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Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function
Author(s) -
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,
BoespflugTanguy Odile,
Briggs Tracy A.,
Brimble Elise,
Dale Russell C.,
Darin Niklas,
Debray FrançoisGuillaume,
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.,
Marti Itxaso,
Mignot Cyril,
Mochel Fanny,
Nougues MarieChristine,
Oppermann Ilena,
PérezDueñas Belén,
Popp Bernt,
Rodero Mathieu P.,
Rodriguez Diana,
Saletti Veronica,
Sharpe Cia,
Tonduti Davide,
Vadlamani Gayatri,
Van Haren Keith,
Tomas 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.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23975
Subject(s) - biology , phenotype , interferon , genotype , mutation , allele , genetics , mutant , in silico , compound heterozygosity , wild type , gene
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.