Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function
Ikusi/ Ireki
Data
2020-01Egilea
Rice, Gillian I.
Park, Sehoon
Gavazzi, Francesco
Adang, Laura A.
Ayuk, Loveline A.
Van Eyck, Lien
Seabra, Luis
Barrea, Christophe
Battini, Roberta
Belot, Alexandre
Berg, Stefan
Billette de Villemeur, Thierry
Bley, Annette E.
Blumkin, Lubov
Boespflug‐Tanguy, Odile
Briggs, Tracy A.
Brimble, Elise
Dale, Russell C.
Darin, Niklas
Debray, François Guillaume
De Giorgis, Valentina
Denecke, Jonas
Doummar, Diane
Drake af Hagelsrum, Gunilla
Eleftheriou, Despina
Estienne, Margherita
Fazzi, Elisa
Feillet, François
Galli, Jessica
Hartog, Nicholas
Harvengt, Julie
Heron, Bénédicte
Heron, Delphine
Kelly, Diedre A.
Lev, Dorit
Levrat, Virginie
Livingston, John H.
Martí Carrera, María Itxaso
Mignot, Cyril
Mochel, Fanny
Nougues, Marie Christine
Oppermann, Ilena
Pérez Dueñas, Belén
Popp, Bernt
Rodero, Mathieu P.
Rodríguez, Diana
Saletti, Veronica
Sharpe, Cia
Tonduti, Davide
Vadlamani, Gayatri
Van Haren, Keith
Tomás Vila, Miguel
Vogt, Julie
Wassmer, Evangeline
Wiedemann, Arnaud
Wilson, Callum J.
Zerem, Ayelet
Zweier, Christiane
Zuberi, Sameer M.
Orcesi, Simona
Vanderver, Adeline L.
Hur, Sun
Crow, Yanick J.
Human Mutation 41(4) : 837-849 (2019)
Laburpena
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.