ASPM基因变异致原发性小头畸形1例患儿的遗传学分析及文献回顾  

Genetic analysis of a child with autosomal recessive primary microcephaly due to variant of ASPM gene and a literature review

作　　者：王杰 王晓华 张丽春 黄艳 沙日娜 安槿 武彦廷 郭志远 贾跃旗 Wang Jie;Wang Xiaohua;Zhang Lichun;Huang Yan;Sha Rina;An Jin;Wu Yanting;Guo Zhiyuan;Jia Yueqi(Department of Genetics,Inner Mongolia Maternity and Child Health Care Hospital,Hohhot,Inner Mongolia 010010,China;Department of Pathology,the Affiliated Hospital of Inner Mongolia Medical University,Hohhot,Inner Mongolia 010050,China;Department of Ultrasonic Medicine,Inner Mongolia Maternity and Child Health Care Hospital,Hohhot,Inner Mongolia 010010,China)

机构地区：[1]内蒙古自治区妇幼保健院遗传优生科,呼和浩特010020 [2]内蒙古医科大学附属医院病理科,呼和浩特010050 [3]内蒙古自治区妇幼保健院超声医学科,呼和浩特010020

出　　处：《中华医学遗传学杂志》2024年第10期1243-1248,共6页Chinese Journal of Medical Genetics

基　　金：内蒙古自治区卫生健康科技计划项目(202201136);内蒙古自治区科技计划项目(2021GG0130);内蒙古草原英才项目(CYYC012074)。

摘　　要：目的探讨1例原发性小头畸形(MCPH)患儿的临床信息与遗传学特征。方法选取2022年9月以智力低下、小头畸形为首发症状就诊于内蒙古自治区妇幼保健院的患儿为研究对象,回顾性分析患儿产前超声影像信息,对患儿进行家系全外显子组测序。针对患儿母亲此次妊娠进行Sanger测序验证。以"ASPM基因""小头畸形""产前诊断""原发性小头畸形""ASPM""MCPH5""MCPH"、"autosomal recessive microcephaly""prenatal diagnosis""prenatally on ultrasonography"等为关键词,检索年限为建库至2023年9月,在PubMed数据库、万方数据知识服务平台及中国知网中检索相关文献进行分析。本研究通过内蒙古自治区妇幼保健院医学伦理委员会的审查(伦理号:2021-093-1)。结果患儿为4岁男性,胎儿期超声双顶径(BPD)、头围(HC)呈进行性减小。患儿的ASPM基因存在父源c.8044C>T(p.R2682X)和母源c.8652dup(p.A2885Sfs*35)复合杂合变异。根据美国医学遗传学与基因组学学会相关变异评级与标准指南,c.8044C>T和c.8652dup均被评级为致病性变异(PVS1+PM2_Supporting+PP4;PVS1+PM2_Supporting+PM3)。家系内高风险胎儿超声未见异常,基因检测为正常基因型。文献检索共11篇文献符合条件,加上上述先证者共15例MCPH患儿。胎儿期影像记录的MCPH5病例均发现不同程度的头BPD/HC减小(100.0%,15/15),继续妊娠至出生病例均表现出不同程度的发育迟缓、智力障碍、注意力缺陷(100.0%,8/8),1例有癫痫发作(12.5%,1/8)。检出基因型包括纯合变异(46.2%,6/13),复合杂合变异(53.8%,7/13),变异类型包含无义变异(45%,9/20)和移码变异(55%,11/20)。结论ASPM基因c.8044C>T(p.R2682X)和c.8652dup(p.A2885Sfs*35)复合杂合变异考虑是上述MCPH患儿在胎儿期表现出BPD、HC减小的遗传学病因。ObjectiveTo explore the clinical and genetic characteristics of a child with autosomal recessive primary microcephaly(MCPH).MethodsA case study has been carried out on a boy who had presented at the Inner Mongolia Maternity and Child Health Care Hospital for microcephaly and mental deficiency in September 2022.Prenatal ultrasound images were retrospectively analyzed,and whole exome sequencing and Sanger sequencing were carried out for his family.A literature review was also carried out using keywords such as"ASPM gene","microcephaly","prenatal diagnosis","primary microcephaly","ASPM","MCPH5","MCPH","autosomal recessive microcephaly",and"prenatal diagnosis on ultrasonography"on the PubMed database,Wanfang Data and China National Knowledge until September 2023.This study was approved by Medical Ethics Committee of the Inner Mongolia Maternity and Child Health Care Hospital(Ethics No.2021-093-1).ResultsThe proband had shown progressive reduction in biparietal diameter(BPD)and head circumference(HC)during the fetal period.He was found to harbor compound heterozygous variants of the ASPM gene,which included a paternally derived c.8044C>T(p.R2682X)and a maternally derived c.8652dup(p.A2885Sfs*35).Both variants were classified as pathogenic(PVS1+PM2_Supporting+PP4;PVS1+PM2_Supporting+PM3)based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).For other fetuses in his family,prenatal ultrasound and genetic testing were all normal.Literature research has identified 11 relevant articles,which included 14 MCPH cases.All of the MCPH5 cases had shown various degrees of reduced BPD/HC on fetal imaging(100%,15/15).Developmental delay,intellectual disability,and attention deficits were noted in all survived cases,with one case having seizures(12.5%,1/8).Their genotypes had included homozygotes(46.2%,6/13)and compound heterozygotes(53.8%,7/13)for nonsense variants(45%,9/20)and frameshifting variants(55%,11/20).ConclusionThe compound heterozygous variants c.8044C>T(p.R2682X)and c.8652dup(p.A2885Sfs

关 键 词：小头畸形 ASPM基因 全外显子组测序 产前诊断 

分 类 号：R725.9[医药卫生—儿科] R742[医药卫生—临床医学]