{"doi":"10.1016/j.jaci.2020.06.032","title":"A novel STING1 variant causes a recessive form of STING-associated vasculopathy with onset in infancy (SAVI)","abstract":"Stimulator of interferon response genes (STING) encoded by stimulator of interferon response cGAMP interactor 1 (STING1), previously known as transmembrane protein 173 (TMEM173) is an important pattern recognition receptor that detects microbial dinucleotides and functions as an adaptor molecule in the cytosolic DNA sensing pathway that binds 2’3’-cyclic GMP-AMP (cGAMP), which is generated when cytosolic DNA activates cyclic GMP-AMP synthase (cGAS).1Ishikawa H. Ma Z. Barber G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.Nature. 2009; 461: 788-792Crossref PubMed Scopus (1674) Google Scholar,2Ablasser A. Chen Z.J. cGAS in action: Expanding roles in immunity and inflammation.Science. 2019; 363Crossref PubMed Scopus (352) Google Scholar STING activation stimulates the induction of type I interferons, which activate interferon responses. Gain-of-function (GOF) variants in STING1 lead to autoactivation without ligand binding and cause a rare autoinflammatory disease named STING-associated vasculopathy with onset in infancy (SAVI) (Online Mendelian Inheritance in Man catalog no. 615934).3Liu Y. Jesus A.A. Marrero B. Yang D. Ramsey S.E. Sanchez G.A.M. et al.Activated STING in a vascular and pulmonary syndrome.N Engl J Med. 2014; 371: 507-518Crossref PubMed Scopus (817) Google Scholar,4Jeremiah N. Neven B. Gentili M. Callebaut I. Maschalidi S. Stolzenberg M.C. et al.Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations.J Clin Invest. 2014; 124: 5516-5520Crossref PubMed Scopus (337) Google Scholar Patients with SAVI present in infancy with the following symptoms: recurrent fevers; cold-induced skin vasculitis that can progress to tissue loss and amputation of fingers and toes; and/or interstitial lung disease, which is the main cause of the mortality that often occurs before patients reach adulthood. So far, all reported cases of SAVI have been caused by autosomal dominant variants, with most of them occurring de novo. We have identified 6 patients from 4 unrelated families, all of whom are of Arabic ethnicity and harbor pathogenic STING1 variants that are disease causing only in homozygosity. The patients had clinical disease suggestive of SAVI and were enrolled into institutional review board–approved protocols, including the National Institutes of Health natural history protocol (NCT02974595). Patient 1, the index patient, presented at 4 weeks of age with a cough and failure to thrive, as well as with a maculopapular violaceous rash with a livedoid appearance (Fig 1, A and B). A chest computed tomography scan showed diffuse bilateral parenchymal opacities. His lung disease progressed despite steroid therapy and short-term treatment with the JAK inhibitor tofacitinib, and he died of respiratory failure at 5 months of age. His older brother (patient 2) died at 18 months of age with chronic cough and failure to thrive. Although genetic testing was not performed, the clinical manifestations and similarities of patient 2 to those of his younger brother strongly suggest that he had SAVI. Patient 3 presented at 3 months of age with recurrent fever, erythematous rash, cough, and dyspnea, ultimately progressing to oxygen dependence. He had a chest computed tomography scan with results consistent with interstitial lung disease and a lung biopsy specimen that showed chronic interstitial pneumonitis with intraalveolar hemorrhage. He is currently taking the JAK inhibitor ruxolitinib. His brother, patient 4, had respiratory symptoms starting at the age of 6 months; he was diagnosed with SAVI at the age of 15 months and was initially treated with steroids, after which baricitinib (a selective JAK1/2 inhibitor) was added to his treatment regimen. Patient 5 presented at the age of 2 months with cough, tachypnea, and recurrent lung infections; she was diagnosed with chronic aspiration pneumonia and had a laryngeal cleft that was repaired at the age of","journal":"Journal of Allergy and Clinical Immunology","year":2020,"id":57009,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":81,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":297407,"name":"Roberta Berard","orcid":"0000-0003-2780-0617","position":1,"is_corresponding":false},{"id":299911,"name":"A. A. Rasheed","orcid":null,"position":2,"is_corresponding":false},{"id":299912,"name":"Buthaina Al‐Adba","orcid":null,"position":3,"is_corresponding":false},{"id":230272,"name":"Philip J. Kranzusch","orcid":"0000-0002-4943-733X","position":4,"is_corresponding":false},{"id":299913,"name":"Maggie Henderlight","orcid":null,"position":5,"is_corresponding":false},{"id":299914,"name":"Alexi Grom","orcid":null,"position":6,"is_corresponding":false},{"id":234138,"name":"Dana Kahle","orcid":null,"position":7,"is_corresponding":false},{"id":297408,"name":"Sofia Torreggiani","orcid":"0000-0003-0439-4046","position":8,"is_corresponding":false},{"id":299915,"name":"Alexander G. Aue","orcid":null,"position":9,"is_corresponding":false},{"id":297409,"name":"Jacob T. Mitchell","orcid":"0000-0002-5370-9692","position":10,"is_corresponding":false},{"id":104156,"name":"Adriana A. de Jesus","orcid":"0000-0001-8966-8362","position":11,"is_corresponding":false},{"id":297410,"name":"Grant S. Schulert","orcid":"0000-0001-5923-7051","position":12,"is_corresponding":false},{"id":104223,"name":"Raphaela Goldbach‐Mansky","orcid":"0000-0001-7865-5769","position":13,"is_corresponding":false},{"id":297406,"name":"Bin Lin","orcid":"0000-0002-8032-937X","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T21:06:31.136481Z","pmid":"32673614","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}