Genetic Epilepsy

Gene: IFIH1

Green List (high evidence)

IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified.
Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant.
Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

Created: 6 Sep 2021, 6:04 a.m. | Last Modified: 6 Sep 2021, 6:17 a.m.

Panel Version: 0.9088

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Inflammatory Bowel Disease

Publications

• 34185153

Green List (high evidence)

Gain-of-function variants in this gene cause AGS, some affected individuals experience episodic neurological regression
Sources: Expert Review

Created: 24 Nov 2019, 6:37 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Aicardi-Goutieres syndrome 7, MIM#615846

Publications

• 24686847

Mode of pathogenicity
Other