Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IRF1

Green List (high evidence)

Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases and functional evidence in support of the association of biallelic IRF1 variants to immunodeficiency. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 5 Aug 2025, 12:04 p.m. | Last Modified: 5 Aug 2025, 12:04 p.m.

Panel Version: 8.32

PMID:36736301 (2023) reported two unrelated children that displayed severe forms of Mendelian susceptibility to mycobacterial disease (MMSD) with both BCG infections and M. avium complex disease at a very young age. Two different homozygous nonsense variants in IRF1 gene were identified in these two patients via whole-exome sequencing and confirmed by Sanger sequencing (p.Arg129Ter and p.Gln35Ter). The asymptomatic relatives were heterozygous for the variants.

Immunological profiles from the patients showed low numbers of NK cells, decreased conventional type 1 dendritic cells, decreased innate lymphoid cell precursors, decreased naive CD8+ T cells, and decreased recent thymic emigrant CD4+ T cells compared to controls.

There is also strong functional evidence available from patient cells, which showed IRF1 is essential for IFN-gamma dependent macrophagic immunity to mycobacteria.

This gene has been associated with relevant phenotypes in OMIM (MIM #620668), but not in Gene2Phenotype.

Created: 5 Aug 2025, 11:47 a.m. | Last Modified: 5 Aug 2025, 11:47 a.m.

Panel Version: 8.29

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Immunodeficiency 117, mycobacteriosis, autosomal recessive, OMIM:620668

Publications

• 36736301

Green List (high evidence)

2 unrelated children, each born of consanguineous parents of Latin American and Turkish descent, respectively, who presented in early childhood with recurrent and severe mycobacterial disease, including BCG infections and infections with M. avium complex. Two different homozygous nonsense variants in IRF1 (p.R129X and p.Q35X).
Also supportive functional data
Sources: Literature

Created: 24 Jul 2025, 2:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Immunodeficiency 117, mycobacteriosis, autosomal recessive

Publications

• PMID: 36736301