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

Human Genetics volume 140, pages 1299–1312 (2021)Cite this article

Abstract

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.

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Abbreviations

CD:

Crohn’s disease

IBD:

Inflammatory bowel disease

IFN:

Interferon

LoF:

Loss-of-function

SNVs:

Single nucleotide variants

UC:

Ulcerative colitis

IBDU:

Undetermined inflammatory bowel disease

VEOIBD:

Very early-onset inflammatory bowel disease

WES:

Whole exome sequencing

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Acknowledgements

The authors acknowledge the assistance of Ms. Helen Matthews. We thank the patients and their families for participating in the research study.

Funding

The work was funded by a grant from Fondazione Città della Speranza ONLUS, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Baylor-Hopkins Center for Mendelian Genomics (NHGRI UM1 HG006542).

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Author notes

  1. Mara Cananzi, Elizabeth Wohler, Antonio Marzollo, Nara Lygia de Macena Sobreira, Helen C. Su and Anthony L. Guerrerio have contributed equally to this work.

Authors and Affiliations

  1. Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy

    Mara Cananzi, Paola Gaio, Luca Bosa & Giorgio Perilongo

  2. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA

    Elizabeth Wohler, Jing You, Renan Martin, David Valle & Nara Lygia de Macena Sobreira

  3. Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy

    Antonio Marzollo, Silvia Bresolin, Maria Gabelli & Alessandra Biffi

  4. Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, Italy

    Antonio Marzollo & Silvia Bresolin

  5. Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy

    Davide Colavito, Maurizio Dalle Carbonare & Alberta Leon

  6. Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Huie Jing, Sangeeta Bade, Wesley Tung, Yu Zhang & Helen C. Su

  7. Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University Hospital of Padova, Padova, Italy

    Claudia Mescoli

  8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Jennifer E. Posey & James R. Lupski

  9. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Shalini N. Jhangiani & James R. Lupski

  10. Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil

    Joselito Sobreira Filho

  11. Section of Pediatric Gastroenterology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    Richard Kellermayer

  12. Department of Pediatrics, Division of Pediatric Gastroenterology & Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA

    Howard A. Kader

  13. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Maria Oliva-Hemker & Anthony L. Guerrerio

  14. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    James R. Lupski

  15. Texas Children’s Hospital, Houston, Texas, USA

    James R. Lupski

Authors
  1. Mara Cananzi
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  2. Elizabeth Wohler
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Contributions

MC, AM: wrote the manuscript and prepared the figures, which all authors reviewed. ALG, EW, HCS and NLMS: performed a critical review of the findings and participated in the preparation of the manuscript. MC, AM, PG, LB, MG, ALG: provided clinical care to the patients, collected and reviewed clinical data. CM: reviewed the histological specimens and prepared the figures. DC, MDC, AL: performed the genetic and the bioinformatic analyses for Italian cohort. EW, RM, NLMS, JEP, SNJ, JSF: performed the genetic analysis for the American cohort and the enrichment analysis. SB performed the connectome analysis. HJ, SB, WT, and YZ: planned and performed experiments to assess for variant function, with supervision by HCS, GP, AB, RK, HAK, MOE, JRL and DV: performed a critical review of the findings.

Corresponding authors

Correspondence to Mara Cananzi or Anthony L. Guerrerio.

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Conflict of interests

Baylor College of Medicine and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories, which performs CMA and clinical ES. J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. A.L. has a share in ownership of Research & Innovation (R&I Genetics) Srl. The other authors declare that they have no conflict of interest.

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Cananzi, M., Wohler, E., Marzollo, A. et al. IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease. Hum Genet 140, 1299–1312 (2021). https://doi.org/10.1007/s00439-021-02300-4

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