Turkdogan Dilsad, Turkyilmaz Ayberk, Sager Gunes, Ozturk Gulten, Unver Olcay, Say Merve
Medical Faculty, Department of Pediatric Neurology, Marmara University, Pendik, Istanbul, Turkey.
Medical Faculty, Department of Medical Genetics, Marmara University, Pendik, Istanbul, Turkey.
Int J Neurosci. 2023 Jul;133(7):683-700. doi: 10.1080/00207454.2021.1967349. Epub 2021 Aug 23.
To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents.
In a selected EIEE group ( = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only.
Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients.
Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes ( and and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.
确定父母大多为近亲结婚的土耳其儿童早期婴儿癫痫性脑病（EIEE）的遗传病因。
在一组基于非遗传和初始遗传检测结果且病因不明的EIEE患者（n = 59）中，49例患者接受了基于芯片的比较基因组杂交（aCGH）检测，49例患者接受了全外显子测序（WES），其中39例aCGH结果为阴性，10例仅接受了WES检测。
aCGH和WES对致病或可能致病变异的诊断率分别为14.3%和38.8%。包括与相容表型相关的意义未明的新发变异后，WES的诊断率提高到61.2%。在38个阳性变异中，18个（47.4%）是新发现的，16个（42.1%）是新发的。21例（56.8%）患者具有从大多为近亲结婚的健康父母遗传而来的隐性变异（85.7%）。14例（37.8%）诊断有结果的患者在已确定的EIEE基因中有阳性变异。32.4%的患者在新生儿期开始出现癫痫发作。40.5%的已诊断患者中，姿势或运动障碍与EIEE并存。我们在8.1%的患者中发现了可治疗的代谢紊乱，在19%的患者中发现了支持使用靶向药物的基因中的致病变异。
详细的电临床表型分析导致一些已知表型的扩展，除癫痫发作外还出现了非神经和神经学表现，以及候选基因（ 和 ）和一个拷贝数变异（Xp21.1p11.4微重复）的提示。隐性遗传的高比例对遗传咨询可能很重要。
