Shamseldin Hanan E, Maddirevula Sateesh, Faqeih Eissa, Ibrahim Niema, Hashem Mais, Shaheen Ranad, Alkuraya Fowzan S
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Genet Med. 2017 May;19(5):593-598. doi: 10.1038/gim.2016.155. Epub 2016 Oct 6.
Clinical exome sequencing (CES) has greatly improved the diagnostic process for individuals with suspected genetic disorders. However, the majority remains undiagnosed after CES. Although understanding potential reasons for this limited sensitivity is critical for improving the delivery of clinical genomics, research in this area has been limited.
We first calculated the theoretical maximum sensitivity of CES by analyzing >100 families in whom a Mendelian phenotype is mapped to a single locus. We then tested the hypothesis that positional mapping can limit the search space and thereby facilitate variant interpretation by reanalyzing 33 families with "negative" CES and applying positional mapping.
We found that >95% of families who map to a single locus harbored genic (as opposed to intergenic) variants that are potentially identifiable by CES. Our reanalysis of "negative" CES revealed likely causal variants in the majority (88%). Several of these solved cases have undergone negative whole-genome sequencing.
The discrepancy between the theoretical maximum and the actual clinical sensitivity of CES is primarily in the variant filtration rather than the variant capture and sequencing phase. The solution to negative CES is not necessarily in expanding the coverage but rather in devising approaches that improve variant filtration. We suggest that positional mapping is one such approach.Genet Med advance online publication 06 October 2016.
临床外显子组测序（CES）极大地改善了疑似遗传性疾病患者的诊断流程。然而，大多数患者在接受CES检测后仍未得到诊断。尽管了解导致这种有限敏感性的潜在原因对于改善临床基因组学的应用至关重要，但该领域的研究一直有限。
我们首先通过分析100多个孟德尔表型定位到单个位点的家系，计算了CES的理论最大敏感性。然后，我们通过重新分析33个CES检测结果为“阴性”的家系并应用定位映射，来检验定位映射可以限制搜索空间从而便于变异解读的假设。
我们发现，定位到单个位点的家系中，超过95%携带可通过CES潜在识别的基因（而非基因间）变异。我们对“阴性”CES结果的重新分析显示，大多数（88%）家系中存在可能的致病变异。其中一些已确诊的病例曾接受过全基因组测序且结果为阴性。
CES的理论最大敏感性与实际临床敏感性之间的差异主要在于变异筛选阶段，而非变异捕获和测序阶段。CES检测结果为阴性的解决办法不一定是扩大覆盖范围，而是设计出改进变异筛选的方法。我们认为定位映射就是这样一种方法。《遗传医学》2016年10月6日在线优先发表。
