Heterozygous gain-of-function variants in IFIH1 are associated with desqamative interstital pneumonia

Hintergrund Heterozygous Interferon Induced With Helicase C Domain 1 (IFIH1)-gain of function (GOF) mutations have been described in the context of type I interferonopathies including Aicardi–Goutieres syndrome (AGS) type 7 or Singleton–Merten syndrome (SMS). The gene product of IFIH1, melanoma differentiation associated gene 5 protein (MDA5) serves as a cytosolic sensor of double–stranded RNA and is responsible for inducing type I interferon (IFN) production thereby initiating antiviral response cascades. Despite the shared feature of upregulated type I IFN responses, the phenotypes associated with IFIH1 variants range from a dominant neuroinflammatory phenotype in AGS, vessel, dental, and bone abnormalities in SMS, to spastic paraparesis and systemic lupus erythematosus.

Methoden We identified different private IFIH1 variants within the chILD-EU cohort. A cellular overexpression model was employed to study the potential pathogenicity of the variants. Their capacity to drive IFN production was analyzed using a luciferase assay. Clinical data, lung biopsy results and whole blood RNA sequencing were used to complement experimental data.

Ergebnisse We found four unrelated patients harbouring heterozygous IFIH1-GOF variants leading to increased baseline IFN production in HEK293 cells. Lung biopsies of affected patients showed desquamative interstitial pneumonia as the dominant histological pattern. Heighthened interferon stimulated gene scores in whole blood confirmed the ex vivo results. While two of the four patients succumbed to disease within the the first six month of life, the other two are still alive, suffering from chronic respiratory disease, but not major neurological impairment.

Schlussfolgerung Our data expand the phenotypic spectrum of IFIH1-GOF variants by describing severe lung disease histologically characterized by desquamative interstitial pneumonia. IFIH1-GOF variants are thus to be added to the growing list of IFN-driven ILDs (like SAVI and COPA syndromes).

 

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Publication History

Article published online:
22 February 2024