摘要
目的对3个中国遗传性对称性色素异常症(DSH)家系进行临床特征分析及致病变异鉴定。方法收集3个中国DSH患者及其家系成员的临床资料并采集外周血,应用全外显子组测序技术(WES)对3个DSH家系的先证者进行变异筛查,并使用Sanger测序技术进行家系基因型-表型共分离验证,最后通过系列生物信息分析软件对新发现变异的致病性进行预测。结果3个中国DSH家系的先证者均表现为肢端色素沉着减少斑间杂色素沉着过度斑。WES结果发现3个先证者均携带ADAR基因(NM_001111.5)变异,先证者1携带ADAR基因c.3546T>G(p.Tyr1182*)无义变异,先证者2携带ADAR基因c.2770T>G(p.Tyr924Asp)错义变异,先证者3携带ADAR基因c.3116A>C(p.Lys1039Thr)错义变异。前两个变异均未在gnomAD和HGMD等公共数据库中收录,第三个变异在HGMD数据库中收录,人群频率为0。Sanger测序结果表明这3个家系中先证者的父母均未携带相应变异,提示这3个变异均为新发变异。这3个变异位点在不同物种中高度保守,且均位于双链RNA特异性腺苷脱氨酶蛋白的腺苷脱氨酶催化结构域。根据美国医学遗传学和基因组学学会(ACMG)指南,ADAR基因c.3546T>G无义变异被判定为致病(PVS1+PS2+PM2+PP3+PP4),c.2770T>G、c.3116A>C错义变异被判定为致病(PS2+PM1+PM2+PP3+PP4)以及(PS1+PS2+PM1+PM2+PP3+PP4)。结论ADAR基因的新发变异c.3546T>G、c.2770T>G和c.3116A>C可能分别是这3个中国DSH患者的发病原因,以上结果丰富了ADAR基因的突变谱。
Objective To analyze the clinical features and to identify the pathogenic variants in three Chinese families with dyschromatosis symmetrica hereditaria(DSH).Methods Clinical information and peripheral blood samples from three trio families with DSH were collected.The variants were detected by whole exome sequencing and then confirmed by Sanger sequencing.Pathogenicity of the variants was evaluated with a series of bioinformatic software.Results All the probands from the three Chinese families showed a mixture of pigmented and depigmented macules on the extremities.Three heterozygote single-nucleotide-variants,c.3546T>G(p.Tyr1182*),c.2770T>G(p.Tyr924Asp)and c.3116A>C(p.Lys1039Thr),in the ADAR(NM_001111.5)gene were detected by WES in the three probands respectively.The first two variants were not present in the public databases such as gnomAD and HGMD,and the third one was previously reported in HGMD but not presented in the public databases.The relevant variants were undetectable in their parents of the three probands shown by Sanger sequencing,and were consequently regarded as de novo variants.These variants located in the highly conservative sites,all of which were located in the double-stranded RNA adenosine deaminase domain of the protein encoded by ADAR.According to the American College of Medical Genetics and Genomics(ACMG)guidelines,the nonsense variant,c.3546T>G in ADAR,was categorized as a pathogenic variant(PVS1+PS2+PM2+PP3+PP4)and the missense variants,c.2770T>G and c.3116A>C in ADAR,were categorized as pathogenic variants(PS2+PM1+PM2+PP3+PP4)and(PS1+PS2+PM1+PM2+PP3+PP4),respectively.Conclusions Three de novo variants in ADAR,c.3546T>G,c.2770T>G and c.3116A>C are probably the genetic pathogenesis of DSH in these three probands respectively,which enriched the genetic profile of ADAR.
作者
杨雪婷
郭可欣
孙阳
王蓉蓉
马东来
张学
YANG Xueting;GUO Kexin;SUN Yang;WANG Rongrong;MA Donglai;ZHANG Xue(McKusick-Zhang Center for Genetic Medicine,State Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences CAMS,School of Basic Medicine PUMC,Beijing 100005;Department of Dermatology,National Clinical Research Center for Skin and Immune Diseases,State Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,CAMS&PUMC,Beijing 100730,China)
出处
《基础医学与临床》
2023年第2期259-264,共6页
Basic and Clinical Medicine
基金
国家自然科学基金(81788101)
中国医学科学院医学与健康科技创新工程项目(2021-I2M-1-018和2022-I2M-JB-004)。
