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

Hum Mutat. 2020 Apr;41(4):837-849. doi: 10.1002/humu.23975. Epub 2020 Jan 14.


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.

Keywords: Aicardi-Goutières syndrome; IFIH1; MDA5; Singleton Merten syndrome; Type I interferonopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Autoimmune Diseases of the Nervous System / diagnosis
  • Autoimmune Diseases of the Nervous System / genetics
  • DNA Mutational Analysis
  • Female
  • Gain of Function Mutation*
  • Genetic Association Studies* / methods
  • Genotype*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Interferon-Induced Helicase, IFIH1 / chemistry
  • Interferon-Induced Helicase, IFIH1 / genetics*
  • Male
  • Models, Molecular
  • Nervous System Malformations / diagnosis
  • Nervous System Malformations / genetics
  • Phenotype*
  • Protein Conformation
  • Structure-Activity Relationship


  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Aicardi-Goutieres syndrome