ImportanceSingle gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated.ObjectiveTo evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies.Data SourcesPublished pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed.Study SelectionNonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included.Data Extraction and SynthesisLiterature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach.Main Outcomes and MeasuresOverall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3.ResultsOf 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality.Conclusions and RelevanceThe findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

中文翻译：

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脑瘫遗传学发现的临床可操作性


重要性单基因变异可导致脑瘫 （CP） 表型，但尚未系统评价基因诊断对 CP 临床管理的影响。目的评估基因检测结果促使 CP 患者护理变化的频率以及精准医学治疗的临床效用。数据来源分析了在临床 （n = 1345） 或研究 （n = 496） CP 队列中通过外显子组测序鉴定的 OMIM 基因中已发表的致病性或可能的致病性变异。对特定遗传病因的有效治疗证据进行了系统的文献综述。研究选择纳入了在具有目标基因变异的个体中导致明确结局可检测改善的非标准干预措施。数据提取和合成使用 PRISMA 指南评估文献。成立了一个多元化的专家工作组，调整了评分量规，并使用改进的 Delphi 方法建立了评分共识。主要结局和措施总体临床效用是根据评估不治疗后结果严重程度、干预的安全性和实用性以及预期干预效果的指标计算的，评分范围为 0 到 3.结果在接受外显子组测序的 1841 名 CP 患者中，502 名 （27%） 具有与其表型相关的致病性或可能的致病性变异。共鉴定出 243 个不同的基因。在 1841 名已确定 CP 遗传病因的患者中，140 名 （8%） 的遗传病因被归类为可操作，定义为促使临床管理发生变化。 还确定了 243 个基因中的 58 个具有致病性或可能致病性变异，具有可操作的治疗方案：16 个针对原发性疾病机制，16 个具有特定的预防策略，26 个具有特定的症状管理。证据水平也根据 ClinGen 标准进行分级;101 项干预中有 45 项 （44.6%） 的证据分级为 D 级或更低。潜在的干预措施具有临床效用，如果不及时治疗，101 种结果中有 98 种 （97%） 为中度至高度严重程度，101 种干预措施中有 63 项 （62%） 预计为中度至高疗效。大多数干预措施 （101 项中的 72 项 [71%]）被认为是中高安全性和实用性。结论和相关性研究结果表明，在转诊进行 CP 基因检测的个体中，有 8% 的个体发生了可操作的遗传发现。对潜在疗效、结果严重性以及干预安全性和实用性的评估表明这些遗传发现具有中高临床效用。基因测序可以识别为 CP 患者提供临床益处的精准医学干预措施。相对有限的证据基础强调了进行额外研究的必要性。