原发性免疫缺陷综合征3家系基因突变及临床特征分析  

Analysis of Genetic Mutations and Clinical Characteristics in 3 Primary Immunodeficiency Syndrome Families

作　　者：张高磊[1] 张升 秦琴 蒋丽潇 李倩 王誉涵 邓维 曹会娜 张海花 刘晓雁[1] ZHANG Gaolei;ZHANG Sheng;QIN Qin;JIANG Lixiao;LI Qian;WANG Yuhan;DENG Wei;CAO Huina;ZHANG Haihua;LIU Xiaoyan(Department of Dermatology,Capital Institute of Pediatrics,Beijing 100020,China)

机构地区：[1]首都儿科研究所皮肤科,北京100020

出　　处：《中国皮肤性病学杂志》2025年第2期133-141,共9页The Chinese Journal of Dermatovenereology

基　　金：国家自然科学基金面上项目(81974473,82073461);首都儿科研究所临床基础结合专项(JHYJ-2023-06)。

摘　　要：目的回顾分析3个原发性免疫缺陷综合征(primary immunodeficiency syndrome,PIDs)家系基因突变及临床特征,揭示致病基因,探索有助于早期诊断的皮肤临床体征。方法收集3个PIDs家系,每个家系检测2代,共10人,各取静脉血2 mL,采用全外显子捕获高通量测序,一代Sanger测序验证,目标基因与Ensembl和NCBI dbSNP数据库比对,生物信息学软件Mutation Taster,GERP++预测目标基因致病性,根据ACMG指南判定基因变异的致病性。结果3个PIDs家系先证者平均年龄7个月(分别为4、5及12个月),经二代高通量测序及Sanger测序验证,生物信息学软件预测及ACMG指南判定,共检测到5个与免疫缺陷相关的致病性基因突变位点。家系1先证者突变基因CYBB c.1414G>A p.G472S,来源于其母亲;家系2先证者突变基因DCLRE1B为复合杂合突变,来源于其父母亲,母亲c.2761G>A p.G921S,父亲c.2771A>G p.H924R;家系3先证者突变基因DCLRE1C为复合杂合突变,来源于其父母亲,母亲c.1314_1329del p.E439Lfs*7,父亲c.497dupC p.T167Yfs*4。所有先证者均反复发生呼吸道、消化道感染,最终因感染死亡;均出现湿疹样、鱼鳞病样及红皮病样皮损;所有先证者粒细胞、淋巴细胞及IgG不同程度降低。结论3个PIDs家系中分别发现了CYBB、DCLRE1B和DCLRE1C基因新的突变位点,PIDs除了感染还常伴有多形性皮损,提示反复感染合并长期不愈的湿疹样、鱼鳞病样及红皮病样皮损应注意鉴别PIDs。Objective To retrospectively analyze genetic mutations and clinical characteristics of 3 families with primary immunodeficiency syndromes(PIDs),identify pathogenic genes,and explore cutaneous clinical signs helpful for early diagnosis.Methods Samples were collected from 3 PID families,including 2 generations totaling 10 individuals.Each provided 2 mL of venous blood for whole exome capture high-throughput sequencing followed by Sanger sequencing validation.Target genes were compared against Ensembl and NCBI dbSNP databases,and bioinformatics tools Mutation Taster and GERP++were used to predict gene pathogenicity.Pathogenicity of gene variants was determined following ACMG guidelines.Results The average age of symptomatic individuals in the 3 PID families was 7 months(4,5 and 12 months respectively).Through second-generation high-throughput sequencing and Sanger sequencing validation,bioinformatics predictions,and ACMG guideline assessments,we identified 5 pathogenic gene mutation sites associated with immunodeficiency.Case 1 exhibited a mutation in the CYBB gene(c.1414G>A p.G472S)inherited from the mother.Case 2 had compound heterozygous mutations in the DCLRE1B gene from both parents(mother:c.2761G>A p.G921S,father:c.2771A>G p.H924R).Case 3 had compound heterozygous mutations in the DCLRE1C gene from both parents(mother:c.1314_1329del p.E439Lfs7,father:c.497dupC p.T167Yfs4).All symptomatic individuals experienced recurrent respiratory and gastrointestinal infections leading to fatal outcomes.They also exhibited eczematous,ichthyosis-like,and erythroderma-like skin lesions,alongside varying degrees of neutropenia,lymphocytopenia,and decreased IgG levels.Conclusion We identified novel mutation sites in the CYBB,DCLRE1B and DCLRE1C genes within the three PID families.Besides recurrent infections,PIDs should be considered in cases presenting with persistent eczematous,ichthyosis-like,and erythroderma-like skin lesions.

关 键 词：免疫缺陷 基因突变 遗传 临床特征 

分 类 号：R758.5[医药卫生—皮肤病学与性病学]