Submission Details

CORO1A was first reported in relation to severe combined immunodeficiency, T cell-negative, B cell-positive, NK cell-positive disease in 2008 (Shiow LR et al., 2008, PMID:18836449). CORO1A deficiency is an autosomal recessive disease that is usually diagnosed in the first few months of life and heterozygous individuals with one copy of the gene altered are not affected. It is characterized by recurrent respiratory and ear infections, EBV-induced B cell lymphoproliferation, and in some cases lymphoma, low total T cell numbers and in particular CD4+ naive T cells . Patients also present decreased T-cell proliferation in response to mitogen and T receptor excision circles (defective TCR recombination). The curation of CORO1A related to autosomal recessive severe combined immunodeficiency with MONDO ID 0014168 (T-B+ severe combined immunodeficiency, immunodeficiency 8) includes both case-level and experimental evidence. Six variants (three missense and three frameshift) reported in six probands in seven publications (PMIDs: 23522482, 19097825, 25073507, 18836449, 25666293, 26476480 and 34913575) are included in this curation. Three of these probands also had one copy of a large deletion know as 16p11.2 deletion syndrome that encompasses the CORO1A gene together with other 20 to 30 genes. This deletion has been reported to confer susceptibility to autism spectrum disorders, features which were also reported in these three probands. A score of 7.7 points for genetic evidence has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease association is also supported by animal models, biochemical function and expression assays (PMIDs: 14734608, 27566541, 16902139, 18836449 and 26476480). Phenotypes of mice with CORO1A mutations were consistent with patients’ phenotypes, presenting low numbers of naive CD4+ T cells. Expression studies of Coro1a in mice show strong mRNA expression in thymus, spleen and lymph nodes and weaker or not present in most other tissues (PMID:14734608). Mutation that alters the C-terminal extension domain and deletes the coiled-coil domain was shown to not undergo oligomerization with other mutated or WT CORO1A and T cells from these patients were defective in survival and had decreased thymic output (PMID:26476480). Three mouse models with Ptcd mutation (PMID: 18836449), Coro1a-KO (PMID: 1692139) and Cre-flox-Coro1a downregulation (PMID: 2756641) showed a decrease in the number of CD4+ T cells, in particular naive CD4+ T cells, which is consistent with the patients’ phenotypes. In these models it was observed in mice with mutated or KO Coro1a a reduced migration in response to chemokines and decrease of mature and naive T cell survival. In the Ptcd mouse and KO mouse an accumulation of F-actin was observed as well as strong interaction between the Ptcd protein and the Arp2/3 complex. Arp2/3 complex is involved in the polymerization of side branches of F-actin filaments. By inhibiting the Arp2/3 complex, Coronin-1 protein impedes the branching of F-actin, promoting its bridging with the cell membrane. A score of 5.5 points for experimental evidence has been reached, increasing the total score to 13.2 points. In summary, CORO1A is definitively associated with autosomal recessive severe combined immunodeficiency, T cell-negative, B cell-positive. 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 GCEP on the meeting date May 19, 2022 (SOP Version 8).