Submission Details

TTC7A was first reported in relation to autosomal recessive congenital combined immunodeficiency and multiple intestinal atresia (CID-MIA) (PMID: 23423984). TTC7A deficiency is associated with an immunodeficiency primarily characterized by T and B cell lymphopenia, very low immunoglobulin levels and variable numbers of intestinal atresias effecting the small and/or large bowel. The reported severity of immunodeficiency is variable and is likely due to the residual activity of TTC7A protein product. There have also been reports of TTC7A variants associated with very early onset inflammatory bowel disease. Over 52 variants have been reported and are predominantly composed of frameshift indels, nonsense and variants in splice sites resulting in loss of exons. Evidence supporting this gene-disease relationship includes case-level and experimental data. 21 unique variants from 15 probands across 5 publications were curated (PMID:23830146, 25174867, 29174094, 23423984, 24292712). Heterozygous carriers have not been shown to have a clinical phenotype. More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts).

Experimentally, in vitro studies primarily use patient derived cells to support this gene-disease relationship for the immunodeficiency component of CID-MIA. Many of the published studies perform mechanistic analysis on enterocytes and are not reviewed here. Pertaining to the immune phenotype of CID-MIA, the TTC7A protein has been shown to be expressed in thymic tissue and lymphoblasts derived from patients (PMID: 23820146, 25174867). As well, functional data has demonstrated T cell from affected patients show impaired proliferation, cytoskeletal defects and increased activation induced cell death (PMID: 25174867, 25745186, 30455981). Mouse models of TTC7A deficiency replicate decreased thymus size and lymphocytopenia, do not phenocopy atresias seen in humans, and show alterations in iron metabolism not noted in human studies (PMID: 7579418, 16093647). This may imply differences in functionality between mouse and human orthologs. Mechanistically, TTC7A has been implicated in cytoskeletal dynamics, generation of phosphatidylinositol 4-phosphate on the inner plasma membrane, as well as regulator of chromatin structure and nuclear organization. However, there is no consensus as to how TTC7A causes immunodeficiency seen in CID-MIA patients. In summary, TTC7A is strongly associated with CID-MIA. 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 SCID-CID Working Group on 8/19/2021 (SOP Version 8).