PDF(Pubmed)
Abstract：
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：癫痫（EP）是一种常见的神经系统疾病，其中70-80％被认为是遗传原因。在癫痫患者中，神经发育迟缓（NDD）普遍存在。下一代测序已广泛用于诊断EP/NDD。然而,诊断率仍为40%-50%。已经开发了许多再分析管道和软件，用于疾病的自动再分析和决策。然而，对于较小的遗传中心或常规的儿科实践，这是一项极具挑战性的任务。为了解决临床和遗传诊断问题，“我们组织了一个多学科分子咨询（MMC）小组，为下级医院转诊的202名EP/NDD儿童进行分子咨询。
方法：所有患者都通过临床的“三重再分析”程序进行了一致和连续的咨询和讨论，遗传专家,和研究人员。
结果：在202例MMC中，我们总共确定了47例(23%)在MMC后的24个基因和15个染色体区域存在致病变异.在15例CNVs阳性的病例中，3例16p11.2缺失或重复，2例1p36缺失或重复。生物信息学再分析发现47例阳性，其中12人(26%)被报告为阴性，VUS或MMC前报告中的错误阳性。此外,在87例阴性病例中，4（5％）在MMC前报告中报告为阳性。
结论：我们建立了一个工作流程，允许由多个领域专家进行“一站式”协作评估，并有助于纠正假阴性和阳性和VUS基因报告的病例的诊断，并可能对干预产生重大影响。儿童癫痫和神经发育障碍的预防和遗传咨询。
方法：所有患者都通过临床的“三重再分析”程序进行了一致和连续的咨询和讨论，遗传专家,和研究人员。
结果：在202例MMC中，我们总共确定了47例(23%)在MMC后的24个基因和15个染色体区域存在致病变异.在15例CNVs阳性的病例中，3例16p11.2缺失或重复，2例1p36缺失或重复。生物信息学再分析发现47例阳性，其中12人(26%)被报告为阴性，VUS或MMC前报告中的错误阳性。此外,在87例阴性病例中，4（5％）在MMC前报告中报告为阳性。
结论：我们建立了一个工作流程，允许由多个领域专家进行“一站式”协作评估，并有助于纠正假阴性和阳性和VUS基因报告的病例的诊断，并可能对干预产生重大影响。儿童癫痫和神经发育障碍的预防和遗传咨询。
