Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study
Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study
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DOI：
10.1016/s1474-4422(23)00246-6
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发表时间：
2023-08-16
期刊：
影响因子：
48
通讯作者：
McTague, Amy
中科院分区：
文献类型：
--
作者：
D'Gama, Alissa M.;Mulhern, Sarah;McTague, Amy
背景大多数新生儿和癫痫发作的癫痫有假定的遗传病因，早期遗传诊断有可能为临床管理提供信息并改善预后。因此，我们旨在确定快速基因组测序在这一人群中的可行性、诊断率和临床实用性。我们进行了一项国际多中心队列研究（Gene-STEPS），这是国际精准儿童健康伙伴关系（IPCHiP）的试点研究。IPCHiP是一个由四个儿科中心组成的联盟，在澳大利亚、加拿大、英国和美国提供三级专科服务。我们从IPCHiP中心招募了新发癫痫或复杂性热性惊厥的婴儿，他们在癫痫发作时年龄小于12个月。我们排除了单纯性热性惊厥、急性激发性惊厥、已知获得性原因或已知遗传性原因的婴儿。从先证者和可用的生物学父母收集血液样品。临床数据收集自医疗记录、治疗临床医生和父母。当父母双方都可用时，进行三重基因组测序，当父母一方或双方都不可用时，进行双或单基因组测序。位点特异性方案用于DNA提取和文库制备。在临床认可的实验室进行快速基因组测序和分析，并将结果返回给家庭。我们分析了队列人口统计学和临床特征以及快速基因组测序的时间、诊断率和临床影响的汇总统计数据。结果在2021年9月1日至2022年8月31日期间，我们招募了100名新发癫痫婴儿，其中41名（41%）为女孩，59名（59%）为男孩。癫痫发作的中位年龄为128天（IQR 46-192）。对于100名婴儿中的43名（43% [二项分布95% CI 33-53]），我们确定了遗传诊断，从癫痫发作到快速基因组测序结果的中位时间为37天（IQR 25-59）。遗传学诊断与新生儿癫痫发作和婴儿癫痫发作相关（19人中的14人[74%]对81人中的29人[36%]; p=0&B; 0.0027），转诊设置（17名重症监护患者中有12名[71%]，43名非重症监护住院患者中有19名[44%]，40名门诊患者中有12名[28%]; p=0&Bethesda;癫痫综合征（自限性癫痫15例中13例[87%]，发育性和癫痫性脑病51例中18例[35%]，其他综合征34例中12例[35%]; p=0 &bt; 0.001）。快速基因组测序揭示了遗传异质性，涉及34个独特的基因或基因组区域。基因诊断具有立即的临床实用性，可为治疗（43例中的24例[56%]）、额外评估（28例[65%]）、预后（37例[86%]）和复发风险咨询（所有病例）提供信息。解释我们的研究结果支持在新发癫痫婴儿的临床护理中实施快速基因组测序的可行性。需要纵向随访以进一步评估快速基因诊断在改善临床、生活质量和经济结果方面的作用。资助美国儿科学会、波士顿儿童医院儿童罕见疾病队列倡议、加拿大卫生研究院、加拿大癫痫病研究所、Feiga Bresver学术基金会、大奥蒙德街医院慈善机构、医学研究理事会、默多克儿童研究所、国家儿童健康和人类发展研究所，国家健康和护理研究所大奥蒙德街医院生物医学研究中心，One 8基金会，安大略脑研究所，罗宾逊家庭转型研究倡议，皇家儿童医院基金会，多伦多大学麦克劳克林中心。版权所有© 2023作者。由Elsevier Ltd.发布，这是CC BY 4.0许可下的开放获取文章。
Background Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. Methods We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing.Findings Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0 & BULL;0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0 & BULL;0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0 & BULL;001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases).Interpretation Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes.Funding American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre.Copyright & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.