Dominant lung involvement and heterozygous IFIH1 variants

Heterozygous gain-of-function (GoF) variants in IFIH1 are associated with rare autoinflammatory diseases characterized by heightened interferons-stimulated gene (ISG) signatures. These include Aicardi-Goutières syndrome, presenting with slowly progressive spastic paraparesis of the lower limbs, intracerebral calcifications, and neuroinflammation, and Singleton-Merten syndrome, defined by tooth loss, bone demineralization, and vascular calcification.

Do rare IFIH1 GoF variants contribute to an interstitial lung disease phenotype, thereby expanding the spectrum of IFIH1-related disorders?

Among 559 children with interstitial lung disease (chILD) and exome sequencing as part of their diagnostic work-up, 12 rare heterozygous IFIH1 variants were identified. Of these, 10 were missense variants of unknown significance, which were functionally assessed in vitro using luciferase assay and ISG-expression profiling. Genome-wide RNA analysis was performed on available patient samples to explore broader transcriptional effects.

Four variants with increased basal IFNβ transcription in vitro and elevated ISG expression in vivo indicating GoF behaviour were identified. Disease severity correlated with GoF potential of the respective variant. Two patients harbouring IFIH1 variants with strong GoF activity displayed multisystem involvement and died from respiratory failure at 3 and 4 months of age, respectively. Two additional patients showed milder phenotypes with chronic lung disease stabilizing by the age of 8 and 10 years, respectively. Lung biopsies showed alveolar hypoplasia and alveolar macrophage pneumonia (=desquamative interstitial pneumonia) of varying severity.

We report a dominant interstitial lung disease phenotype in individuals harbouring novel IFIH1 variants, expanding IFIH1-related disease to the group of type I interferonopathies with pulmonary manifestations like STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome.