St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Eur J Hum Genet. 2022 Oct;30(10):1121-1131. doi: 10.1038/s41431-022-01162-2. Epub 2022 Aug 15.
Whole genome sequencing (WGS) improves Mendelian disorder diagnosis over whole exome sequencing (WES); however, additional diagnostic yields and costs remain undefined. We investigated differences between diagnostic and cost outcomes of WGS and WES in a cohort with suspected Mendelian disorders. WGS was performed in 38 WES-negative families derived from a 64 family Mendelian cohort that previously underwent WES. For new WGS diagnoses, contemporary WES reanalysis determined whether variants were diagnosable by original WES or unique to WGS. Diagnostic rates were estimated for WES and WGS to simulate outcomes if both had been applied to the 64 families. Diagnostic costs were calculated for various genomic testing scenarios. WGS diagnosed 34% (13/38) of WES-negative families. However, contemporary WES reanalysis on average 2 years later would have diagnosed 18% (7/38 families) resulting in a WGS-specific diagnostic yield of 19% (6/31 remaining families). In WES-negative families, the incremental cost per additional diagnosis using WGS following WES reanalysis was AU$36,710 (£19,407;US$23,727) and WGS alone was AU$41,916 (£22,159;US$27,093) compared to WES-reanalysis. When we simulated the use of WGS alone as an initial genomic test, the incremental cost for each additional diagnosis was AU$29,708 (£15,705;US$19,201) whereas contemporary WES followed by WGS was AU$36,710 (£19,407;US$23,727) compared to contemporary WES. Our findings confirm that WGS is the optimal genomic test choice for maximal diagnosis in Mendelian disorders. However, accepting a small reduction in diagnostic yield, WES with subsequent reanalysis confers the lowest costs. Whether WES or WGS is utilised will depend on clinical scenario and local resourcing and availability.
全基因组测序（WGS）优于全外显子组测序（WES）提高孟德尔疾病的诊断率；然而，额外的诊断收益和成本仍未确定。我们研究了在疑似孟德尔疾病的队列中，WGS 和 WES 在诊断和成本结果上的差异。WGS 是在之前接受过 WES 的 64 个家系孟德尔队列中 38 个 WES 阴性家系中进行的。对于新的 WGS 诊断，通过原始 WES 或 WGS 独有的变体是否可诊断的当代 WES 重新分析确定。模拟如果这两种方法都应用于 64 个家系，估计了 WES 和 WGS 的诊断率。计算了各种基因组测试方案的诊断成本。WGS 诊断了 38%（13/38）的 WES 阴性家系。然而，平均 2 年后的当代 WES 重新分析将诊断 18%（7/38 个家系），导致 WGS 特异性诊断率为 19%（6/31 个剩余家系）。在 WES 阴性家系中，在 WES 重新分析后使用 WGS 增加一个额外诊断的增量成本为 36710 澳元（19407 英镑；23727 美元），而单独使用 WGS 为 41916 澳元（22159 英镑；27093 美元），与 WES 重新分析相比。当我们模拟单独使用 WGS 作为初始基因组测试时，每个额外诊断的增量成本为 29708 澳元（15705 英镑；19201 美元），而当代 WES 随后是 WGS 则为 36710 澳元（19407 英镑；23727 美元），与当代 WES 相比。我们的研究结果证实，WGS 是孟德尔疾病中获得最大诊断的最佳基因组测试选择。然而，接受诊断率略有下降，WES 后进行重新分析则具有最低的成本。是选择 WES 还是 WGS 将取决于临床情况和当地资源和可用性。
