英国剑桥大学Patrick F Chinnery团队利用全基因组测序确定疑似线粒体疾病的遗传基础。相关论文于2021年11月4日发表于《英国医学杂志》上。
为了确定全基因组测序是否可用于确定疑似线粒体疾病的分子基础，研究组基于英国国民卫生服务（包括二级和三级保健）进行了一项队列研究。2015至2018年，研究组在英格兰招募了345名疑似线粒体疾病的患者参加10万基因组项目。
对参与者进行短读全基因组测序。根据表型、临床致病性变异/可能致病性变异以及来自Exomiser中排名前10位的变异基因组，对核变异进行优先排序。线粒体DNA变异体通过内部通道进行调用，并与一系列致病性变异体进行比较。研究组还分析了13种神经系统疾病的拷贝数变异和短串联重复序列。变异的分类遵循美国医学遗传学学会指南。主要结局为明确或可能的基因诊断。
研究组在98/319（31%）个家庭中确定了明确或可能的基因诊断，另有6个（2%）可能的诊断。其中14个（319个家庭中的4%）家庭仅解释了部分临床特征。共涉及95个不同的基因。在104个确诊家庭中，39个（38%）为线粒体诊断，65个（63%）为非线粒体诊断。
研究结果表明，全基因组测序是对疑似线粒体疾病患者的有效诊断测试，排除常见原因后，诊断率进一步提高31%。大多数诊断为非线粒体疾病，包括智力残疾的发育障碍、癫痫性脑病、其他代谢障碍、心肌病和脑白质营养不良。如果采取针对性的策略，有些人可能会避免患该类疾病，有些人则会进行特定治疗。
附：英文原文
Title: Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study
Author: Katherine R Schon, Rita Horvath, Wei Wei, Claudia Calabrese, Arianna Tucci, Kristina Ibaez, Thiloka Ratnaike, Robert D S Pitceathly, Enrico Bugiardini, Rosaline Quinlivan, Michael G Hanna, Emma Clement, Emma Ashton, John A Sayer, Paul Brennan, Dragana Josifova, Louise Izatt, Carl Fratter, Victoria Nesbitt, Timothy Barrett, Dominic J McMullen, Audrey Smith, Charulata Deshpande, Sarah F Smithson, Richard Festenstein, Natalie Canham, Mark Caulfield, Henry Houlden, Shamima Rahman(, Patrick F Chinnery
Issue&Volume: 2021/11/04
Abstract:
Objective To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.
Design Cohort study.
Setting National Health Service, England, including secondary and tertiary care.
Participants 345 patients with suspected mitochondrial disorders recruited to the 100000 Genomes Project in England between 2015 and 2018.
Intervention Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.
Main outcome measure Definite or probable genetic diagnosis.
Results A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.
Conclusion Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.
DOI: 10.1136/bmj-2021-066288
Source: https://www.bmj.com/content/375/bmj-2021-066288
BMJ-British Medical Journal:《英国医学杂志》，创刊于1840年。隶属于BMJ出版集团，最新IF：93.333
官方网址：http://www.bmj.com/
投稿链接：https://mc.manuscriptcentral.com/bmj
本期文章：《英国医学杂志》：Online/在线发表
