Autoinflammatory disorders

Gene: ITCH

Green List (high evidence)

Comment on list classification:
There are at least 14 patients from 5 unrelated families with biallelic variants in ITCH. ITCH deficiency may result in multi-systemic immune dysregulation (present in 9/14 reported patients), dysmorphic features (14/14), developmental delay (14/14), relative macrocephaly (13/14), chronic lung disease (13/14), hepatomegaly/splenomegaly (10/14), and hypotonia (8/14). Based on available evidence, ITCH should be rated Green for autoinflammatory disorders.

Created: 13 Oct 2025, 1:25 p.m. | Last Modified: 13 Oct 2025, 1:25 p.m.

Panel Version: 2.29

As reviewed by Nicholas Head, this gene is already Green on the Primary immunodeficiency or monogenic inflammatory bowel disease panel.
ITCH is associated with AR Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 (accessed 10th Oct 2025).

PMID: 36338154 Wolfe et al., 2022
20yo non-consanguineous Caucasian female with novel ITCH variants: c.599dupC; p.(Ser201Ilefs*8) & deletion of exons 24 and 25. Phenotype: dysmorphic facial features, autoimmune disease including polymyositis, enteropathy, arthritis, psoriasis, hepatitis, and respiratory insufficiency; history of multiple hospitalizations for infections. Muscle biopsy showed 57% of expected mitochondrial DNA copy number but no change in the mitochondrial morphology. Demonstrated mitochondrial energy dysfunction in patient-derived ITCH-deficient fibroblasts, including reduced oxygen consumption (OCR) and a decrease in cellular ATP production.

PMID: 33894394 Patel et al., 2022
Male patient compound heterozygous NM_001257137(ITCH): (c.337+2T>C) and (c.772C>T; p.Arg258*). Method: WES. Phenotype: multi-system immune dysregulation presenting with growth failure, very early onset inflammatory bowel disease (VEO-IBD), arthritis, uveitis, psoriasis and type 1 diabetes mellitus. Reported reduced expression of ITCH mRNA and absent ITCH protein. Immune dysregulation was successfully treated with hematopoietic cell transplantation.

PMID: 31091003 Brittain et al, 2019
Report of a 23 yo female with biallelic truncating variants ITCH: paternally inherited c.726del; p.(Leu243SerfsTer63) and maternally inherited c.2125_2128del; p.(Glu710PhefsTer2) - neither variant found in gnomAD v4. No known consanguinity. Method: Trio Exome. Phenotype: marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect.

PMID: 30705142 Kleine-Eggebrecht et al., 2019
1-year-old girl of consanguineous parents with a homozygous mutation in ITCH: c.1570-1G > A. Method: trio WES. Phenotype: dystrophy, short stature, psychomotor retardation, and muscular hypotonia, as well as multisystemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia).

PMID: 20170897 Lohr et al., 2010
Described 10 Amish patients from 8 consanguineous and related families with multisystem autoimmune disease with delayed gross motor and cognitive skills, and facial dysmorphism. 6 of the children had evidence of autoimmune disease, including hypothyroidism in four, autoimmune hepatitis in three, autoimmune enteropathy with chronic diarrhea in two, and one had diabetes. All individuals were homozygous for the variant NM_031483.6(ITCH): c.394dupA p.(Ile132Asnfs) - founder effect.

Functional evidence:
PMID: 18727493 Matesic et al. 2008
itch−/− mice develop an autoimmune-like disease characterized histologically by a mixed infiltrate in nearly every organ system, lymphoproliferation resulting in splenomegaly and lymphadenopathy, and cortical atrophy of the thymus; the KO mice also produce antinuclear antibodies.

Created: 10 Oct 2025, 4:32 p.m. | Last Modified: 13 Oct 2025, 1:25 p.m.

Panel Version: 2.29

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; syndromic multisystem autoimmune disease due to ITCH deficiency, MONDO:0013245

Publications

• 18727493
• 20170897
• 30705142
• 31091003
• 33894394
• 36338154

Green List (high evidence)

Currently listed as a green gene on R15 panel. Causes a autoinflammatory disorder with multisystem involvement.
Sources: Other

Created: 19 Aug 2025, 11:26 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoimmune disease, multisystem, with facial dysmorphism, 613385

Publications

• PMID: 36338154

Variants in this GENE are reported as part of current diagnostic practice