BACKGROUND There is increasing evidence that certain genetic variants increase the risk of schizophrenia and other neurodevelopmental disorders. Exome sequencing has been shown to have a high diagnostic yield for developmental disability and testing for copy number variants has been advocated for schizophrenia. The diagnostic yield for exome sequencing in schizophrenia is unknown. METHOD A sample of 591 exome-sequenced schizophrenia cases and their parents were screened for disruptive and damaging variants in autosomal genes listed in the Genomics England panels for intellectual disability and other neurological disorders. RESULTS Previously reported disruptive de novo variants were noted in SETD1A, POGZ, SCN2A, and ZMYND11. Although the loss of function of ZMYND11 is a recognized cause of intellectual disability, it has not previously been noted as a risk factor for schizophrenia. A damaging de novo variant of uncertain significance was noted in NRXN1. A previously reported homozygous damaging variant in BLM is predicted to cause Bloom syndrome in 1 case and 1 case was homozygous for a damaging variant in MCPH1, a result of uncertain significance. There were more than 400 disruptive and damaging variants in the target genes in cases but similar numbers were seen among untransmitted parental alleles and none appeared to be clinically significant. CONCLUSIONS The diagnostic yield from exome sequencing in schizophrenia is low. Disruptive and damaging variants seen in known neuropsychiatric genes should not be automatically assumed to have an etiological role if observed in a patient with schizophrenia.

中文翻译：

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外显子组测序在精神分裂症中的潜在临床作用评估。


背景越来越多的证据表明某些遗传变异会增加精神分裂症和其他神经发育障碍的风险。外显子组测序已被证明对发育障碍具有较高的诊断率，并且提倡对精神分裂症进行拷贝数变异检测。精神分裂症外显子组测序的诊断率尚不清楚。方法 对 591 例外显子组测序的精神分裂症病例及其父母的样本进行筛查，以检测英国基因组学小组中列出的智力障碍和其他神经系统疾病常染色体基因的破坏性和破坏性变异。结果 先前报道的破坏性从头变异在 SETD1A、POGZ、SCN2A 和 ZMYND11 中被发现。尽管 ZMYND11 功能丧失是公认的智力障碍原因，但此前并未被认为是精神分裂症的危险因素。 NRXN1 中发现了具有不确定意义的破坏性从头变异。先前报道的 BLM 中的纯合破坏性变异预计会导致 1 例布卢姆综合征，而 1 例则为 MCPH1 中的破坏性变异纯合子，但结果的意义不确定。病例中的目标基因中有超过 400 个破坏性和破坏性变异，但在未传播的亲本等位基因中也发现了类似的数量，而且似乎没有一个具有临床意义。结论 外显子组测序对精神分裂症的诊断率较低。如果在精神分裂症患者中观察到已知神经精神基因中出现的破坏性和破坏性变异，则不应自动假定其具有病因学作用。