Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.
J Med Genet. 2022 Apr;59(4):393-398. doi: 10.1136/jmedgenet-2020-107303. Epub 2021 Apr 20.
The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.
Retrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.
Abnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.
Our results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
随着基因组策略在临床中的广泛应用，诊断实验室提高变异解读效率已刻不容缓。临床外显子组测序（CES）正成为一种有价值的诊断工具，能够满足各种罕见单基因疾病带来的诊断需求。我们评估了一种以临床医生为主导、基于表型的方法，用于在单一机构中为患有罕见疾病的患者进行靶向 CES 的虚拟基因面板分析。
对 400 例连续就诊的、被临床医生认为患有罕见单基因疾病的患者进行回顾性调查，这些患者均为单病例就诊并接受靶向 CES。我们评估了诊断收益和变异工作量，以确定临床医生主导的虚拟基因面板生成方法的有用性，该方法可以整合多达三种不同的基于表型的基因选择方法。
神经系统异常（54.5%），包括智力障碍、头颈部（19%）、骨骼系统（16%）、耳朵（15%）和眼睛（15%）是转诊中最常见的临床特征。基于表型的综合策略用于 57%的病例进行虚拟基因面板生成。平均每个病例保留了 7.3 个变异（中位数=5）用于临床解释。使用个性化表型驱动的虚拟基因面板进行 CES 检测的先证者总体诊断率为 24%。
我们的结果表明，个性化虚拟基因面板是 CES 变异分析的一种具有成本效益的方法，在临床中既能保持诊断收益，又能优化临床基因组测序的资源利用。
