BRWD3基因变异相关婴儿癫痫性痉挛综合征临床表型及遗传学分析

Clinical phenotype and genetic analysis of BRWD3 gene variation related infantile epileptic spasm syndrome

目的探讨BRWD3基因变异所致婴儿癫痫性痉挛综合征患儿临床表型及遗传学特征。方法收集2019年8月2日于临沂市人民医院小儿神经内科收治的1例BRWD3基因变异相关婴儿癫痫性痉挛综合征患儿的临床资料并随访观察,应用全外显子测序技术及Sanger测序法对患儿及其父母进行基因检测,并对突变位点进行致病性分析。以"BRWD3"为检索词查阅在线人类孟德尔遗传数据库、PubMed数据库、中国知网数据库及万方数据库建库至2023年6月相关文献,总结BRWD3基因变异相关癫痫患儿的临床表型及遗传学特征。结果患儿为男性,4岁4个月,临床表型包括重度全面发育迟缓、局灶性发作(4月龄首发)、痉挛发作(6月龄首发)、孤独症、大头畸形、前额凸出和视频脑电图高度失律。全外显子测序结果显示患儿存在BRWD3基因新发移码变异c.43184319del(p.Q1441Efs*20)(NM153252),此位点目前国内外尚未报道。根据美国医学遗传学与基因组学学会变异分类标准与指南,判读c.43184319del变异为致病性突变(PVS1+PS2+PM2)。父母均未携带该变异且临床表型正常。共检索到7篇英文文献报道BRWD3基因变异相关癫痫患儿16例(其中仅1例BRWD3基因变异相关婴儿癫痫性痉挛综合征患儿),国内未见报道。加上本例共17例。皆为X染色体显性遗传,其中15例为微小变异,包括7例错义变异、3例框移变异、3例剪切变异、2例无义变异,其余2例为大片段缺失;共发现15种变异。临床表现主要包括癫痫发作(17/17)、智力障碍(10/17)、运动发育障碍(7/17)、言语障碍(9/17)、大头畸形(8/17)、面部畸形(8/17)、孤独症(4/17)和肌张力低下(4/17)等。癫痫发作形式以局灶性发作为主,偶有痉挛发作和强直发作。结论BRWD3基因变异相关癫痫为X染色体显性遗传疾病,其临床表型谱广泛。BRWD3基因c.43184319del(p.Q1441Efs*20)变异可致婴儿癫痫性痉挛综合征,表现为重度全面发育落后、痉挛发作、局灶性发作、孤独症、颅面部畸形和视频脑电图高度失律,丰富了BRWD3基因突变谱。

Objective To investigate the clinical phenotype and genetic characteristics of infantile epileptic spasm syndrome caused by BRWD3 gene mutation.Methods Clinical data of a child with BRWD3 related infantile epileptic spasm syndrome who was admitted to Department of Pediatric Neurology of Linyi People's Hospital on August 2,2019 were collected and followed up,whole exome sequencing technology and Sanger sequencing were applied to verify the child and his parents,and the pathogenicity of mutation site was analyzed.The studies till June 2023 were searched with keywords of"BRWD3"in both English and Chinese databases of China National Knowledge Infrastructure,Wanfang,Online Mendelian Inheritance in Man,and PubMed.The clinical phenotype and genetic characteristics of patients with BRWD3 related epilepsy were summarized.Results The patient was a 4 years and 4 months old boy,with a clinical phenotype including severe global development delay,focal seizures(the onset age was 4 months),epileptic spasm(the onset age was 6 months),autism,megacephaly,high forehead as well as hypsarrhythmia.The whole exome sequencing results showed a de novo and frameshift variation c.4318_4319del(p.Q1441Efs*20)(NM_153252)in the BRWD3 gene,and the variation was interpreted as pathogenic(PVS1+PS2+PM2)according to the American College of Medical Genetics and Genomics variant classification criteria and guidelines.A total of 7 English literature articles were retrieved reporting 16 cases of BRWD3 gene related epilepsy in children(including 1 case of infantile epileptic spasm syndrome),and there has been no report in China yet.Totally there were 17 cases of BRWD3 gene related epilepsy including this case.All the cases showed X chromosome dominant inheritance,of whom 15 cases showed minor variations,including 7 missense variations,3 frameshift variations,3 splicing variations,2 nonsense variations,and the remaining 2 cases showed large segment deletions.A total of 15 different variants were found.The phenotypes of the 17 patients mainly included epileptic seizures(17/17),intellectual disability(10/17),motor development disorder(7/17),speech impairment(9/17),megacephaly(8/17),facial malformation(8/17),autism(4/17)and hypotonia(4/17).The common seizure types were found to be focal seizures,occasionally epileptic spasm seizures and tonic seizures.Conclusions BRWD3 gene variation related epilepsy is an X chromosome dominant genetic disease with a wide clinical phenotype spectrum.BRWD3 gene mutation c.4318_4319del(p.Q1441Efs*20)could cause infantile epileptic spasm syndrome,manifested as severe global developmental delay,epileptic spasm,focal seizures,autism,craniofacial malformation and hypsarrhythmia.This research enriches BRWD3 gene mutation spectrum.