Essajee Farida, Urban Michael, Smit Liani, Wilmshurst Jo M, Solomons Regan, van Toorn Ronald, Moosa Shahida
Department of Paediatrics and Child Health, Tygerberg Hospital, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape town, South Africa.
Division of Molecular biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Seizure. 2022 Oct;101:197-204. doi: 10.1016/j.seizure.2022.09.001. Epub 2022 Sep 2.
The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of rare neurodevelopmental disorders, characterised by early-onset seizures that are often intractable, electroencephalographic abnormalities, and developmental delay or regression. There is a paucity of data from sub-Saharan Africa on the genetic basis of DEE. The aim of this study was to investigate the genetic background of DEE using targeted next generation sequencing (NGS) analysis in a tertiary pediatric neurology outpatient department at Tygerberg Hospital, South Africa. In addition, we assessed the value of the genetic results to the parents and managing physicians.
A prospective cohort study of 41 consecutive children with DEE (onset before 3 years of age) that were recruited over a 2-year period (2019-2021). Pre- and post-test genetic counselling were offered to all study participants. The results were categorized as either: positive (pathogenic/likely pathogenic variant identified), inconclusive (variant(s) of unknown significance identified), or negative (no variants identified). Result interpretation and careful matching of the variant to the clinical phenotype was performed. Subsequently, questionnaires were administered to both the physicians and the parents.
A genetic underlying cause for DEE was identified in 18 of 41 children (diagnostic yield 43.9%). Variants in SCN1A (n=7), KANSL1 (n=2), KCNQ2 (n=2) and CDKL5 (n=2) were identified in more than one patient. Rarer genes included IQSEC2, SMC1A and STXBP1. All of the identified pathogenic variants fully explained and matched the respective phenotypic description of the patient at the time of clinical diagnosis. In 26% of patients the genetic result facilitated precision medicine management changes to anti-seizure medication. Both parents and physicians expressed benefit of genetic testing in patients with DEE.
Targeted NGS analysis proved an efficient diagnostic tool in detection of a genetic cause of DEE in a large proportion of South African children. The 43.9% diagnostic yield is similar to previously reported international pediatric cohorts. Additionally, the genetic findings proved useful for targeted therapeutic decision-making and accurate genetic counseling.
发育性癫痫性脑病（DEE）是一组异质性罕见神经发育障碍，其特征为早发性癫痫发作（通常难以控制）、脑电图异常以及发育迟缓或倒退。撒哈拉以南非洲地区关于DEE遗传基础的数据匮乏。本研究的目的是在南非泰格堡医院的三级儿科神经科门诊，采用靶向新一代测序（NGS）分析来探究DEE的遗传背景。此外，我们评估了遗传结果对患儿父母及主治医生的价值。
一项前瞻性队列研究，纳入了在2年期间（2019 - 2021年）连续招募的41例DEE患儿（发病年龄在3岁之前）。为所有研究参与者提供了检测前和检测后的遗传咨询。结果分为以下几类：阳性（鉴定出致病/可能致病变异）、不确定（鉴定出意义不明的变异）或阴性（未鉴定出变异）。对结果进行解释，并将变异与临床表型进行仔细匹配。随后，向医生和患儿父母发放了问卷。
41例患儿中有18例（诊断率43.9%）确定了DEE的遗传病因。在不止一名患者中鉴定出SCN1A（n = 7）、KANSL1（n = 2）、KCNQ2（n = 2）和CDKL5（n = 2）的变异。较罕见的基因包括IQSEC2、SMC1A和STXBP1。所有鉴定出的致病变异在临床诊断时都充分解释并匹配了患者各自的表型描述。26%的患者中，遗传结果促进了抗癫痫药物精准治疗管理的改变。患儿父母和医生均表示DEE患者进行基因检测有益。
靶向NGS分析被证明是一种有效的诊断工具，可在很大比例的南非儿童中检测出DEE的遗传病因。43.9%的诊断率与先前报道的国际儿科队列相似。此外，遗传结果被证明有助于进行靶向治疗决策和准确的遗传咨询。
