Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

Rice G, Park S, Gavazzi F, Adang LA, Ayuk LA, Van Eyck L, Seabra L, Barrea C, Battini R, Belot A, Berg S, De Villemeur TB, Bley AE, Blumkin L, Boespflug-Tanguy O, Briggs TA, Brimble E, Dale RC, Darin N, Debray FG, De Giorgis V, Denecke J, Doummar D, Af Hagelsrum GD, Eleftheriou D, Estienne M, Fazzi E, Feillet F, Galli J, Hartog N, Harvengt J, Heron B, Heron D, Kelly DA, Lev D, Levrat V, Livingston JH, Marti I, Mignot C, Mochel F, Nougues MC, Oppermann I, Perez-Duenas B, Popp B, Rodero MP, Rodriguez D, Saletti V, Sharpe C, Tonduti D, Vadlamani G, Van Haren K, Vila MT, Vogt J, Wassmer E, Wiedemann A, Wilson CJ, Zerem A, Zweier C, Zuberi SM, Orcesi S, Vanderver AL, Hur S, Crow YJ (2020)

Publication Type: Journal article

Publication year: 2020


DOI: 10.1002/humu.23975


IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres 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.

Authors with CRIS profile

Involved external institutions

Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Centre Hospitalier Annecy Genevois FR France (FR) Queen Silvia Children’s Hospital SE Sweden (SE) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia IT Italy (IT) University of Pisa / Università di Pisa (UniPi) IT Italy (IT) Harvard University US United States (USA) (US) Wolfson Medical Center IL Israel (IL) Stanford University US United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) Starship Children's Health NZ New Zealand (NZ) Tel Aviv University IL Israel (IL) Michigan State University US United States (USA) (US) Royal Hospital for Children GB United Kingdom (GB) Hôpital Armand-Trousseau (AP-HP) FR France (FR) Centre Hospitalier Universitaire de Nancy / CHU Hôpitaux de Brabois FR France (FR) NHS Dumfries & Galloway GB United Kingdom (GB) University of Sydney (USYD) AU Australia (AU) Children's Hospital of Philadelphia US United States (USA) (US) Foundation of the Carlo Besta Neurological Institute (IRCCS) IT Italy (IT) V. Buzzi Children's Hospital IT Italy (IT) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) Fondazione IRCCS: Istituto Nazionale dei Tumori IT Italy (IT) University of Manchester GB United Kingdom (GB) Fondazione "Istituto Neurologico Nazionale Casimiro Mondino" IT Italy (IT) University of Paris 4 - Paris-Sorbonne / Université paris IV Paris-Sorbonne FR France (FR) Centre Hospitalier Universitaire de Liège (CHU Liège) BE Belgium (BE) University College London (UCL) GB United Kingdom (GB) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) University of Paris 7 - Denis Diderot / Université Paris VII Denis Diderot FR France (FR) University of Liège (ULg) / Université de Liège BE Belgium (BE) University of Gothenburg / Göteborgs universitet SE Sweden (SE) Université Claude Bernard Lyon 1 (UCB) FR France (FR) University of Basque Country / Universidad del Pais Vasco (UPV) / Euskal Herriko Unibersitatea (EHU) ES Spain (ES) Leeds General Infirmary GB United Kingdom (GB) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Hospital Universitario y Politécnico de La Fe ES Spain (ES)

How to cite


Rice, G., Park, S., Gavazzi, F., Adang, L.A., Ayuk, L.A., Van Eyck, L.,... Crow, Y.J. (2020). Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Human Mutation.


Rice, Gillian, et al. "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function." Human Mutation (2020).

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