复杂神经运动表型儿童的基因组测序结果解读
Interpretation of genome sequencing results in children with complex neuromotor phenotypes.
一句话结合完整临床表型解读基因组测序，在100个家庭中为53个家庭明确了可解释神经运动表型的遗传病。
研究问题
数据与样本
研究流程
- 1纳入与测序：对100个家庭的108名复杂神经运动表型儿童进行家系三联体基因组测序。
- 2整合临床信息：汇总每名儿童的完整病史、临床病程、家族史、体格检查、影像学及其他实验室检查结果。
- 3确认疑似致病变异：在具有临床资质认证的实验室进行正交确认，并依据ACMG/AMP指南对所报告变异分类。
- 4综合诊断与结果评估：由多学科临床研究团队结合临床信息和测序发现诊断遗传病，统计获得可解释神经运动表型诊断的家庭。
关键方法与工具
- trio genome sequencing
- 检测家系基因组变异
- orthogonal confirmation
- 确认疑似致病变异
- ACMG/AMP
- 对报告的遗传变异分类
设计思路
主要发现
- 在100个家庭中，53个家庭获得了能够解释儿童神经运动表型的遗传病诊断。
- 获得相关遗传病诊断的儿童几乎均在神经运动损害之外，伴有智力障碍、癫痫性疾病和/或孤独症谱系障碍。
- 研究指出，使用完整临床表型是获得高诊断率的重要因素，仅凭ACMG/AMP分类不足以确立或排除变异与疑似遗传病之间的因果关系。
可借鉴之处
- 开展复杂表型的测序诊断研究时，可借鉴本文将完整病史、病程、家族史及多类检查结果纳入多学科判读的做法，而不把变异分类直接等同于疾病诊断。
- 可将疑似致病变异的正交确认与临床表型解释分为相互衔接的环节，分别支撑变异真实性与疾病解释。
- 报告诊断率时应明确分析单位：本文纳入108名儿童，但诊断结果以100个家庭为分母报告。
数据与代码
局限
- 研究对象为复杂神经运动表型儿童，其诊断结果不能直接外推至所有神经运动障碍患者。
摘要（中文翻译）
背景：尽管遗传病至少造成30%的神经运动障碍，但基因组测序尚未常规用于此类患者的诊断。我们评估了其在复杂神经运动表型儿童中的诊断价值。
方法：我们对来自100个家庭的108名复杂神经运动表型儿童进行了家系三联体基因组测序。多学科临床研究团队依据每名儿童的完整病史、临床病程、家族史、体格检查、影像学检查及所有其他实验室检查结果，并结合基因组测序发现，作出遗传病诊断。对疑似致病的遗传变异，在具有临床资质认证的实验室进行正交确认，该实验室依据ACMG/AMP指南对其报告的变异进行分类。
结果：在所研究的100个家庭中，我们为53个家庭诊断出了能够解释神经运动表型的遗传病。这些儿童几乎均在神经运动损害之外，还伴有智力障碍、癫痫性疾病和/或孤独症谱系障碍。促成这一高诊断率的一个重要因素，是使用每名患者的完整临床表型，而不是仅依据ACMG/AMP变异分类作出“分子诊断”。
结论：我们的发现表明，儿童复杂神经运动表型通常是更广泛的神经发育障碍的表现，仅凭ACMG/AMP分类不足以确立或排除基因组变异与疑似遗传病之间的因果关系。
资助：Canadian Institutes of Health Research、British Columbia Children's Hospital Foundation和Michael Smith Health Research BC。
英文原文摘要
Background:Although genetic diseases cause at least 30% of neuromotor disorders, genome sequencing is not routinely used for diagnosis in such patients. We assessed the diagnostic value in children with complex neuromotor phenotypes.
Methods:We performed trio genome sequencing in 108 children with complex neuromotor phenotypes in 100 families. Genetic disease was diagnosed by a multidisciplinary clinical research team on the basis of each child's complete medical history, clinical course, family history, physical examination, imaging studies, and all other laboratory test results, as well as the findings on genome sequencing. Genetic variants that were suspected of being disease causing were subjected to orthogonal confirmation in a clinically accredited laboratory, which classified the variants it reported according to the ACMG/AMP guidelines.
Findings:We diagnosed genetic diseases that explained the neuromotor phenotype in 53 of the 100 families studied. Almost all of these children had intellectual disability, a seizure disorder, and/or autism spectrum disorder in addition to neuromotor impairment. An important factor contributing to this high diagnostic rate was the use of each patient's complete clinical phenotype, instead of a "molecular diagnosis" based only on the ACMG/AMP variant classification.
Conclusions:Our findings demonstrate that complex neuromotor phenotypes in children are usually manifestations of a more generalized neurodevelopmental disorder and that the ACMG/AMP classification alone is insufficient to establish or exclude a causal relationship between a genomic variant and a suspected genetic disease.
Funding:Canadian Institutes of Health Research, British Columbia Children's Hospital Foundation, and Michael Smith Health Research BC.
摘要来自 PubMed。翻译与解读由模型根据摘要生成，可能有误，不构成诊疗建议；数据以原文为准，版权归原出版方所有。