Increased interferon I signaling, DNA damage response and evidence of T-cell exhaustion in a patient with combined interferonopathy (Aicardi-Goutières Syndrome, AGS) and cohesinopathy (Cornelia de Lange Syndrome, CdLS).

Publisher: BioMed Central Country of Publication: England NLM ID: 101248897 Publication Model: Electronic Cited Medium: Internet ISSN: 1546-0096 (Electronic) Linking ISSN: 15460096 NLM ISO Abbreviation: Pediatr Rheumatol Online J Subsets: MEDLINE

Publication: 2007- : [London] : BioMed Central
Original Publication: [Chicago, Ill. : University of Chicago, 2003]-

De Lange Syndrome*/genetics ; De Lange Syndrome*/immunology ; De Lange Syndrome*/complications ; Autoimmune Diseases of the Nervous System*/genetics ; Autoimmune Diseases of the Nervous System*/immunology ; Autoimmune Diseases of the Nervous System*/complications ; Cell Cycle Proteins*/genetics ; Nervous System Malformations*/genetics ; Nervous System Malformations*/immunology ; Nervous System Malformations*/complications ; DNA Damage* ; Interferon Type I*/metabolism ; Chromosomal Proteins, Non-Histone*/genetics ; T-Lymphocytes*/immunology; Humans ; Male ; Young Adult ; SAM Domain and HD Domain-Containing Protein 1/genetics ; Signal Transduction ; Cohesins ; Structural Maintenance of Chromosome Protein 1 ; Exome Sequencing ; Mutation ; T-Cell Exhaustion

Competing Interests: Declarations. Ethics approval and consent to participate: The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Attikon University Hospital, (Athens, Greece, protocol 10|22-6-2017). Written informed consent was obtained from all participants or their guardians. Consent for publication: Patients or guardian of patients gave informed consent for publishing the research results or images after anonymization. Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. The authors have no relevant financial or non‑financial interests to disclose.
Background: 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.
Case and Methods: 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.
Results: 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.
Conclusions: 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.
(© 2025. The Author(s).)

