BACKGROUND The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.

中文翻译：

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染色质重塑功能障碍扩大了精神分裂症的病因谱：一例报告。

背景技术有害的拷贝数变异在精神分裂症中的作用已被很好地确立，而有关病原变异的数据仍然很少。我们首次报告了一个儿童的精神分裂症病例，该儿童患有染色体结构域解旋酶DNA结合蛋白2（CHD2）基因的致病性突变。案例介绍先证者是无亲父母的第二个孩子。10个月大时出现焦虑和睡眠障碍。他出现高热惊厥，并在8岁时出现两次全身性强直阵挛性惊厥。10岁时出现情绪低落，伴有扁平化的情感，混乱和想法偏执，而没有癫痫发作。他开始说话，对自己开玩笑。最终，患者出现了每日的听觉和视觉幻觉。然后引起对儿童发作性精神分裂症（DSM V）的诊断。脑影像学检查无异常。唤醒脑电图显示背景正常，并且某些双侧峰值波放电不能解释精神病的特征。比较基因组杂交阵列（180 K，Agilent，圣塔克拉拉，加利福尼亚州，美国）显示了867kb 16p13.3重复序列，这被定量PCR证实具有未知显着性，并显示出其母本遗传。利培酮（每天1.5 mg）导致临床改善。在11岁时，癫痫发作突然复发，每天发作各种类型。单基因癫痫性疾病小组的测序和Sanger测序揭示了CHD2中的从头致病性杂合过渡（NM_001271.3：c.4003G> T）。结论该病例强调精神分裂症有时可能是 以孟德尔病为基础。它解决了在出现诸如儿童精神分裂症发作或抗药性癫痫等预警信号的情况下进行系统遗传研究的问题。它指出，在没有致病性拷贝数变异的情况下，研究还应包括寻找致病性变异，这意味着某些精神分裂症患者应受益于下一代测序工具。最后但并非最不重要的是，CHD2编码参与染色质重塑的染色体结构域解旋酶DNA结合（CHD）家族的成员。该观察结果将精神分裂症增加到了染色体结构域重塑障碍的表型谱中，这可能导致创新的治疗方法。它解决了在出现诸如儿童精神分裂症发作或抗药性癫痫等预警信号的情况下进行系统遗传研究的问题。它指出，在没有致病性拷贝数变异的情况下，研究还应包括寻找致病性变异，这意味着某些精神分裂症患者应受益于下一代测序工具。最后但并非最不重要的是，CHD2编码参与染色质重塑的染色质域解旋酶DNA结合（CHD）家族的成员。该观察结果将精神分裂症增加到了染色体结构域重塑障碍的表型谱中，这可能导致创新的治疗方法。它解决了在出现诸如儿童精神分裂症发作或抗药性癫痫等预警信号的情况下进行系统遗传研究的问题。它指出，在没有致病性拷贝数变异的情况下，研究还应包括寻找致病性变异，这意味着某些精神分裂症患者应受益于下一代测序工具。最后但并非最不重要的是，CHD2编码参与染色质重塑的染色体结构域解旋酶DNA结合（CHD）家族的成员。该观察结果将精神分裂症增加到了染色体结构域重塑障碍的表型谱中，这可能导致创新的治疗方法。调查还应包括寻找病原体变异，这意味着某些精神分裂症患者应受益于下一代测序工具。最后但并非最不重要的是，CHD2编码参与染色质重塑的染色体结构域解旋酶DNA结合（CHD）家族的成员。该观察结果将精神分裂症增加到了染色体结构域重塑障碍的表型谱中，这可能导致创新的治疗方法。调查还应包括寻找病原体变异，这意味着某些精神分裂症患者应受益于下一代测序工具。最后但并非最不重要的是，CHD2编码参与染色质重塑的染色体结构域解旋酶DNA结合（CHD）家族的成员。该观察结果将精神分裂症增加到了染色体结构域重塑障碍的表型谱中，这可能导致创新的治疗方法。