Boiu Sorina, Paschalidis Nikolaos, Sentis George, Manolakou Theodora, Nezos Andrianos, Gialitakis Manolis, Grigoriou Maria, Atsali Erato, Giorgi Melpomeni, Ntinopoulos Argirios, Mavragani Clio, Makrythanasis Periklis, Boumpas Dimitrios T, Banos Aggelos
Third Department of Pediatrics, Pediatric Rheumatology Unit, National and Kapodistrian University of Athens, 'Attikon' General University Hospital, Athens, Greece.
Department for Community Health, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Pediatr Rheumatol Online J. 2025 Jan 27;23(1):11. doi: 10.1186/s12969-024-01050-7.
Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present a Case with combined AGS and Cornelia de Lange Syndrome (CdLS)-a cohesinopathy-with comprehensive analysis of the immune and genomic abnormalities.
A 20-year old man presented with chilblain lesions and resorption of distal phalanges of fingers and toes, somatic and psychomotor retardation, microcephaly, synophrys, hearing losing and other aberrancies consistent with the phenotype of CdLS. We used whole exome sequencing to genetically map the associated mutations and performed transcriptome profiling and enrichment analysis in CD14 monocytes of the patient and immune phenotyping by mass cytometry (CyToF), comparing to healthy individuals and lupus patients as disease controls. DNA damage response was assayed by confocal microscopy in the peripheral blood of this patient.
Next generation exome sequencing confirmed a homozygous SAMHD1 gene mutation and a hemizygous non-synonymous mutation on SMC1A gene, responsible for the AGS and CdLS, respectively. Transcriptome profiling of CD14 monocytes of the patient showed enrichment of type I IFN signaling and enhanced DNA damage response pathway. Broad immune phenotype of the peripheral blood of the patient revealed absence of activated T cell populations, increased frequency of NK cells and plasmablasts and enhanced granulocytic lineage. Further analysis suggested activation of the ATM branch of DNA damage response and increased apoptosis in the periphery of the patient.
A rare case of a patient bearing two genetic lesions (responsible for AGS/CdLS syndromes) exhibits distinctive features of genomic damage and interferon responses. Immune phenotype revealed granulocytic skewing and absence of activated T cells compatible with chronic antigenic stimulation and/or homing of these cells at sites of inflammation.
包括艾卡迪-古铁雷斯综合征（AGS）在内的I型干扰素病代表了一组异质性临床表型。在此，我们报告一例合并AGS和科妮莉亚·德朗格综合征（CdLS，一种黏连蛋白病）的病例，并对免疫和基因组异常进行了全面分析。
一名20岁男性患者出现冻疮样皮损、手指和脚趾远端指骨吸收、躯体和精神运动发育迟缓、小头畸形、连眉、听力丧失以及其他与CdLS表型相符的异常表现。我们使用全外显子组测序对相关突变进行基因定位，并在患者的CD14单核细胞中进行转录组分析和富集分析，同时通过质谱流式细胞术（CyToF）进行免疫表型分析，与健康个体和狼疮患者作为疾病对照。通过共聚焦显微镜对该患者外周血中的DNA损伤反应进行检测。
下一代外显子组测序证实了一个纯合的SAMHDl基因突变和一个半合子的SMC1A基因非同义突变，分别导致AGS和CdLS。患者CD14单核细胞的转录组分析显示I型干扰素信号富集和DNA损伤反应途径增强。患者外周血广泛的免疫表型显示活化T细胞群体缺失、自然杀伤细胞和浆母细胞频率增加以及粒细胞谱系增强。进一步分析表明患者外周血中DNA损伤反应的ATM分支激活且凋亡增加。
一名患有两种遗传病变（导致AGS/CdLS综合征）的罕见患者表现出独特的基因组损伤和干扰素反应特征。免疫表型显示粒细胞偏移以及活化T细胞缺失，这与慢性抗原刺激和/或这些细胞在炎症部位的归巢情况相符。
