Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NOX1

I don't know

Comment on list classification: Although there are over 10 patients reported with inflammatory bowel disease (IBD) and with NOX1 variants, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder and that other genetic modifiers or environmental factors may contribute to disease pathogenesis. Hence, this gene should be rated amber with the current evidence.

Created: 5 Aug 2026, 5:10 p.m. | Last Modified: 5 Aug 2026, 5:10 p.m.

Panel Version: 9.63

PMID:26301257 (2015) reported targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), of which three unrelated patients were identified with two different missense variants in NOX1 (c.988G>A, p.Pro330Ser in one patient; c.967G>A, p.Asp360Asn in two patients). The NOX1 p.Asp360Asn variant is a common polymorphism (rs34688635) and was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. However, p.Pro330Ser is not found in gnomAD v4.1.1.

PMID:29091079 (2018) reported eight male VEOIBD patients with six hemizygous non-synonymous NOX1 variants, identified via either whole-genome or whole-exome sequencing. Loss-of-function was validated in p.Asn122His and p.Thr497Ala, and to a lesser degree in p.Tyr470His, p.Arg287Gln, p.Ile67Met, p.Gln293Arg as well as the previously described p.Pro330Ser, and the common NOX1 SNP p.Asp360Asn (rs34688635) variant. The missense variant p.Asn122His abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 inflammatory bowel disease (IBD) patients of non-Jewish European ancestry did not reveal an association between p.Asp360Asn and IBD. The authors suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier.

PMID:32064493 (2020) reported the identification of a stop-gain variant in NOX1 (c.160C>T, p.Arg54Ter) in two patients from a single family with early-onset IBD. Functional studies demonstrated that loss of NOX1 function causes abrogated ROS activity and is associated with complex alterations of cell migration dynamics, wound healing, and epithelial cytoskeletal function that affect barrier function and repair.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 05 August 2026).

Created: 31 Jul 2026, 12:02 p.m. | Last Modified: 5 Aug 2026, 5:06 p.m.

Panel Version: 9.62

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
inflammatory bowel disease, MONDO:0005265

Publications

• 26301257
• 29091079
• 32064493

Red List (low evidence)

NOX1 is an X-linked gene encoding NADPH Oxidase 1, an enzyme highly expressed in the colonic epithelium. At the apical brush border, NOX1 constitutively generates reactive oxygen species (ROS) into the crypt lumen. This localized ROS production is a critical component of the intestinal epithelial barrier, mediating innate antimicrobial defense and regulating host-microbe interactions at the mucosal interface without playing a role in systemic phagocytic oxidative bursts.

Defects in NOX1 are associated with mucosal immune dysregulation and Very Early-Onset Inflammatory Bowel Disease (VEO-IBD). Hemizygous loss-of-function missense variants (e.g., p.N122H) have been identified in male patients presenting with severe, early-onset ulcerative colitis-like pathology and pancolitis. Functional analyses of patient-derived organoids and ex vivo colonic explants demonstrate that these variants profoundly abrogate epithelial ROS production, leading to impaired host resistance to enteric microbes and subsequent severe intestinal inflammation (Hayes et al., 2015; Schwerd et al., 2018).

Unlike defects in the phagocytic NADPH oxidase (CYBB/NOX2), which cause classical Chronic Granulomatous Disease with systemic susceptibility to infection, NOX1 deficiency specifically impairs the epithelial innate immune compartment. Furthermore, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder, but rather act as a high-impact genetic modifier that drastically lowers the threshold for VEO-IBD when combined with specific microbial or environmental triggers (Schwerd et al., 2018).
Sources: Literature

Created: 17 Jun 2026, 3 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Inflammatory bowel disease; IBD; VEOIBD

Publications

• 32064493
• 26301257
• 29091079