IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

TitleIFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsCananzi, M, Wohler, E, Marzollo, A, Colavito, D, You, J, Jing, H, Bresolin, S, Gaio, P, Martin, R, Mescoli, C, Bade, S, Posey, JE, Carbonare, MDalle, Tung, W, Jhangiani, SN, Bosa, L, Zhang, Y, Filho, JSobreira, Gabelli, M, Kellermayer, R, Kader, HA, Oliva-Hemker, M, Perilongo, G, Lupski, JR, Biffi, A, Valle, D, Leon, A, Sobreira, NLygia de M, Su, HC, Guerrerio, AL
JournalHum Genet
Date Published2021 Sep
KeywordsChild, Preschool, Female, Humans, Infant, Inflammatory Bowel Diseases, Interferon-Induced Helicase, IFIH1, Italy, Loss of Function Mutation, Male, Whole Genome Sequencing

Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). 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.

Alternate JournalHum Genet
PubMed ID34185153
PubMed Central IDPMC8423350
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
ZIA AI001059 / ImNIH / Intramural NIH HHS / United States

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