ArticleHuman mutation2020
Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.
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Article in Human mutation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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71citing papers in PubMed, 1 pooled it
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 110 citations in OpenAlex.
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- Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis.Journal of human immunity · 2026Article
- Anifrolumab to Treat Severe Hepatic Involvement in a De Novo IFIH1 Mutation.Journal of clinical immunology · 2026Article
- The STING HAQ haplotype and clinical non-penetrance in COPA syndrome.The Journal of experimental medicine · 2026Article
- Repeated Episodes of GPP Induced by Respiratory Infections Are Mediated by Loss-of-Function IFIH1.Immunity, inflammation and disease · 2026Article
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- Mouse models of type I interferonopathies.Human molecular genetics · 2025Review
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11 more citing papers are in PubMed but not listed here.
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Authors and funding
63 authors at 20 institutions in 11 countries.
Gillian I RiceDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.ORCID 0000-0002-4223-0571
Sehoon ParkDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
Francesco GavazziDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Laura A AdangDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Loveline A AyukPaediatric Department, Dumfries and Galloway Royal Infirmary, Cargenbridge, United Kingdom.
Lien Van EyckLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
Luis SeabraLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
Christophe BarreaDepartment of Neuropaediatrics, CHU & University of Liège, Liege, Belgium.
Roberta BattiniDepartment Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Alexandre BelotUniversité de Lyon, INSERM U1111, CIRI, Lyon, France.
Stefan BergPediatric Immunology and Rheumatology, The Queen Silvia Children's Hospital, Goteborg, Sweden.
Thierry Billette de VillemeurNeuropédiatrie, Centre de référence Neurogénétique, Hôpital Trousseau, Sorbonne Université, Paris, France.
Annette E BleyUniversity Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Lubov BlumkinPediatric Neurology Unit, Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.
Odile Boespflug-TanguyGénétique Médicale, Université Paris Diderot, Paris, France.
Tracy A BriggsDivision of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
Elise BrimbleDepartment of Neurology, Stanford University School of Medicine, Stanford, California.
Russell C DaleFaculty of Medicine and Health, Kids Neuroscience Centre, Brain and Mind Centre, Children's Hospital at Westmead, University of Sydney, Sydney, Australia.
Niklas DarinDepartment of Pediatrics, Institute of Clinical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
François-Guillaume DebrayMetabolic Unit, Department of Medical Genetics, CHU & University of Liège, Gembloux, Belgium.
Valentina De GiorgisChild Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.
Jonas DeneckeUniversity Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Diane DoummarGHUEP, département de neuropédiatrie, Centre de référence neurogénétique mouvement anormaux de l'enfant, Hôpital Armand Trousseau, Paris, France.
Gunilla Drake Af HagelsrumPediatric Neurology, The Queen Silvia Children's Hospital, Goteborg, Sweden.
Despina EleftheriouPaediatric Rheumatology, ARUK Centre for Adolescent Rheumatology, Institute of Child Health, University College London (UCL) Great Ormond Street Hospital, London, United Kingdom.
Margherita EstienneU.O. Neuropsichiatria Infantile, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy.
Elisa FazziUnit of Child Neurology and Psichiatry, ASST Spedali Civili of Brescia, Brescia, Italy.
François FeilletService de Médecine Infantile, Centre de Référence des maladies métaboliques de Nancy, CHU Brabois Enfants, Unité INSERM NGERE U1256, Nancy, France.
Jessica GalliUnit of Child Neurology and Psichiatry, ASST Spedali Civili of Brescia, Brescia, Italy.
Nicholas HartogDepartment of Allergy/Immunology, Spectrum Health Helen Devos Children's Hospital, Michigan State University College of Human Medicine, East Lansing, Michigan.
Julie HarvengtDepartment of Medical Genetics, CHU & University of Liège, Gembloux, Belgium.
Bénédicte HeronService de Neuropédiatrie, Centre Référence des Maladies Lysosomales, Hôpital Trousseau, Paris, France.
Delphine HeronUF Génétique Médicale et Centre de Référence "Déficiences Intellectuelles", Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Diedre A KellyThe Liver Unit, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom.
Dorit LevSackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Virginie LevratService de pédiatrie, Centre Hospitalier Annecy Genevois, Pringy, France.
John H LivingstonDepartment of Paediatric Neurology, Leeds General Infirmary, Leeds, United Kingdom.
