French Courtney E, Dolling Helen, Mégy Karyn, Sanchis-Juan Alba, Kumar Ajay, Delon Isabelle, Wakeling Matthew, Mallin Lucy, Agrawal Shruti, Austin Topun, Walston Florence, Park Soo-Mi, Parker Alasdair, Piyasena Chinthika, Bradbury Kimberley, Ellard Sian, Rowitch David H, Raymond F Lucy
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK.
Boston Children's Hospital, Boston, MA 02115, USA.
HGG Adv. 2022 Apr 25;3(3):100113. doi: 10.1016/j.xhgg.2022.100113. eCollection 2022 Jul 14.
To facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high risk for rare pediatric disease presentations.
为促进对重症儿童尽早开展全基因组测序（WGS），需要一个标准化的WGS分析流程，实现及时交付结果并让基层医疗儿科医生能够采用。我们开发了一种生物信息学流程，用于对疑似患有未确诊单基因疾病的儿童进行全面的基因非特异性三联体WGS分析，包括检测和解释疾病的主要遗传机制，如单核苷酸变异/插入缺失（SNVs/indels）、拷贝数变异/结构变异（CNVs/SVs）、单亲二体（UPD）、印记基因、短串联重复序列扩增、移动元件插入、拷贝数判定以及线粒体基因组变异。我们在一个由521个家庭组成的大型队列（其中90%为WGS三联体）中评估了基层医疗从业者的经验和能力。儿童由基层医疗从业者识别以进行招募，我们使用英国多重贫困指数来确认不存在患者社会经济地位确定偏差。在测序的521名儿童中，176名（34%）获得了分子诊断，神经科诊所的诊断率高达45%。23例确诊病例（13%）需要常规SNV/CNV分析之外的定制方法。在我们的多学科临床医生用户体验评估中，儿科医生和临床遗传学家都对在诊疗路径早期快速进行WGS表示强烈支持，但要求在确定患者选择、获取知情同意和变异解读方面接受进一步培训。当由基层医疗从业者在罕见儿科疾病高发的临床环境中开展时，快速三联体WGS为儿童提供了一种有效的一次性筛查检测。
