Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy
Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy
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DOI：
10.1001/jama.2020.26148
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发表时间：
2021-02-02
影响因子：
120.7
通讯作者：
Martin, Christa L.
中科院分区：
文献类型：
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作者：
Moreno-De-Luca, Andres;Millan, Francisca;Martin, Christa L.
问题 脑瘫患者中外显子组测序（致病性和可能致病性变异的患病率）的分子诊断率是多少？结果 在这项包含 1526 名脑瘫患者的 2 个独立队列的横断面研究中，外显子组测序的分子诊断率在主要由儿童患者组成的队列中为 32.7%，在主要由成人患者组成的队列中为 10.5%。意义 这项研究确定了一些脑瘫患者的致病性和可能的致病性变异，尽管还需要进一步的研究来了解这些发现的临床意义。 重要性 脑性瘫痪是一种常见的神经发育障碍，影响运动和姿势，通常与其他神经发育障碍同时发生。个别脑瘫病例常归因于出生窒息；然而，最近的研究表明，窒息在脑瘫病例中所占比例不到 10%。目的 确定脑瘫患者外显子组测序（致病性和可能致病性变异的患病率）的分子诊断率。设计、设置和参与者 脑瘫患者的回顾性队列研究，包括临床实验室转诊队列和 2012 年至 2018 年期间积累的数据，以及基于医疗保健的队列，其数据在 2007 年至 2017 年期间积累。主要结果和措施 主要结果是外显子组测序的分子诊断率。结果 在来自临床实验室转诊队列的 1345 名患者中，中位年龄为 8.8 岁（四分位数范围，4.4-14.7 岁；范围，0.1-66 岁），其中 601 名患者 (45%) 为女性。在基于医疗保健的队列中的 181 名患者中，中位年龄为 41.9 岁（四分位数范围，28.0-59.6 岁；范围，4.8-89 岁），其中 96 名患者 (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% CI，30.2%-35.2%），在医疗保健队列中为 10.5%（95% CI，6.0%-15.0%）。分子诊断率范围从无智力障碍、癫痫或自闭症谱系障碍患者的 11.2%（95% CI，6.4%-16.2%）到患有所有 3 种合并症的患者的 32.9%（95% CI，25.7%-40.1%）。在 229 个基因中鉴定出致病性和可能致病性变异（1526 名患者中的 29.5%）； 2 名或更多患者中有 86 个基因发生突变（1526 名患者中的 20.1%），并且在两个队列中独立鉴定出 10 个具有突变的基因（1526 名患者中的 2.9%）。结论和相关性 在接受外显子组测序的 2 个脑瘫患者队列中，在主要由儿童患者组成的队列中，致病性和可能致病性变异的患病率为 32.7%，在主要由成人患者组成的队列中为 10.5%。需要进一步的研究来了解这些发现的临床意义。这项横断面研究描述了在接受基因检测的脑瘫儿童和成人的外显子组测序中检测到的致病性和可能致病性变异的流行情况。
Question What is the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) among patients with cerebral palsy? Findings In this cross-sectional study that included 2 independent cohorts of 1526 patients with cerebral palsy, the molecular diagnostic yield of exome sequencing was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Meaning This study identified pathogenic and likely pathogenic variants among some patients with cerebral palsy, although further research is needed to understand the clinical implications of these findings.Importance 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. Objective 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. Exposures Exome sequencing with copy number variant detection. Main Outcomes and Measures The primary outcome was the molecular diagnostic yield of exome sequencing. Results 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). Conclusions and Relevance 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.This cross-sectional study describes the prevalence of pathogenic and likely pathogenic variants detected on exome sequencing of children and adults with cerebral palsy referred for genetic testing.