FCHO1 was first reported in relation to autosomal recessive immunodeficiency 76 in 2019 (Calzoni E, et al., 2019, PMID: 30822429). This primary immunologic disorder is characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. Genetic evidence was included in this curation from 8 probands in two publications (PMID: 30822429, PMID: 32098969). The proposed mechanism of disease is loss of function and the reported variants include missense, splice site, frameshift, and nonsense. There is no in vivo evidence of T-cell dysfunction in healthy carriers. More evidence is available in the literature however, the maximum score for genetic evidence was reached. In patients, the absence of functional FCHO1 results in perturbed clathrin-mediated endocytosis (CME) in several tissues, as well as dysfunctional internalization of transferrin (PMID: 30822429) and the T-cell receptor (PMID: 32098969). Experimentally, this gene-disease relationship is supported by its function as a CME nucleator (PMID: 20448150) and enhanced expression in lymphoid cells (PMID: 30822429), however the relationship between the molecular mechanism of impaired CME and the resulting immunodeficiency requires further elucidation. Functional alteration in patient cells demonstrated defective CME, impaired T-cell proliferation, and increased activation-induced T-cell death, suggesting that defective T-cell proliferation and increased activation-induced cell death, rather than impaired thymic output, are major contributors to the T-cell lymphopenia observed in patients with FCHO1 deficiency (PMID: 30822429) and FCHO1 knockout cells provide evidence that FCHO1 plays a role in TCR-dependent T-cell activation (PMID: 32098969). In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.