母源PAK3新发剪接变异导致X连锁智力障碍1例患儿的分析  

Analysis of a child with X-linked intellectual disability due to a maternal de novo splicing variant of the PAK3 gene

作　　者：王陈[1] 邱雪平[1] 胡绘[1] 靳冰玉 程亚婷 赵悦 周春[2] 马玲[2] 张元珍[2] 郑芳[1,2] Wang Chen;Qiu Xueping;Hu Hui;Jin Bingyu;Cheng Yating;Zhao Yue;Zhou Chun;Ma Ling;Zhang Yuanzhen;Zheng Fang(Center for Genetic Diagnosis&Department of Laboratory Medicine,Zhongnan Hospital of Wuhan University,Wuhan,Hubei 430071,China;Clinical Research Center for Prenatal Diagnosis and Birth Health of Hubei Province Reproductive Medicine Center,Zhongnan Hospital of Wuhan University,Wuhan,Hubei 430071,China)

机构地区：[1]武汉大学中南医院基因诊断中心·检验科,武汉430071 [2]湖北省产前诊断与优生优育临床医学研究中心,武汉大学中南医院生殖医学中心,武汉430071

出　　处：《中华医学遗传学杂志》2023年第7期865-870,共6页Chinese Journal of Medical Genetics

摘　　要：目的探讨1例具有严重智力障碍和明显行为异常的患儿的遗传学病因。方法采集2020年12月2日就诊于武汉大学中南医院的1例具有智力障碍和行为异常患儿及其父母的外周血样,进行全外显子组测序,并通过Sanger测序对其家系成员进行共分离验证。采用短串联重复序列分析对患儿母亲携带的变异进行溯源,并通过minigene实验对剪接变异进行体外功能验证。结果全外显子组测序发现患儿携带母源性PAK3基因c.176-2A>G剪接变异。Sanger测序及短串联重复序列分析证实其母亲携带的变异为新发变异。Minigene实验结果证实其第2外显子存在异常剪接。根据美国医学遗传学与基因组学学会变异相关指南,该变异评级为致病性变异(PVS1+PS3+PM2_Supporting+PP3)结论PAK3基因c.176-2A>G变异可能是患儿的遗传学病因。上述发现丰富了PAK3基因的变异谱,为患儿家庭的遗传咨询和产前诊断提供了依据。Objective To explore the genetic etiology for a child with profound intellectual disabilities and obvious behavioral abnormalities.Methods A male child who had presented at the Zhongnan Hospital of Wuhan University on December 2,2020 was selected as the study subject.Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing(WES).Candidate variant was verified by Sanger sequencing.Short tandem repeat(STR)analysis was carried out to determine its parental origin.The splicing variant was also validated in vitro with a minigene assay.Results WES results revealed that the child had harbored a novel splicing variant of c.176-2A>G in the PAK3 gene,which was inherited from his mother.The results of minigene assay have confirmed aberrant splicing of exon 2.According to the guidelines from the American College of Medical Genetics and Genomics,it was classified as a pathogenic variant(PVS1+PM2_Supproting+PP3).Conclusion The novel splicing variant c.176-2A>G of the PAK3 gene probably underlay the disorder in this chlid.Above finding has expanded the variation spectrum of the PAK3 gene and provided a basis for genetic counseling and prenatal diagnosis for this family.

关 键 词：X连锁智力障碍 全外显子组测序 PAK3基因 Minigene实验 

分 类 号：R725.9[医药卫生—儿科]