*CARMIL2 *(i.e., RLTPR) was first reported in relation to autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency in 2016 (Sorte HS et al., PMID: 27896283). Severe combined immunodeficiency due to CARMIL2 deficiency is a combined immunodeficiency with prominent immune dysregulation. This is a heterogeneous disorder characterized by failure to thrive, recurrent upper and lower respiratory infections, skin abnormalities (note the occurrence of these require infection and/or immune-mediated processes in addition to CARMIL2 defects), eczema, warts, seborrheic dermatitis, allergies, and asthma. Additional features of disease often observed include candidiasis, herpes infection, Molloscum contagiosum infection, early-onset inflammatory bowel disease, chronic diarrhea, and Epstein Barr virus-related smooth muscle tumors. Immunologically, these patients typically display impaired naïve T-cell activation, differentiation, proliferation, and effector function, and defective T-cell memory responses.
More than 50 individuals with autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency have been reported to date (PMID: 34287962). Six variants (missense and frameshift) that have been reported in 7 probands in 3 publications (PMIDs: 27896283, 34287962, 36727012) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 23793062, 27647348, 27647349, 28112205). CARMIL2 has been shown to be expressed in immune organs and T cells (PMID: 23793062, 27647349), function in CD28 signaling, and facilitate scaffold interactions with CD28 and CARD11 downstream of T-cell receptor stimulation (PMID: 27647348, 28112205). Two different mouse models demonstrate T-cell abnormalities when CARMIL2 is either deleted or mutated to impair function (PMID: 23793062, 27647348). T-cell abnormalities in cytokine production, proliferation, and migration have been observed in cells derived from many different patients (PMID: 27647349, 28112205).
In summary, there is definitive evidence supporting the relationship between CARMIL2 and autosomal recessive severe combined immunodeficiency due to CARMIL2 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, 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).
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