Purpose

Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing.

Methods

We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2.

Results

GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS.

Conclusion

GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.

中文翻译：

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基因组测序可提高临床诊断的 Alagille 综合征患者先前检测结果为阴性的诊断率

目的

在一次测试中检测所有主要类别的基因组变异将降低成本并提高基因组诊断的效率。基因组测序 (GS) 有可能提供这种水平的综合检测。我们试图证明 GS 在 18 名临床定义的 Alagille 综合征 (ALGS) 患者的分子诊断中的效用，这些患者的护理标准检测结果为阴性或不确定。

方法

我们对 16 名致病性变异阴性先证者和两名结果不确定的先证者（406 名 ALGS 先证者）进行了 GS，并分析了JAG1和NOTCH2中序列、拷贝数和结构变异的数据。

结果

GS 鉴定了四种新的致病性改变，包括 JAG1 中的拷贝中性倒位、部分缺失和启动子变异，以及部分NOTCH2缺失，额外的诊断率为 0.9%。此外，GS 解决了两个复杂的重排，导致在 GS 后 97.5% ( n  = 396/406) 的患者中鉴定出致病变异。

结论

GS 为临床定义为 ALGS 的个体提供了更高的诊断率，这些人之前通过其他方法进行了阴性或不完整的基因检测。我们的结果表明，GS 可以检测所有主要类别的变异，并有可能成为孟德尔疾病的单一一级诊断测试。