TCN2 was first reported in relation to autosomal recessive transcobalamin II deficiency and megaloblastic anemia in 1971 (Hakami et al., PMID:5096637). This condition is primarly characterized by megaloblastic anemia and often includes phenotypes such as neurologic deficits, neutropenia, pancytopenia, failure to thrive, and recurrent infections. TCN2 deficiency is often accompanied by elevations in methylmalonic acid levels and plasma homocysteine levels. One cohort study from Trakadis YJ, et al. of 30 patients with TCN2 deficiency demonstrated that 17% had agammaglobulinemia, low IgGs, or low T and B cell counts, and 8% had recurrent infections (PMID:24305960). At least 48 variants have been identified in association with TCN2 deficiency (Luo et al., PMID: 36035190). In this curation, 12 variants were scored including frameshift, nonsense, and splice site variants across 10 probands from 9 publications (PMIDs: 32841161, 33685478, 35866322, 36035190, 31666257, 20352340, 24305960, 30185401, 33023511). Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity is loss of function.
This gene-disease association is also supported by the biochemical function of TCN2 (PMID: 7742531).TCN2 is a transport protein that binds vitamin B12 and facilitates its uptake via endocytosis. Phenotypes displayed by patients with TCN2 deficiency are driven by the inability of cells to use vitamin B12. Vitamin B12 and folate are crucial to DNA synthesis. A lack of vitamin B12 causes impaired cell synthesis and manifests with deficits in rapidly dividing cells. It also manifests with elevated methylmalonic acid and homocysteine levels. Phenotypes observed in probands with TCN2 deficiency are in line with deficits consistent with vitamin B12 deficiency including pancytopenia, megaloblastic anemia, and neurologic defects. Additionally, the gene-disease relationship is supported by knock out TCN2 zebrafish (PMID: 34132337). TCN2 (-/-) zebrafish displayed phenotypes such as developmental delay and elevated methylmalonic acid levels consistent with vitamin B12 insufficiency. In summary, there is definitive evidence to support this gene-disease relationship. This classification was approved by the SCID-CID GCEP (SOP version 9).
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