Nature子刊评估全外显子测序,有望成为新生儿的首个一线分子检测技术
2016/03/29
3月3日,发表在Nature子刊上的研究前瞻性评估了全外显子测序作为新生儿单基因疾病一线分子检测技术的临床效用性,结果表明,从诊断率及诊断效益上看,单例模式全外显子测序胜过标准诊断。


近两年,NEJM、JAMA及Sci Transl Med杂志的研究证实了全外显子测序的临床诊断率为25-45%。发文情况如下:


其中2013年NEJM杂志上以《Clinical whole-exome sequencing for the diagnosis of Mendelian disorders》为题刊文,2014年JAMA杂志发表了两篇文章,分别为《Molecular findings among patients referred for clinical whole-exome sequencing》和《Clinical exome sequencing for genetic identification of rare Mendelian disorders》,同年Sci Transl Med杂志也以《Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders》为题刊登了与外显子测序诊断率相关的文章。

这些研究为全外显子测序应用到罕见病的临床诊断提供了强有力的证据,但要成为最佳临床技术仍存在一些悬而未决的问题。首先,与标准治疗相比,如何利用单例模式全外显子测序进行诊断?其次,全外显子测序是否能作为所有罕见遗传疾病个体或复杂的、未确诊个体的一线检测手段,或者是在代谢、成像和定向基因测序之后再使用?

为了回答这些问题,3月3日发表在Nature子刊上的研究前瞻性评估了新生儿单基因疾病单例模式全外显子测序(singleton WES )作为一线分子检测技术的临床效用性,测试对象来自三级儿科中心的新生儿,并以标准诊断作为对照,包括单基因或多基因测序。评估指标包括诊断率、临床效用以及外显子测序对医疗管理的影响。

在80名参加测试的新生儿中,46名接受了单例模式全外显子测序的分子诊断技术,同批患者群体中,有11名新生儿接受标准诊断作为对照组。在46名接受外显子测序的新生儿中,其中有15名的临床管理发生了改变,12 名亲属在级联测试后接受了基因诊断,28名夫妇被认为未来妊娠具有高复发风险。

因此研究人员得出以下结论:这项前瞻性研究为单例模式全外显子测序作为新生儿单基因疾病的一线分子检测技术提供了强有力的证据。从诊断率及诊断效益上看,单例模式全外显子测序胜过标准诊断,换句话说,全外显子测序在儿童的临床管理以及阐明大家族的生殖风险上具有及时有效性。

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  • A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

    Purpose: To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease. Methods: Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated. Results: Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies. Conclusions: This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.

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