Lewis Sara A, Chopra Maya, Cohen Julie S, Bain Jennifer, Aravamuthan Bhooma, Carmel Jason B, Fahey Michael C, Segel Reeval, Wintle Richard F, Zech Michael, May Halie, Haque Nahla, Fehlings Darcy, Srivastava Siddharth, Kruer Michael C
medRxiv. 2023 Sep 11:2023.09.08.23295195. doi: 10.1101/2023.09.08.23295195.
Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care.
We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall was calculated from metrics assessing if left untreated, of the intervention, and anticipated intervention .
We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as , defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the , 16 had , and 26 had recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have with 97% of outcomes being moderate-high if left untreated and 62% of interventions predicted to be of moderate-high . Most interventions (71%) were considered moderate-high .
Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential , outcome , and intervention / indicates moderate-high of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.
单基因突变越来越被认为是脑性瘫痪（CP）表型的病因，但目前尚无衡量其临床影响的标准化框架。我们评估了在CP患者中鉴定出的致病性/可能致病性（P/LP）变异，以确定基因检测结果促使护理改变的频率。
我们使用CP患者的外显子组测序分析了在临床队列（n = 1345例个体）或研究队列（n = 496）中鉴定出的OMIM基因中的已发表P/LP变异。我们成立了一个由临床和研究遗传学家、发育儿科医生、遗传咨询师和神经学家组成的工作组，并对现有文献进行了系统综述，以寻找与遗传疾病相关的临床管理方法的证据。调整了评分标准，并采用改良的德尔菲法达成共识并确定对患者护理的预期影响。总体影响是根据评估如果不治疗的影响、干预的可行性以及预期干预影响的指标计算得出的。
我们发现，在已发表的CP队列中，140/1841（8%）的个体有被归类为可采取行动的基因诊断，可采取行动的基因诊断被定义为基于与遗传病因相关的知识促使临床管理发生改变。58/243个有P/LP变异的基因被归类为可采取行动的；16个有针对潜在病因的治疗选择，16个有监测建议，26个有遗传咨询建议。证据水平也根据ClinGen标准进行分级；44.6%的干预措施的证据等级为“D”级或更低。如果不治疗，潜在干预措施对97%的结果有影响，且预计62%的干预措施具有中度至高度影响。大多数干预措施（71%）被认为具有中度至高度影响。
我们的研究结果表明，在接受基因检测的CP患者中，8%的个体有可采取行动的基因发现。对潜在病因、结果影响和干预可行性/影响的评估表明这些基因发现具有中度至高度影响。因此，通过基因测序来识别这些个体以进行精准医学干预可以改善结果，并为CP患者提供临床益处。大多数干预措施的证据基础相对有限，这突出了进一步研究的必要性。
