Department of Pediatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.
Department of Neurology and Neurobiology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.
Mol Genet Genomic Med. 2023 Nov;11(11):e2243. doi: 10.1002/mgg3.2243. Epub 2023 Jul 24.
BACKGROUND: Epilepsy (EP) is a common neurological disease in which 70-80% are thought to have a genetic cause. In patients with epilepsy, neurodevelopmental delay (NDD) was prevalent. Next generation of sequencing has been widely used in diagnosing EP/NDD. However, the diagnostic yield remains to be 40%-50%. Many reanalysis pipelines and software have been developed for automated reanalysis and decision making for the diseases. Nevertheless, it is a highly challenging task for smaller genetic centers or a routine pediatric practice. To address the clinical and genetic "diagnostic odyssey," we organized a Multidisciplinary Molecular Consultation (MMC) team for molecular consultation for 202 children with EP/NDD patients referred by lower level hospitals. METHODS: All the patients had undergone an aligned and sequential consultations and discussions by a "triple reanalysis" procedure by clinical, genetic specialists, and researchers. RESULTS: Among the 202 cases for MMC, we totally identified 47 cases (23%) harboring causative variants in 24 genes and 15 chromosomal regions after the MMC. In the 15 cases with positive CNVs, 3 cases harbor the deletions or duplications in 16p11.2, and 2 cases for 1p36. The bioinformatical reanalysis revealed 47 positive cases, in which 12 (26%) were reported to be negative, VUS or incorrectly positive in pre-MMC reports. Additionally, among 87 cases with negative cases, 4 (5%) were reported to be positive in pre-MMC reports. CONCLUSION: We established a workflow allowing for a "one-stop" collaborative assessments by experts of multiple fields and helps for correct the diagnosis of cases with falsenegative and -positive and VUS genetic reports and may have significant influences for intervention, prevention and genetic counseling of pediatric epilepsy and neurodevelopmental disorders.
背景:癫痫(EP)是一种常见的神经系统疾病,其中 70-80%的患者被认为具有遗传原因。在癫痫患者中,神经发育迟缓(NDD)较为普遍。下一代测序已广泛应用于癫痫/NDD 的诊断。然而,诊断率仍保持在 40%-50%。许多重新分析管道和软件已经开发出来,用于疾病的自动重新分析和决策。尽管如此,对于较小的遗传中心或常规儿科实践来说,这仍然是一项极具挑战性的任务。为了解决临床和遗传的“诊断探索”问题,我们组织了一个多学科分子咨询(MMC)团队,为 202 名来自低级别医院的癫痫/NDD 患者进行分子咨询。
方法:所有患者均接受了由临床、遗传专家和研究人员进行的“三重重新分析”程序的对齐和顺序咨询和讨论。
结果:在参加 MMC 的 202 例病例中,我们共在 24 个基因和 15 个染色体区域中鉴定出 47 例(23%)存在致病变异。在 15 例阳性 CNV 病例中,有 3 例在 16p11.2 区域存在缺失或重复,2 例在 1p36 区域存在缺失或重复。生物信息学重新分析发现了 47 例阳性病例,其中 12 例(26%)在 MMC 前的报告中被认为是阴性、VUS 或假阳性。此外,在 87 例阴性病例中,有 4 例(5%)在 MMC 前的报告中被认为是阳性。
结论:我们建立了一个工作流程,允许多个领域的专家进行“一站式”协作评估,有助于纠正假阴性、假阳性和 VUS 遗传报告的病例诊断,并可能对儿科癫痫和神经发育障碍的干预、预防和遗传咨询产生重大影响。
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