KCNQ2基因变异致不伴癫痫的全面性发育迟缓/智力障碍一例分析并文献复习

A study on a case of global developmental delay/intellectual disability without epilepsy caused by KCNQ2 gene mutation and literature review

目的总结KCNQ2基因变异相关不伴癫痫的全面性发育迟缓(GDD)/智力障碍(ID)患儿的临床特点及变异位点并进行文献复习,探讨KCNQ2基因变异与孤立性GDD/ID的相关性,明确患者病因。方法收集2022年6月在丽水市妇幼保健院儿科就诊的1例不伴癫痫GDD/ID患儿及其家族成员的临床资料;提取患儿及其父母的外周血DNA,采用单核苷酸多态性微阵列分析及核心家系全外显子组测序进行遗传学分析。以“KCNQ2、intellectual disability/智力障碍、global developmental delay/全面性发育迟缓”为关键词,在HGMD、Pubmed、中国期刊全文数据库(CNKI)和万方医学文献数据库检索文献,检索时间为建库至2022年7月。收集文献已报道的KCNQ2基因变异相关不伴癫痫的GDD/ID病例,对所收集病例的临床资料及变异位点进行汇总分析。结果先证者单核苷酸多态性微阵列分析未发现异常;全外显子组测序检测到与患儿表型相关的KCNQ2基因变异c.430C>T,为新发错义突变,根据ACMG标准评定为可能致病性变异。文献检索共收集到KCNQ2基因致病性变异相关不伴癫痫的GDD/ID病例7例,加上本例,共8例,其中男性3例,女性5例;8例病例既往均无癫痫表现,8例有语言发育落后,7例有认知能力落后,5例有运动发育落后,临床表现为非特异性的,部分表型与BFNS、DEE重叠。8例病例均为KCNQ2杂合错义突变,共涉及5个变异位点,包含3例c.430 C>T,2例c.628 C>T,1例c.431 G>A,1例c.628 C>T,1例c.223 C>T,其中功能获得的位点2个,功能缺失位点3个。结论KCNQ2:c.430 C>T变异很可能为本例患儿的遗传学病因,KCNQ2功能缺失和功能获得均可能导致不伴癫痫的孤立性GDD/ID,男、女均可发病,且临床表型具有明显异质性。

Objective This paper aims to summarize the clinical characteristics of KCNQ2 gene variation and its variant site in children with global developmental delay(GDD)/intellectual disability(ID)without epilepsy,review the literature,explore the correlation between KCNQ2 gene variants and isolated GDD/ID,and identify the patient's etiology.Methods The clinical data of a GDD/ID child without epilepsy and his family members who were admitted to the Pediatric Department of Lishui Maternal and Child Health Care Hospital in June 2022 were collected.The peripheral blood DNA of the child and his parents was extracted,and genetic analysis was performed by single nucleotide polymorphism microarray detection and whole exome sequencing of the core family.Using"KCNQ2,intellectual disability,global developmental delay"as keywords,literature search was conducted in HGMD,PubMed,China National Knowledge Infrastructure(CNKI)and Wanfang databases(up to July 2022).CDD/ID cases without epilepsy related KCNQ2 gene mutation reported in the literature were collected,and the clinical data and mutation sites of all cases were summarized and analyzed.Results No abnormality was found in the proband's SNP microarray analysis.Whole exome sequencing detected the KCNQ2 gene mutation,c.430 C>T,related to the patient phenotype,which was a new missense mutation and was assessed as a probable pathogenic variant according to ACMG criteria.A total of 7 cases of GDD/ID without epilepsy associated with pathogenic variants in KCNQ2 gene were collected from literature search,and this case increased them to eight,including 3 males and 5 females.All the 8 cases were heterozygous missense mutations,involving 5 mutation sites,including 3 cases of c.430 C>T,2 cases of c.628 C>T,1 case of c.431 G>A,1 case of c.628 C>T and 1 case of c.223 C>T.There were 2 functional gain sites and 3 functional loss sites.Conclusion The KCNQ2:c.430 C>T mutation is likely to be the genetic etiology of this patient.Both loss of function and retrieval of function of KCNQ2 may lead to GDD/ID without epilepsy,which may occur in both males and females,and the clinical phenotype is significantly heterogeneous.