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

Gillian I. Rice, Sehoon Park, Francesco Gavazzi, Laura A. Adang, Loveline A. Ayuk, Lien Van Eyck, Luis Seabra, Christophe Barrea, Roberta Battini, Alexandre Belot, Stefan Berg, Thierry Billette de Villemeur, Annette E. Bley, Lubov Blumkin, Odile Boespflug-Tanguy, Tracy A. Briggs, Elise Brimble, Russell C. Dale, Niklas Darin, François Guillaume DebrayValentina De Giorgis, Jonas Denecke, Diane Doummar, Gunilla Drake af Hagelsrum, Despina Eleftheriou, Margherita Estienne, Elisa Fazzi, François Feillet, Jessica Galli, Nicholas Hartog, Julie Harvengt, Bénédicte Heron, Delphine Heron, Diedre A. Kelly, Dorit Lev, Virginie Levrat, John H. Livingston, Itxaso Marti, Cyril Mignot, Fanny Mochel, Marie Christine Nougues, Ilena Oppermann, Belén Pérez-Dueñas, Bernt Popp, Mathieu P. Rodero, Diana Rodriguez, Veronica Saletti, Cia Sharpe, Davide Tonduti, Gayatri Vadlamani, Keith Van Haren, Miguel Tomas Vila, Julie Vogt, Evangeline Wassmer, Arnaud Wiedemann, Callum J. Wilson, Ayelet Zerem, Christiane Zweier, Sameer M. Zuberi, Simona Orcesi, Adeline L. Vanderver, Sun Hur*, Yanick J. Crow

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)837-849
Number of pages13
JournalHuman Mutation
Issue number4
StatePublished - 1 Apr 2020


  • Aicardi–Goutières syndrome
  • IFIH1
  • MDA5
  • Singleton Merten syndrome
  • Type I interferonopathy


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