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.
Highlights
In 2014, heterozygous gain‐of‐function mutations in IFIH1 were reported to cause a spectrum of neuroimmune phenotypes including classical Aicardi–Goutières syndrome (AGS; Oda et al, 2014; Rice et al, 2014)
It was initially considered that Singleton Merten syndrome (SMS) was a distinct, mutation‐specific disorder, subsequent reports indicate that SMS and the neuroinflammatory phenotypes seen in the context of IFIH1 gain‐of‐function constitute part of the same disease spectrum (Buers, Rice, Crow, & Rutsch, 2017; Bursztejn et al, 2015)
We have noted previously that in silico algorithms are not always reliable in differentiating IFIH1 disease‐causing variants from benign polymorphisms (Ruaud et al, 2018). Such difficulty in assigning molecular pathogenicity is compounded by marked variability in disease expression, sometimes even within the same family, and the observation of complete non‐penetrance in certain pedigrees (Rice et al, 2014). We considered it important to provide an update of our experience of sequencing individuals for pathogenic IFIH1 mutations associated with a type I interferonopathy state
Summary
In 2014, heterozygous gain‐of‐function mutations in IFIH1 were reported to cause a spectrum of neuroimmune phenotypes including classical Aicardi–Goutières syndrome (AGS; Oda et al, 2014; Rice et al, 2014). We have noted previously that in silico algorithms are not always reliable in differentiating IFIH1 disease‐causing variants from benign polymorphisms (Ruaud et al, 2018) Such difficulty in assigning molecular pathogenicity is compounded by marked variability in disease expression, sometimes even within the same family, and the observation of complete non‐penetrance in certain pedigrees (Rice et al, 2014). Given this background, we considered it important to provide an update of our experience of sequencing individuals for pathogenic IFIH1 mutations associated with a type I interferonopathy state. Our data confirm variable expression and nonpenetrance as important characteristics of these mutant genotypes, and the consistent association with enhanced type I interferon signaling as assessed by interferon‐stimulated gene (ISG) expression, referred to as the interferon score
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