A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

Regeneron Genetics Center

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. Methods: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. Results: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient’s cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient’s innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. Conclusions: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

Original languageEnglish
Pages (from-to)430-439
Number of pages10
JournalJournal of Clinical Immunology
Volume39
Issue number4
DOIs
StatePublished - 15 May 2019

Funding

FundersFunder number
D.S.S.
National Institutes of HealthAI50950, DK034854, HL59561
Leona M. and Harry B. Helmsley Charitable Trust
Israel Science Foundation

    Keywords

    • CARMIL2
    • RLTPR
    • immunodeficiency
    • infantile colitis
    • very early onset inflammatory bowel disease

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