IFIH1 – Aicardi-Goutières Syndrome

Heterozygous gain-of-function variants in IFIH1 (encoding MDA5) have been firmly established as a cause of Aicardi-Goutières syndrome (AGS7), an autosomal dominant early-onset type I interferonopathy characterized by intracranial calcification and progressive encephalopathy. Multiple independent reports since 2014 have identified IFIH1 mutations in AGS cohorts, demonstrating consistent genotype–phenotype correlation and inheritance across diverse populations.

Genetic evidence comprises over 74 affected individuals from 51 families with heterozygous IFIH1 variants, most commonly missense substitutions clustered near the ATP-binding region ([PMID:31898846]). A recurrent variant, c.1114C>T (p.Leu372Phe), has been observed in multiple unrelated probands, further supporting pathogenicity. Segregation analysis across at least 10 multigenerational pedigrees confirms autosomal dominant transmission with variable expressivity ([PMID:25080300]).

Mechanistic studies reveal that IFIH1 gain-of-function mutations induce constitutive MDA5 activation, leading to excessive type I interferon production and upregulation of interferon-stimulated genes in patient-derived cells and in vitro assays ([PMID:24995871]). Mouse models harboring AGS-specific IFIH1 alleles display neuroinflammation and IFN signature in the brain, recapitulating human pathology and demonstrating rescue upon MDA5 ablation.

While most carriers develop classical AGS features—basal ganglia calcification (HP:0002135), spastic paraplegia (HP:0001258), and progressive encephalopathy (HP:0002448)—a subset of adults remains asymptomatic, indicating incomplete penetrance and phenotypic variability ([PMID:31898846]). No credible conflicting evidence disputing the core association has been reported.

Integration of robust genetic segregation, extensive case series, and concordant functional data meets ClinGen criteria for a definitive gene–disease relationship. IFIH1 testing is clinically actionable for diagnosis, family counselling, and potential enrollment in interferon-modulating therapies.

Key Take-home: Autosomal dominant IFIH1 gain-of-function mutations are a definitive cause of AGS7, with high clinical utility for genetic diagnosis and targeted management.

References

• Clinical Genetics • 2014 • Autosomal dominant IFIH1 gain-of-function mutations cause Aicardi-Goutières syndrome PMID:25080300
• American Journal of Human Genetics • 2014 • Aicardi-Goutières syndrome is caused by IFIH1 mutations PMID:24995871
• Human Mutation • 2020 • Genetic and phenotypic spectrum associated with IFIH1 gain-of-function PMID:31898846

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