Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul, Korea.
Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Pediatr Neurol. 2019 Oct;99:47-54. doi: 10.1016/j.pediatrneurol.2019.02.017. Epub 2019 Feb 27.
Whole exome sequencing on family trios gives the highest diagnostic yield, but high cost limits its application. Here, we performed proband-only clinical exome sequencing in a population of patients with neurodevelopmental disabilities and tested the diagnostic yield.
This observational, retrospective study included 108 unrelated patients with neurodevelopmental disabilities who underwent clinical exome sequencing at the outpatient clinics of the Severance Children's Hospital, Seoul, South Korea, between March 2017 and May 2018. Clinical exome sequencing targeted 4503 disease-causing genes.
The overall diagnostic rate was 38.0% (41 of 108) when proband-only clinical exome sequencing was performed without additional parental testing. Four sequence variants were reclassified as likely pathogenic after parental testing, representing an additional 3.7% of the diagnostic yield. The final diagnostic rate was 41.7% (45 of 108). Of 45 patients with genetic abnormalities, a total of 38 sequence variations were detected in 33 (30.6%) patients with five homozygous cases, and 13 chromosomal copy number variants were detected in 12 (11.1%) patients. Novel variants of known causal genes for neurodevelopmental disabilities were detected in 18 (16.7%) patients. These were variants that could be reclassified as likely pathogenic if the de novo nature of the mutation was confirmed after testing of parental samples.
Proband-only clinical exome sequencing is a practical diagnostic tool that may be implemented in the clinical setting for patients with neurodevelopmental disabilities. A cost-effective approach to neurodevelopmental disabilities would be a proband-only clinical exome sequencing followed by parental testing of selective candidate variants.
对家系三例进行全外显子组测序可获得最高的诊断率，但费用较高限制了其应用。在此，我们对一组神经发育障碍患者进行了仅先证者的临床外显子组测序，并检测了其诊断率。
这是一项观察性、回顾性研究，纳入了 2017 年 3 月至 2018 年 5 月期间在韩国首尔 Severance 儿童医院门诊就诊的 108 例神经发育障碍无关患者，这些患者均进行了临床外显子组测序。临床外显子组测序靶向了 4503 个致病基因。
在未进行额外的父母检测的情况下，仅对先证者进行临床外显子组测序的总体诊断率为 38.0%（41/108）。经父母检测后，4 个序列变异被重新归类为可能致病性，使诊断率额外增加了 3.7%。最终诊断率为 41.7%（45/108）。在 45 例存在遗传异常的患者中，在 33 例（30.6%）患者中检测到了 38 个序列变异，其中 5 例存在纯合子病例，在 12 例（11.1%）患者中检测到了 13 个染色体拷贝数变异。在 18 例（16.7%）患者中检测到了神经发育障碍已知致病基因的新变异。这些变异如果经父母样本检测证实其为新发突变，则可重新归类为可能致病性。
仅先证者临床外显子组测序是一种实用的诊断工具，可在临床环境中用于神经发育障碍患者。一种具有成本效益的神经发育障碍方法是先证者临床外显子组测序，然后对选择性候选变异进行父母检测。
