英国伦敦玛丽女王大学Mark Caulfield团队进行了一项10万基因组在医疗保健中进行罕见疾病诊断的试点研究。该成果发表在2021年11月10日出版的《新英格兰医学杂志》上。

英国10万基因组项目正在调查基因组测序在未确诊罕见疾病患者常规治疗后的作用，并将该研究与英国国民健康服务的医疗保健实施相结合。该项目的其他部分侧重于癌症和感染患者。

课题组人员进行了一项初步研究，涉及来自2183个家庭的4660名参与者，其中有161种疾病涉及广泛的罕见疾病。研究组使用人类表型本体术语收集临床特征数据，进行基因组测序，在应用虚拟基因面板和表型的基础上应用自动化变异体优先排序，并通过研究分析确定新的致病性变异体。

诊断率因家庭结构而异，在家庭三人组（父母和先证者）和家族谱系较大的家庭中最高。对于可能有单基因原因的疾病（35%）的诊断率远高于可能有复杂原因的疾病（11%）。智力残疾、听力障碍和视力障碍的诊断率从40%到55%不等。研究组对25%的先证者进行了基因诊断。

共有14%的诊断通过研究和自动化方法相结合的方式进行，这对于发现病因非编码、结构和线粒体基因组变异以及外显子组测序覆盖率低的编码变异病例来说至关重要。通过对57000个基因组的共有负担测试，发现了三个新的疾病基因和19个新的关联。在该研究的基因诊断结果中，有25%直接影响对患者或其亲属的临床决策。

研究组在国家卫生保健系统中对基因组测序的初步研究表明，一系列罕见疾病的诊断率均有所提高。

附：英文原文

Title: 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

Author: The , Genomes Project Pilot Investigators

Issue&Volume: 2021-11-10

Abstract:

BACKGROUND

The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.

METHODS

We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.

RESULTS

Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.

CONCLUSIONS

Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases.

DOI: 10.1056/NEJMoa2035790

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2035790