Lewis Sara A, Chopra Maya, Cohen Julie S, Bain Jennifer M, 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
Department of Child Health, University of Arizona, Phoenix.
Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona.
JAMA Pediatr. 2025 Feb 1;179(2):137-44. doi: 10.1001/jamapediatrics.2024.5059.
Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated.
To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies.
Published 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.
Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included.
Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach.
Overall 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.
Of 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.
The 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.
单基因变异可导致脑性瘫痪（CP）表型，但基因诊断对CP临床管理的影响尚未得到系统评估。
评估基因检测结果促使CP患者护理发生改变的频率以及精准医学疗法的临床效用。
分析了临床（n = 1345）或研究（n = 496）CP队列中通过外显子组测序在OMIM基因中鉴定出的已发表的致病或可能致病变异。对特定基因病因有效疗法的证据进行了系统的文献综述。
纳入导致有感兴趣基因变异个体的既定结局有可检测改善的非标准干预措施。
使用PRISMA指南评估文献。成立了一个多元化的专家工作组，调整评分标准，并采用改良德尔菲法达成评分共识。
总体临床效用通过评估如果不治疗结局严重程度、干预措施的安全性和实用性以及预期干预疗效的指标计算得出，范围为0至3。
在1841例接受外显子组测序的CP患者中，502例（27%）有与其表型相关的致病或可能致病变异。共鉴定出243个不同基因。在1841例已确定CP基因病因的患者中，140例（8%）的基因病因被归类为可采取行动的，即促使临床管理发生改变。还从243个有致病或可能致病变异且有可采取行动治疗方案的基因中鉴定出58个：其中16个针对主要疾病机制，16个有特定预防策略，26个有特定症状管理方法。证据水平也根据临床基因组学标准进行分级；101项干预措施中有45项（44.6%）的证据等级为D级或更低。潜在干预措施具有临床效用，101项结局中有98项（97%）如果不治疗为中高严重程度，101项干预措施中有63项（62%）预计为中高效能。大多数干预措施（101项中的72项[71%]）被认为具有中高安全性和实用性。
研究结果表明，在接受基因检测的CP患者中，8%存在可采取行动的基因发现。对潜在疗效、结局严重程度以及干预措施的安全性和实用性的评估表明，这些基因发现具有中高临床效用。基因测序可识别出能为CP患者带来临床益处的精准医学干预措施。相对有限的证据基础凸显了进一步研究的必要性。
