本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2314761

摘要内容如下：

背景

引起罕见疾病的基因变异，即使经过广泛的测试，如外显子组测序，可能仍然难以捉摸。基因组测序的诊断产量，特别是在阴性评估后，仍然不明确。

方法

我们对具有不同表型的家族的基因组进行了测序和分析，这些家族被怀疑患有一种罕见的单基因疾病，并且基因检测没有发现诊断结果，我们还对一个独立临床中心的复制队列的基因组进行了测序和分析。

结果

我们对822个家庭（初始队列744个，重复队列78个）进行了基因组测序，并对744个家庭中的218个（29.3%）进行了分子诊断。在218个家族中，61个（28.0%）-初始队列中8.2%的家族-具有需要基因组测序鉴定的变异，包括编码变异、内含子变异、小结构变异、复制中性倒位、复杂重排和串联重复序列扩增。在先前的非诊断性外显子组测序后进行分子诊断的大多数家族（63.5%）具有变异，这些变异可以通过外显子组序列数据的重新分析（53.4%）或通过额外的分析方法，如外显子组序列数据的拷贝数变异调用（10.8%）来检测。我们在重复队列中获得了类似的结果：在33%的进行了分子诊断的家族中，或在8%的队列中，需要进行基因组测序，这表明这些发现适用于研究和临床环境。

结论

在一个大型的、多样化的研究队列和一个小型的、以前接受过基因检测的临床队列中，基因组测序的诊断率约为8%，其中包括几种以前未通过外显子组测序或其他技术检测到的致病变异。（由美国国家人类基因组研究所等资助）。

英文原文如下：

Abstracts

BACKGROUND  Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined.

METHODS  We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center.

RESULTS  We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments.

CONCLUSIONS  The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

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