NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment.
NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment.
复制标题
DOI：
10.2174/0929867324666170718101946
复制
发表时间：
2018-01-30
影响因子：
4.1
通讯作者：
Couce ML
中科院分区：
文献类型：
--
作者：
Fernandez-Marmiesse A;Gouveia S;Couce ML
大约2500万至5000万美国人，3000万欧洲人和8%的澳大利亚人口患有罕见疾病。因此，罕见病是临床医生的常见问题，由于难以确定具体诊断，罕见病在全球范围内造成了巨大的医疗费用。在这篇文章中，我们回顾了自下一代测序（NGS）技术出现以来，我们对罕见疾病的理解所取得的里程碑，并分析了这些进展如何影响研究和诊断。本文的前半部分描述了NGS如何改变诊断工作流程，并提供了一种前所未有的、简单的方法来发现新的疾病相关基因。我们特别关注代谢和神经发育障碍。NGS使廉价和快速的遗传诊断成为可能，突出了镶嵌和新生突变的相关性，揭示了大多数基因的广泛表型谱，检测了双基因遗传或同一患者中存在多种罕见疾病，并为有前途的新疗法铺平了道路。在综述的第二部分中，我们将探讨NGS的局限性和挑战，包括变异因果关系的确定，编码区和非编码区变异的丢失，体细胞嵌合变异和表观遗传突变的检测，并讨论如何在不久的将来克服这些问题。
Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Aus-tralian population have a rare disease. Rare diseases are thus a common problem for clini-cians and account for enormous healthcare costs worldwide due to the difficulty of establish-ing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedent-ed, simple way of discovering novel disease-associated genes. We focus particularly on meta-bolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide pheno-typic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the sec-ond part of the review, we look at the limitations and challenges of NGS, including determina-tion of variant causality, the loss of variants in coding and non-coding regions, and the detec-tion of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future.