Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
Am J Hum Genet. 2023 Sep 7;110(9):1454-1469. doi: 10.1016/j.ajhg.2023.07.010. Epub 2023 Aug 17.
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
短读基因组测序（GS）有望成为评估自闭症谱系障碍（ASD）和胎儿结构异常（FSA）的主要诊断方法。然而，很少有研究全面评估其与当前标准护理诊断测试（核型分析、染色体微阵列（CMA）和外显子组测序（ES））的性能。为了评估 GS 的临床实用性，我们在包括 1612 个四重家族（包括一个 ASD 个体）和 295 个产前家族的研究中，比较了其与这三种测试的诊断效果。我们的 GS 分析框架在 7.8%的 ASD 先证者中发现了一个诊断性变异，几乎是 CMA（4.3%）的两倍，是 ES（2.7%）的三倍。然而，当我们从外显子组数据中系统地捕获拷贝数变异（CNVs）时，ES 的诊断效果（7.4%）就与之非常接近，但仍未超过 GS。同样，我们估计 GS 可以在未选择的 FSA 中实现 46.1%的总体诊断效果，比核型分析提高了 17.2%，比 CMA 提高了 14.1%，比有 CNV 调用的 ES 提高了 4.1%，比没有 CNV 发现的 ES 提高了 36.1%。总体而言，GS 在 ASD 和 FSA 中分别比三种标准护理测试的组合增加了 0.4%和 0.8%的诊断效果。这对应于 9 个 GS 独特的诊断变异，包括 ES 无法捕获的外显子序列变异、现有标准护理测试无法检测到的结构变异（SV）以及 GS 分辨率改变变异分类的 SV。总的来说，这项大规模评估表明，GS 显著优于每种单独的标准护理测试，也优于三种测试的组合，因此有理由将其作为 ASD 和 FSA 评估的一线诊断方法。
