罕见病遗传诊断技术进展——外显子组测序之外的探索

Advances in genetic diagnosis technology for rare diseases—explorations beyond exome sequencing

罕见病因其发病率低、病种繁多、机制复杂的特点,给临床诊断带来极大挑战。遗传性因素约占罕见病发病原因的80%,因此遗传学检测是罕见病病因学诊断的重要手段。近年来外显子组测序已逐渐成为明确罕见病遗传病因的一线检测技术,大幅提升了罕见病患者的诊断率。本文将概述罕见病遗传学检测技术发展,探讨外显子组测序后仍未明确诊断的病例可能采用的下一步检测策略,包括全基因组测序、长读长测序等在覆盖范围及检测变异类型方面更具优势的测序技术,以及转录组、表观遗传组、蛋白质组、代谢组等辅助检测手段,并述评各技术在罕见病遗传变异发现和解读中的优势及局限性。此外,总结了各国现有罕见病数据库的建立和使用状况,并讨论了基于数据库进行自动化重分析基因组数据以识别具有相似表型或相似基因突变的患者的重要性。本文旨在为临床医生和研究人员提供外显子组测序未明诊断时可考虑的其它遗传学检测策略及技术选择。

Rare diseases pose great challenges to clinical diagnosis due to their low incidence rate,diverse disease types,and complex mechanisms.Genetic factors account for approximately 80%of the causes of rare diseases.Therefore,genetic testing is a crucial tool for etiological diagnosis of rear diseases.In recent years,exome sequencing has gradually become a frontline detection technology for clarify the genetic causes of rare diseases.It has significantly improved the diagnostic rate of patients with rare diseases.This article provides an overview of the development of genetic testing technologies for rare diseases and explores potential next-step testing strategies for cases that remain undiagnosed after exome sequencing.The next-step testing strategies include sequencing techniques such as whole genome sequencing and long-read sequencing,which have more advantages in coverage and detections of variant types.Some auxiliary testing methods such as transcriptomics,epigenetics,proteomics,and metabolomics analysis should be also included.We also evaluate the advantages and the limitations of each technology in the discovery and interpretation of genetic variations in rare diseases.Furthermore,we summarize the establishment and utilization of existing rare disease databases in different countries.We also discuss the importance of automated reanalysis of genomic data based on databases to identify patients with similar phenotypes or genetic mutations.All in all,aims of this article are to provide clinicians and researchers with alternative genetic testing strategies and technology options when exome sequencing fails to provide a diagnosis.