Tan Natalie B, Stapleton Rachel, Stark Zornitza, Delatycki Martin B, Yeung Alison, Hunter Matthew F, Amor David J, Brown Natasha J, Stutterd Chloe A, McGillivray George, Yap Patrick, Regan Matthew, Chong Belinda, Fanjul Fernandez Miriam, Marum Justine, Phelan Dean, Pais Lynn S, White Susan M, Lunke Sebastian, Tan Tiong Y
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.
Mol Genet Genomic Med. 2020 Nov;8(11):e1508. doi: 10.1002/mgg3.1508. Epub 2020 Sep 23.
Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases.
We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18 months considered all disease-associated genes. At 25-34 months we reviewed all cases and the strategies which solved them.
Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months.
Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.
我们的主要目的是评估对因任何指征转诊的未确诊病例进行单例外显子组测序（ES）数据的系统性重新分析。次要目标是对检查未确诊病例基因组数据重新分析的研究进行文献综述。
我们检查了2016年6月至2017年3月期间转诊的58例未确诊病例的数据。在初始报告后4 - 13个月进行首次重新分析，考虑自原始分析以来新发现的与疾病相关的基因；在9 - 18个月进行第二次重新分析，考虑所有与疾病相关的基因。在25 - 34个月时，我们回顾了所有病例及其确诊策略。
仅在两个时间点对现有ES数据进行重新分析未得出新的诊断结果。在同一时间段内，通过其他策略（如微阵列检测拷贝数变异、重复测序以提高覆盖度和三联体测序）获得了10个新诊断结果（17%）。在文献综述中确定了27篇经过同行评审的文章，通过重新分析得出的新诊断率中位数为15%，重新分析的时间框架中位数为22个月。
我们的研究结果表明，自原始报告起超过18个月的间隔可能是重新分析的最佳时间。我们还建议对单例ES后仍未确诊的病例采用多方面的策略。