Bioinformatics. 2009 Jul 15;25(14):1754-60. (PMID: 19451168)
Cell Host Microbe. 2013 Oct 16;14(4):422-34. (PMID: 24139400)
N Engl J Med. 2020 Nov 26;383(22):2190-2191. (PMID: 33252884)
Nat Immunol. 2008 Sep;9(9):949-52. (PMID: 18711431)
J Immunol. 2009 Jan 15;182(2):999-1010. (PMID: 19124743)
Mol Immunol. 2018 Sep;101:450-460. (PMID: 30099227)
Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021)
BMC Bioinformatics. 2013 Jan 16;14:7. (PMID: 23323831)
Biochem Soc Trans. 2009 Jun;37(Pt 3):535-8. (PMID: 19442247)
Cancer Med. 2023 Jun;12(11):12881-12895. (PMID: 37096492)
J Exp Med. 2019 Jan 7;216(1):152-175. (PMID: 30530755)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
Nature. 2009 Jul 16;460(7253):410-3. (PMID: 19458616)
Semin Cell Dev Biol. 2019 Jun;90:187-193. (PMID: 30096363)
J Clin Med. 2020 Apr 01;9(4):. (PMID: 32244809)
J Cell Physiol. 2016 Mar;231(3):613-22. (PMID: 26206533)
N Engl J Med. 2000 Oct 5;343(14):1020-34. (PMID: 11018170)
Nat Commun. 2022 Jul 27;13(1):4342. (PMID: 35896525)
N Engl J Med. 2018 Dec 06;379(23):2275-7. (PMID: 30566312)
Front Pediatr. 2021 Oct 27;9:725868. (PMID: 34778129)
Nucleic Acids Res. 2021 Jan 8;49(D1):D916-D923. (PMID: 33270111)
Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199)
World J Pediatr. 2023 Jul;19(7):635-643. (PMID: 36650407)
Oncotarget. 2016 Aug 23;7(34):54370-54379. (PMID: 27494846)
J Clin Invest. 2017 Jun 30;127(7):2789-2804. (PMID: 28581446)
Nat Commun. 2018 Apr 16;9(1):1485. (PMID: 29662124)
Biomedicines. 2022 Nov 04;10(11):. (PMID: 36359340)
Nat Genet. 2006 Aug;38(8):917-20. (PMID: 16845398)
Cytometry B Clin Cytom. 2020 Mar;98(2):146-160. (PMID: 31758746)
Front Immunol. 2023 Feb 09;14:1112761. (PMID: 36845138)
F1000Res. 2017 May 26;6:748. (PMID: 28663787)
Gigascience. 2021 Feb 16;10(2):. (PMID: 33590861)
Neuron. 2021 Dec 15;109(24):3962-3979.e6. (PMID: 34655526)
Nucleic Acids Res. 2010 Sep;38(16):e164. (PMID: 20601685)
Clin Immunol. 2019 Jun;203:28-36. (PMID: 30930144)
Am J Med Genet A. 2015 Feb;167A(2):296-312. (PMID: 25604658)
Front Immunol. 2023 Jul 05;14:1203848. (PMID: 37475860)
Nat Commun. 2022 Jul 25;13(1):4301. (PMID: 35879286)
Bioinformatics. 2016 Sep 15;32(18):2847-9. (PMID: 27207943)
Annu Rev Immunol. 2019 Apr 26;37:521-546. (PMID: 30726153)
Cell Rep. 2017 Aug 22;20(8):1921-1935. (PMID: 28834754)
N Engl J Med. 2020 Sep 3;383(10):986-989. (PMID: 32877590)
Nat Immunol. 2018 Sep;19(9):932-941. (PMID: 30127433)
Nat Commun. 2022 May 26;13(1):2961. (PMID: 35618715)
Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Sci Adv. 2024 Mar;10(9):eadk0820. (PMID: 38427731)
Nat Med. 2012 Nov;18(11):1682-7. (PMID: 22972397)
Blood. 2014 Feb 13;123(7):1021-31. (PMID: 24335234)
Nat Genet. 2020 Dec;52(12):1364-1372. (PMID: 33230297)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
Lab Invest. 2017 Jun;97(6):669-697. (PMID: 28346400)
Nature. 2011 May 25;474(7353):654-7. (PMID: 21613998)
J Autoimmun. 2015 Sep;63:47-58. (PMID: 26183766)
Arthritis Rheumatol. 2014 Jun;66(6):1583-95. (PMID: 24644022)
Cytometry A. 2021 May;99(5):446-461. (PMID: 33496367)
Front Immunol. 2023 Jan 25;14:1071623. (PMID: 36761741)
Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
Nat Rev Genet. 2018 Oct;19(10):649-666. (PMID: 29995837)
Nat Immunol. 2019 Jul;20(7):902-914. (PMID: 31209404)
Sci Adv. 2022 Oct 28;8(43):eabo5840. (PMID: 36306362)
Neuron. 2021 Dec 15;109(24):3897-3900. (PMID: 34914915)
Ann Rheum Dis. 2015 Mar;74(3):e17. (PMID: 24445253)
Hum Mol Genet. 2015 Mar 15;24(6):1540-55. (PMID: 25378554)
Nat Rev Rheumatol. 2019 Dec;15(12):731-746. (PMID: 31705045)
iScience. 2023 Jun 10;26(7):107090. (PMID: 37416470)
Clin Immunol. 2023 Oct;255:109765. (PMID: 37678715)

Keywords: Aicardi-Goutiéres Syndrome; Cohesinopathy; Cornelia de Lange Syndrome; DNA damage response; Interferonopathy; Lupus

0 (Cell Cycle Proteins)
0 (Interferon Type I)
0 (Chromosomal Proteins, Non-Histone)
EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1)
EC 3.1.5.- (SAMHD1 protein, human)
0 (Cohesins)
0 (Structural Maintenance of Chromosome Protein 1)

Aicardi-Goutieres syndrome

Date Created: 20250128 Date Completed: 20250128 Latest Revision: 20250504

20250505

PMC11770959

10.1186/s12969-024-01050-7

39871364