马兰综合征1例患儿的遗传学分析  

Genetic analysis of a child with Malan syndrome

作　　者：王宝松 张学习 李蕴佳 刘涛[1] 李琳[3] 孟琴 Wang Baosong;Zhang Xuexi;Li Yunjia;Liu Tao;Li Lin;Meng Qin(Department of Reproductive Medicine,Linyi People′s Hospital,Linyi,Shandong 276003,China;Traditional Chinese Medicine University Of Guangzhou,Postgraduate Training Base of Linyi People′s Hospital,Linyi,Shandong 276003,China;Department of Medical Genetics,Linyi People′s Hospital,Linyi,Shandong 276003,China;Shandong Medical College(Linyi Campus),Linyi,Shandong 276003,China)

机构地区：[1]临沂市人民医院生殖医学科,临沂276003 [2]广州中医药大学临沂市人民医院研究生培养基地,临沂276003 [3]临沂市人民医院遗传检验科,临沂276003 [4]山东医学高等专科学校(临沂校区),临沂276003

出　　处：《中华医学遗传学杂志》2024年第11期1330-1334,共5页Chinese Journal of Medical Genetics

基　　金：山东省重点研发计划(2017GSF218072);徐州医科大学附属医院科技发展基金(XYFM202347)。

摘　　要：目的探讨1例智力低下、发育迟缓患儿的遗传学病因。方法选取2023年10月至2024年4月期间在临沂市人民医院就诊的1例患儿作为研究对象。用简化Peabody量表评估其智力及发育情况。收集患儿的脑电图及影像学检查资料,采集患儿及其父母的外周血样,进行遗传代谢病筛查、染色体核型分析以及家系全基因组测序(trio-WGS)。对候选变异进行Sanger测序验证,并通过RNA测序验证其造成的可变剪接。本研究通过了临沂市人民医院医学伦理委员会的审查[伦理号:医学伦审第(YX200083)号]。结果患儿为8岁11个月女性,其父母外观均正常。患儿经简化Peabody量表评估为智力障碍、发育迟缓。MRI检查脑实质内未见确切异常信号。患儿脑电图、外周血遗传代谢病筛查以及染色体核型检查均未见异常。trio-WGS发现患儿NFIX基因第4内含子存在c.697+1G>A杂合变异,另发现8个基因的9个变异位点。c.697+1G>A变异可能导致NFIX基因RNA转录物发生异常剪接。根据美国医学遗传学与基因组学学会(ACMG)相关指南判读为致病性(PVS1+PS2+PM2_Supporting),其余9个变异均判断为致病证据不充分。结论患儿被诊断为马兰综合征,其NFIX基因的c.697+1G>A变异可能通过造成RNA的异常剪接而致病。Objective To explore the genetic basis of a child with mental retardation and developmental delay.Methods A child who had attended the genetic clinic of Linyi People′s Hospital from October 2023 to April 2024 was selected as the study subject.Intelligence and development were assessed with simplified Peabody scale.Electroencephalogram and imaging data were collected.Peripheral blood samples of the child and her parents were collected for the screening of genetic metabolic diseases,chromosomal karyotyping,and trio-whole genome sequencing(trio-WGS)analysis.Candidate variant was verified by Sanger sequencing,and RNAseq was carried out to verify the alternative splicing due to the candidate variant.This study has been approved by the Medical Ethics Committee of Linyi People′s Hospital(No.YX200083).Results The patient was an 8-year-and-11-month-old girl.Both of her parents had normal phenotypes.The child was assessed by the simplified Peabody scale as having intellectual disability and developmental delay.MRI showed no definite abnormal signals within the brain parenchyma,and electroencephalogram was normal.Screening of genetic metabolic diseases showed no obvious abnormality.Chromosomal karyotype was normal.Trio-WGS has detected a c.697+1G>A variant in the intron 4 of the NFIX gene,along with 9 other variants within eight genes.The c.697+1G>A variant may cause abnormal splicing of the NFIX gene transcript.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.697+1G>A variant was predicted to be pathogenic(PVS1+PS2+PM2_Supporting),while the evidence for pathogenicity of the other 9 variants was insufficient.Conclusion The novel de novo c.697+1G>A variant of the NFIX gene probably underlay the pathogenesis of the child,which may have caused the disease by leading to abnormal splicing.

关 键 词：智力障碍 发育迟缓 NF1X基因 基因变异 马兰综合征 

分 类 号：R725.9[医药卫生—儿科]