Submission Details

The first report indicating a relationship of the ITCH gene with autosomal recessive syndromic multisystem autoimmune disease due to ITCH deficiency was reported by Lohr et al., 2010 (PMID 20170897). This publication featured 10 children from an extended family of Old Order Amish, each presenting with a syndrome characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features, and autoimmune inflammatory cell infiltration of the lungs, liver, and gut. It is estimated that fewer than 1,000 people in the US have this disease (www.rarediseases.info.nih.gov).

Numerous variants have been reported in the ITCH gene, in both ClinVar and in LOVD (https://databases.lovd.nl/shared/genes/ITCH). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship was established in humans 15 years ago, and has ITCH been studied in cell and animal models for over 30 years; therefore, a significant amount of case-level data, segregation data, and experimental data is available. The maximum score for genetic evidence (12 points) has been reached, and 4 points for experimental evidence have been obtained. This curation effort is exhaustive in terms of all known clinical reports of ITCH-related disease, and includes all known experimental evidence regarding ITCH variants known to cause disease in humans.

The mechanism for the gene-disease relationship is protein loss of function, as the ITCH protein product is a member of an E3 ubiquitin ligase that helps degrade other proteins involved in the immune response. A list of the targets of this ubiquitin ligase and their roles in the immune response is provided by Yin et al, 2020 (PMID 32165318). In summary, ITCH is DEFINITIVELY associated with autosomal recessive syndromic multisystem autoimmune disease due to ITCH deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immunodeficiencies Gene Curation Expert Panel on August 19, 2025.

Diabetes Addendum Proposed by MDEP GCEP:

Autosomal recessive variants in the ITCH gene, which encodes an E3 ubiquitin ligase, were first reported in 2010 in association with multisystem autoimmune disease, dysmorphic features, developmental abnormalities, and diabetes in humans (PMID: 20170897). In this study, ten Old Order Amish children were identified with organomegaly, failure to thrive, developmental delay, dysmorphic features, and autoimmune inflammatory infiltration of the lungs, liver, and gut. However, only one subject was diagnosed with type 1 diabetes. The clinical manifestations of multisystem autoimmunity varied: two children had enteropathy, and six developed autoantibodies and one or more organ-specific autoimmune diseases, including autoimmune hepatitis, hypothyroidism and type 1 diabetes.

In 2019, a case described a 1-year-old girl with ITCH deficiency due to a homozygous splice variant c.1693-1G>A, who developed a systemic autoimmune disease including autoimmune type 1 diabetes as part of a multisystem phenotype. The diagnosis was supported by elevated islet-cell antibodies, GAD antibodies, and insulin autoantibodies, confirming an autoimmune mechanism. While Amish patients with ITCH variants had diabetes in only a minority (~10%), this report provided further evidence that biallelic ITCH variants can directly manifest with autoimmune diabetes alongside hepatitis, thyroiditis, and other immune-mediated conditions (PMID: 30705142).

Subsequently, Patel et al. (2021) reported a patient with compound heterozygous ITCH variants who presented with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and developed diabetes at age 14 that was insulin- requiring and autoantibody (GAD65) positive. Although glycemic control improved after hematopoietic cell transplantation (HCT) with temporary discontinuation of insulin, long- acting insulin had to be resumed. Unlike other autoimmune features that resolved post- HCT, the diabetes persisted, reflecting permanent β-cell destruction (PMID: 33894394).

While evidence for a role of ITCH in diabetes as a component of this rare autoimmune disorder is currently limited to three cases, it is prudent for individuals presenting with features of ITCH-related disorders and found to have biallelic pathogenic ITCH variants to undergo antibody testing and glycemic screening to enable early diagnosis and treatment for diabetes. While diabetes does not appear to be an isolated presenting feature in the few cases of ITCH-related multisystem autoimmune disease to date, identification of a biallelic pathogenic or likely pathogenic ITCH variant in an individual presenting with diabetes warrants awareness and screening for other autoimmune features. This amendment was approved by the Monogenic Diabetes GCEP on meeting date September 24, 2025.