Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania.
Genomic Medicine Institute, Geisinger, Danville, Pennsylvania.
JAMA. 2021 Feb 2;325(5):467-475. doi: 10.1001/jama.2020.26148.
Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases.
To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy.
DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017.
Exome sequencing with copy number variant detection.
The primary outcome was the molecular diagnostic yield of exome sequencing.
Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients).
Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.
脑瘫是一种常见的神经发育障碍，影响运动和姿势，常与其他神经发育障碍同时发生。脑瘫的个别病例通常归因于出生窒息；然而，最近的研究表明，窒息仅占脑瘫病例的不到 10%。
确定外显子组测序（致病性和可能致病性变异的患病率）在脑瘫患者中的分子诊断率。
设计、设置和参与者：这是一项回顾性队列研究，纳入了脑瘫患者，包括一个临床实验室转诊队列和一个健康护理为基础的队列。临床实验室转诊队列的数据在 2012 年至 2018 年期间收集，健康护理为基础的队列的数据在 2007 年至 2017 年期间收集。
外显子组测序与拷贝数变异检测。
主要结局是外显子组测序的分子诊断率。
在临床实验室转诊队列的 1345 名患者中，中位年龄为 8.8 岁（四分位距，4.4-14.7 岁；范围，0.1-66 岁），601 名（45%）为女性。在健康护理为基础的队列的 181 名患者中，中位年龄为 41.9 岁（四分位距，28.0-59.6 岁；范围，4.8-89 岁），96 名（53%）为女性。外显子组测序的分子诊断率在临床实验室转诊队列中为 32.7%（95%置信区间，30.2%-35.2%），在健康护理为基础的队列中为 10.5%（95%置信区间，6.0%-15.0%）。在无智力障碍、癫痫或自闭症谱系障碍的患者中，分子诊断率为 11.2%（95%置信区间，6.4%-16.2%），而在同时患有所有 3 种合并症的患者中，分子诊断率为 32.9%（95%置信区间，25.7%-40.1%）。在 229 个基因中发现了致病性和可能致病性变异（1526 名患者中有 29.5%）；有 86 个基因在 2 个或更多患者中发生突变（1526 名患者中有 20.1%），在这两个队列中均独立发现了 10 个具有突变的基因（1526 名患者中有 2.9%）。
在接受外显子组测序的 2 个脑瘫患者队列中，致病性和可能致病性变异的患病率在主要由儿科患者组成的队列中为 32.7%，在主要由成年患者组成的队列中为 10.5%。需要进一步研究以了解这些发现的临床意义。
