Clinically Relevant Copy Number Variations Detected in Cerebral Palsy. Homo sapiens

Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age-of-onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of etiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (~1% rate in controls). In four children, large chromosomal abnormalities deemed pathogenic were found, and they were significantly more likely to have severe neuro-motor impairments than those CP subjects without such alterations. Overall the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families. Dr. Maryam Oskoui* , Mr. Matthew Gazzellone* , Ms. Bhooma Thiruvahindrapuram , Dr. Mehdi Zarrei , Dr. John Andersen , Dr. John Wei , Dr. Zhouzhi Wang , Dr. Richard Wintle , Dr. Christian Marshall , Dr. Ronald Cohn , Dr. Rosanna Weksberg , Dr. James Stavropoulos , Dr. Darcy Fehlings , Dr. Michael Shevell, Dr. Stephen Scherer. Clinically Relevant Copy Number Variations Detected in Cerebral Palsy. Nature Communications, 2015. Overall design: Following our rigorous quality control procedure, we successfully genotyped 147 proband samples from individuals with cerebral palsy (81 males and 66 females) and 282 samples obtained from parents (134 males and 148 females). This facilitated the identification of de novo and rare inherited copy number variations of clinical interest.

脑性瘫痪（Cerebral palsy, CP）是一组非进展性、临床异质性的疾病，以运动功能受损与早发为核心特征，常伴随多种共病。长期以来，CP的病因被归因于可导致脑损伤的环境应激因素；尽管遗传危险因素也与该病存在关联，但CP的诊断评估指南并不推荐开展常规基因检测。
鉴于其他神经发育障碍疾病中已有大量关于病因性拷贝数变异（copy number variations, CNVs）的研究报道，本研究采用微阵列芯片技术，对一组基于人群的CP儿童及其父母构成的前瞻性队列进行基因分型。本研究在115例CP患者中的8例（7.0%）检出了新发CNVs，对照人群中的检出率约为1%。其中4名患儿被检出具有致病性的大型染色体异常；相较于未检出此类变异的CP患者，这类患儿出现严重神经运动功能受损的概率显著更高。总体而言，CNV相关数据可对115个家庭中的11个（9.6%）的CP诊断或分类产生影响。

玛丽安·奥斯库伊博士*、马修·加泽洛内先生*、布胡马·特里瓦欣德拉普拉姆女士、迈赫迪·扎雷伊博士、约翰·安徒生博士、约翰·魏博士、王周智博士、理查德·温特尔博士、克里斯蒂安·马歇尔博士、罗纳德·科恩博士、罗斯安娜·韦克斯伯格博士、詹姆斯·斯塔夫鲁普洛斯博士、达西·费林格斯博士、迈克尔·谢维尔博士、斯蒂芬·谢勒博士。《脑性瘫痪中检出的临床相关性拷贝数变异》，《自然·通讯》，2015年。

研究设计：经过严格的质量控制流程，我们成功对147份CP先证者（proband）样本（81名男性、66名女性）以及282份父母样本（134名男性、148名女性）完成了基因分型，这有助于筛选出具有临床意义的新发CNVs与罕见遗传性CNVs。