Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria.
Department of Paediatrics, The University of Melbourne, Victoria.
Dev Med Child Neurol. 2023 Jan;65(1):50-57. doi: 10.1111/dmcn.15308. Epub 2022 Jun 14.
To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs).
Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated.
Of the 103 patients recruited (54 males, 49 females; aged 2 weeks-17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high-density chromosomal microarray testing.
We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice.
The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs.
评估外显子组测序在发育性和癫痫性脑病（DEE）患者中的临床应用价值。
在 2 年多的时间里，招募了 DEE 患者进行单体外显子组测序。在有指征的情况下进行了父母分离。
在招募的 103 例患者（54 名男性，49 名女性；年龄 2 周至 17 岁）中，103 例中有 36 例（35%）确定了遗传病因，其中 13 例（36%）的治疗方案有改变。外显子组测序显示 103 例患者中有 30 例（29%）存在致病性或可能致病性变异，39 例（38%）存在意义不明的变异，34 例（33%）外显子分析为阴性。在描述了新的遗传疾病后，随后对 6 名患者或通过新的可用高密度染色体微阵列检测进行了分子诊断。
我们证明了外显子组测序在 DEE 儿童常规临床护理中的实用性。我们强调，分子诊断通常会导致治疗方案的改变，并提供准确的预后和生殖咨询。我们的研究结果强调了需要对基因组数据进行持续分析，以确定病因未知的患者的病因。在 DEE 患儿的护理中实施基因组检测应成为临床实践的常规。
35%的发育性和癫痫性脑病患者确定了病因。KCNQ2、CDKL5、SCN1A 和 STXBP1 是最常发现的基因。对基因组数据的重新分析发现了另外 6 例患者的病因。在发病年龄小于 2 岁的儿童中，遗传病因的检出率为 41%，而发病年龄大于 2 岁的儿童为 18%。在 DEE 患者中，发现分子病因导致 36%的患者治疗方案发生改变。
