摘要
目的探讨1例RELA基因变异所致RELA相关自身炎症性疾病(RAID)患儿的临床表型与遗传学特征,并对已报道的相关病例进行文献复习。方法选取1例2023年8月因"反复发热伴呕吐、口腔溃疡5年余"于宁波大学附属妇女儿童医院就诊的1例RAID患儿为研究对象。采集患儿临床资料,抽取患儿及其家系成员的外周血样用于全外显子组测序(WES)与Sanger测序,筛选并验证候选变异位点,对变异位点作致病性分析。分别以"RELA基因""NF-κB""自身炎症性疾病""托法替布片""沙利度胺片"和"RELA""NF-κB""autoinflammatory disease""tofacitinib""sulfasalazine"为中、英文关键词,在中国知网、万方数据知识服务平台和PubMed等数据库中检索文献,检索时间为2000年1月1日至2023年12月13日。本研究已通过宁波大学附属妇女儿童医院医学伦理委员会的审查(批准号:EC2020-048)。结果①患儿主要表现为反复发热、呕吐和口腔溃疡。②WES检测发现患儿RELA基因存在杂合无义变异:c.985C>T(p.Arg329Ter);经Sanger测序验证,该变异遗传自患儿母亲;根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》与临床基因组资源中心(ClinGen)制定的《PVS1 ACMG/AMP变异判据的解读建议》,该变异被判定为致病性(PVS1+PM2Supporting+PP4)。③经阿达木单抗、托珠单抗治疗后,患儿症状仍有反复发作;改用托法替布治疗后,患儿口腔溃疡得以缓解,但发热与呕吐症状仍反复发作;加用沙利度胺片治疗后,患儿发热与呕吐症状得以改善,生长发育情况未见异常。④文献检索出14个无血缘关系的RAID家系,加上本研究患儿共纳入35个病例,其主要临床特征包括反复口腔溃疡、生殖器溃疡、皮肤问题、发热、腹泻、腹痛和呕吐。结论RELA基因c.985C>T(p.Arg329Ter)无义变异可能是上述患儿反复发热、呕吐和口腔溃疡的遗传学病因。WES检测有助于及时明确诊断RAID,为该疾病临床治疗方案提供依据。
Objective To explore the clinical phenotype and genetic characteristics of a pediatric child with RELA-associated autoinflammatory disease(RAID)caused by a RELA gene variant,and to review the reported cases in the literature.Methods A pediatric child with RAID who presented with recurrent fever,vomiting,and oral ulcers for over 5 years was selected as the study subject.The child visited the Women and Children's Hospital of Ningbo University in August 2023.Clinical data were collected,and peripheral blood samples were obtained from the child and his family members for whole exome sequencing(WES)and Sanger sequencing to identify and validate candidate variants.The pathogenicity of the variants was analyzed accordingly.Using the keywords"RELA""NF-B""autoinflammatory disease""tofacitinib""sulfasalazine"a literature search was conducted in the China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,and PubMed from January 1,2000 to December 13,2023.This study was approved by the Medical Ethics Committee of the Women and Children's Hospital of Ningbo University(Ethics No.EC2020-048).Results The child primarily manifested with recurrent fever,vomiting,and oral ulcers.@WES identified a heterozygous nonsense variant c.985C>T(p.Arg329Ter)in the RELA gene,which was inherited from the mother.According to the American College of Medical Genetics and Genomics(ACMG)Standards and Guidelines for the Interpretation of Sequence Variants and the Clinical Genome Resource(ClinGen)recommendations for PVS1,this variant was classified as pathogenic(PVS1+PM2_Supporting+PP4).③Despite treatment with adalimumab and tocilizumab,the child's symptoms persisted.Switching to tofacitinib improved oral ulcers,but fever and vomiting continued.The addition of thalidomide significantly alleviated fever and vomiting,and the patient's growth and development remained normal.A literature review identified 14 unrelated RAID families,including a total of 35 cases(including the present child).The main clinical features were recurrent oral ulcers,genital ulcers,skin problems,fever,diarrhea,abdominal pain,and vomiting.Conclusion The nonsense variant c.985C>T(p.Arg329Ter)in the RELA gene is likely the genetic cause of the child's recurrent fever,vomiting,and oral ulcers.WES is valuable for timely diagnosis of RAID and provides a basis for clinical treatment strategies.
作者
李蕴言
张玉鑫
钟世玲
陈圆玲
吴菱
李海波
Li Yunyan;Zhang Yurin;Zhong Shiling;Chen Yuanling;Wu Ling;Li Haibo(Department of Pediatrics,Women and Children's Hospital Affiliated to Ningbo University,Ningbo,Zhejiang 315012,China;Central Laboratory of Birth Defects Prevention and Control,Women and Children's Hospital Affiliated to Ningbo University,Ningbo,Zhejiang 315012,China;Ningbo Key Laboratory forFetal Diseases,Ningbo,Zhejiang 315012,China)
出处
《中华医学遗传学杂志》
2025年第3期336-342,共7页
Chinese Journal of Medical Genetics
基金
宁波市公益重点项目(2022S035)
宁波市医疗卫生高端团队(2022020405)
宁波市揭榜挂帅市重点研发计划项目(2023Z178)
宁波市儿童健康与疾病临床医学研究中心(2019A21002)
宁波市重点学科儿科学(2022-B17)
宁波市医疗品牌学科-儿科重症学(PPX62024-06)。
