两例发育性癫痫性脑病66型患儿的临床表型及PACS2基因变异分析

Clinical and genetic analysis of PACS2 gene variant in two child patients with developmental and epileptic encephalopathy 66

目的探讨两例发育性癫痫性脑病66型患儿的临床表型及基因变异特点。方法采集患儿和父母的外周血样,应用全外显子测序的方法对患儿基因进行检测,并采用Sanger测序的方法对变异位点进行验证。结果两例患儿均为足月儿,主要表现为新生儿期起病的癫痫发作、肌张力低下、全面性发育落后及特殊面容。头颅磁共振提示1例小脑发育不全,1例髓鞘化不良。全外显子测序结果显示两例患儿PACS2基因均发生了c.625G>A(p.Glu209Lys)杂合变异(NM_001100913.3),c.625G>A(p.Glu209Lys)变异为已报道过的致病变异。根据《ACMG遗传变异分类标准与指南》,该变异判定为致病性变异(PS2+PM2+PP3)。两例患儿均予丙戊酸钠联合左乙拉西坦治疗后发作控制。至末次随访,两例患儿运动及智力发育情况得到改善。与已报道病例相比,本研究的两例患儿临床症状及体征相对较轻,治疗效果较好。结论PACS2基因c.625G>A(p.Glu209Lys)变异为发育性癫痫性脑病66型的变异热点,基因检测可以为临床诊断和治疗提供依据。

Objective To explore the clinical phenotype and genetic characteristics of two children with developmental epileptic encephalopathy type 66.Methods Genomic DNA was extracted from peripheral blood samples of the two children and their parents.Whole-exome sequencing(WES)was carried out and suspected variant was verified by Sanger sequencing.Results The main manifestations of the two children were neonatal onset seizures,hypotonia,global developmental delay,and facial dysmorphisms.Cranial MRI showed delayed myelination in case 1 and cerebellar dysgenesis in case 2.WES has identified a de novo pathogenic variant in thePACS2 gene in both patients,namely c.625G>A(p.Glu209Lys)(NM_001100913.3),which was reported as a pathogenic variant before.This variant was predicted to be pathogenic according to the American College of Medical Genetics and Genomics guideline(PS2+PM2+PP3).The seizures were controlled after combination treatment of sodium valproate and levetiracetam in both cases.At last follow-up,the motor and intellectual development of the 2 cases were improved.Compared with the cases reported,the clinical symptoms and signs of our cases were relatively mild,and the treatment effects were fairly good.Conclusion The variant of c.625G>A(p.Glu209Lys)inPACS2 gene is a hotspot variant of developmental epileptic encephalopathy 66.Gene testing can facilitate the clinical diagnosis and treatment.