*TGFB1 *was first reported in relation to autosomal recessive inflammatory bowel disease, immunodeficiency, and encephalopathy in 2018 (Koltraz et al., PMID:29483653). Evidence of inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE) is predicted to be caused by a homozygous or compound heterozygous mutation in the *TGFB1 *gene.
Three variants (missense) that have been reported in three patients in one publication (PMID:29483653) are included in this curation. Phenotypes varied but severe inflammatory bowel disesase and central nervous system disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy were common features.
While TGFB1 gene polymorphisms have previously been described as potential risk for development of inflammatory bowel disease, this association is controversial and has not been consistently replicated. (PMID 24074435, PMID: 22140658).
The gene-disease relationship is supported by two animal models. (PMIDs: 17481928, 1436033, 29204904). Shull et al. (PMID 1436033) observed that mice deficient in TGF-beta 1 developed a wasting syndrome characterized by a multifocal, mixed multi-organ inflammatory cell response affecting heart, stomach, liver, lung, pancreas, salivary gland and striated muscle. Li et al described mice with T cell-specific deletion of TGFB1 - mice developed severe colitis, with inflammatory infiltrates involving the lung and liver as well.
In summary, there is limited evidence to support the role of TGFB1 in autosomal recessive inflammatory bowel disease, immunodeficiency, and encephalopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date November 19th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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