. Multiparametric scoring systems which include cosegregation and functional studies seem to perform better than individual prediction software.
随着深度测序技术的发展，已在研究中列出的相当一部分突变的致病性尚无定论。我们旨在确定可进行家族性研究且共分离分析具有参考价值的病例比例。我们还将共分离分析与计算机软件及提议的致病性评分进行比较。回顾了204例连续的阳性检测结果。使用了4种不同的计算机软件程序。还计算了斯帕恩东克 - 茨瓦特的致病性评分。共有73个错义变体根据该评分可被分类为可能或肯定致病。在桥粒基因中发现了高比例的无义变体，在肌节基因中发现了错义变体。在我们的队列中，被分类为极可能或肯定致病的错义变体中有36.3%是新发现的。共分离分析阳性率为19.5%，可排除率为15.6%。在遗传性心脏病的研究中，所使用的计算机工具之间存在显著差异。包括共分离和功能研究的多参数评分系统似乎比单个预测软件表现更好。