Itxaso MartiPediatric Neurology, Hospital Universitario Donostia, Universidad del País Vasco UPV-EHU, San Sebastian, Spain.
Cyril MignotDepartement de Génétique & Centre de Référence Déficience Intellectuelle de cause rare, GH Pitié-Sapêtrière, Paris, France.
Fanny MochelInstitut du Cerveau et de la Moelle épinière, INSERM U 1127, Sorbonne Universités, Paris, France.
Marie-Christine NouguesService de Neuropédiatrie, GHUEP, Hôpital Armand Trousseau, APHP, Paris, France.
Ilena OppermannUniversity Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Belén Pérez-DueñasPediatric Neurology Research Group, Hospital Vall d'Hebron-Research Institute (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.
Bernt PoppInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Mathieu P RoderoLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
Diana RodriguezGRC n°19, pathologies Congénitales du Cervelet-LeucoDystrophies, CRMR maladies neurogénétiques, Sorbonne Université, Paris, France.
Veronica SalettiDevelopmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Cia SharpePaediatric Neurology, Starship Children's Hospital, Auckland, New Zealand.
Davide TondutiPediatric Neurology Unit, V. Buzzi Children's Hospital, Milan, Italy.
Gayatri VadlamaniDepartment of Paediatric Neurology, Leeds General Infirmary, Leeds, United Kingdom.
Keith Van HarenDepartment of Neurology, Stanford University School of Medicine, Stanford, California.
Miguel Tomas VilaNeuropediatría, Hospital Universitari i Pôlitecnic La Fe, Valencia, Spain.
Julie VogtWest Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, United Kingdom.
Evangeline WassmerDepartment of Paediatric Neurology, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, United Kingdom.
Arnaud WiedemannService de Médecine Infantile, Centre de Référence des maladies métaboliques de Nancy, CHU Brabois Enfants, Unité INSERM NGERE U1256, Nancy, France.
Callum J WilsonNational Metabolic Service, Starship Children's Hospital, Auckland, New Zealand.
Ayelet ZeremPediatric Neurology Unit, Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.
Christiane ZweierInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.ORCID 0000-0001-8002-2020
Sameer M ZuberiPaediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom.
Simona OrcesiChild Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.
Adeline L VanderverDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Sun HurDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
Yanick J CrowLaboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
Inserm · FRSorbonne Université · FRBirmingham Women’s and Children’s NHS Foundation Trust · GBChildren's Hospital of Philadelphia · USInstitut des Maladies Génétiques Imagine · FRTel Aviv University · ILUniversität Hamburg · DEUniversity of Liège · BEAzienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia · ITBoston Children's Hospital · USDrottning Silvias barn- och ungdomssjukhus · SEFondazione IRCCS Istituto Neurologico Carlo Besta · ITFriedrich-Alexander-Universität Erlangen-Nürnberg · DELeeds General Infirmary · GBManchester Academic Health Science Centre · GBStanford Medicine · USStarship Children's Health · NZCentre Hospitalier Annecy Genevois · FRDélégation Paris 5 · FRDumfries and Galloway Royal Infirmary · GB
Funding
Institutional Clinical and Translational Science AwardKL2TR001879 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI MEAGHER, EMMA ANNE · 2016 to 2025
$13.7MClinical Outcomes in Aicardi Goutières SyndromeU01NS106845 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI VANDERVER, ADELINE LUCIE · 2019 to 2023
$7.5MReverse Transcriptase Inhibitors in Aicardi Goutieres SyndromeU01HD082806 · NICHD · CHILDREN'S RESEARCH INSTITUTE · PI VANDERVER, ADELINE LUCIE · 2015 to 2018
$1.6MDepartment of Health TRF-2016-09-002National Center for Advancing Translational Sciences of the National Institutes of Health KL2TR001879NCATS NIH HHS KL2 TR001879NICHD NIH HHS U01 HD082806NINDS NIH HHS U01 NS106845
Abstract
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Indexed as
Gain of Function MutationGenetic Association StudiesGenotypePhenotypeAllelesAutoimmune Diseases of the Nervous SystemDNA Mutational AnalysisFemaleHigh-Throughput Nucleotide SequencingHumansInterferon-Induced Helicase, IFIH1MaleModels, MolecularNervous System MalformationsProtein ConformationStructure-Activity RelationshipIFIH1 protein, humanInterferon-Induced Helicase, IFIH1Aicardi-Goutières syndromeIFIH1MDA5Singleton Merten syndromeType I interferonopathy
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