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Other entities represented in this entry:
SNOMEDCT: 715982006; ORPHA: 275; DO: 0090012;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p13 | Severe combined immunodeficiency, Athabascan type | 602450 | Autosomal recessive | 3 | DCLRE1C | 605988 |
A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+) severe combined immunodeficiency with sensitivity to ionizing radiation (RS-SCID) and Athabaskan-type SCID (SCIDA) are caused by homozygous or compound heterozygous mutation in the gene encoding Artemis (DCLRE1C; 605988).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.
Schwarz et al. (1991) found that a subset of cells from T-, B- SCID patients showed increased radiosensitivity. Nicolas et al. (1998) reported 3 sibs, born of consanguineous parents, and 1 unrelated patient with T-, B- SCID whose cells showed increased sensitivity to ionizing radiation. Functional expression studies in cells derived from these patients showed a defect in the DNA repair machinery necessary for the completion of recombination of the variable (V), diversity (D), joining (J) segments that generate variable types of immunoglobulins and T-cell receptors required for proper immune function. There was a lack of coding joint formation; however, normal signal joint formation suggested that the final ligation step of the broken DNA ends was not affected. Susceptibility to radiation also implicated a defect in the DNA repair machinery. Nicolas et al. (1998) excluded involvement of the RAG1, RAG2, PRKDC (600899), XRCC4 (194363), DNA ligase I (LIG1; 126391), and DNA ligase IV (LIG4; 601837) genes, all of which are involved in the process of V(D)J recombination or DNA repair.
Cavazzana-Calvo et al. (1993) found that cells from 3 patients with autosomal recessive T-, B- SCID had increased radiosensitivity of granulocyte macrophage colony-forming units (GM-CFU) similar to scid mice, whereas cells from controls and a patient with the X-linked SCID phenotype (300400) showed normal radiosensitivity.
Athabaskan-type SCID
Murphy et al. (1980) reported 5 infants with T-, B- SCID from the Navajo and Jicarilla Apache Indians of the U.S. Southwest. All patients presented within the first months of life with oral thrush, diarrhea, fever, pneumonia, and/or failure to thrive. All had lymphopenia and hypogammaglobulinemia, and most had absent tonsils and lymph nodes. No skeletal abnormalities were detected on radiographic examination, and 3 patients tested had normal adenosine deaminase (608958) and purine nucleoside phosphorylase (164050) activity (see also POPULATION GENETICS below). Hu et al. (1988) and Erickson (1999) commented on the high frequency of SCID among Athabascan Indians.
Kwong et al. (1999) evaluated the occurrence of oral and genital ulcerations in 12 Athabascan-speaking American Indians with a diagnosis of SCIDA and 21 non-Athabascan-speaking SCID patients. Ten patients in the SCIDA group developed oral and/or genital ulcers, 7 before bone marrow transplantation (BMT) and 3 after. These ulcers were clinically unrelated to the conditioning regimens for BMT or BMT itself (e.g., graft-vs-host disease). BMT with successful T-cell engraftment, regardless of B-cell recovery, appeared to be curative in the resolution of the ulcers, with recurrences only in patients who had inadequate T-cell reconstitution. Oral and genital ulcerations had not been observed in non-Athabascan-speaking patients and patients of non-American Indian origin, indicating a genetic contribution.
Clinical Variability
Moshous et al. (2003) reported 3 sibs with partial SCID. In all 3, signs of immunodeficiency began in infancy and included candidiasis, diarrhea, recurrent pulmonary infections, lymphopenia, and hypogammaglobulinemia; however, all patients had low levels of polyclonal T and B cells. Two of the patients developed a B-cell lymphoproliferative disease involving lymph nodes, liver, lung, and skeletal muscle. Flow cytometric analysis detected clonal B-cell populations, confirming lymphoma. One of the lymphomas had clonal trisomy 9, a chromosomal alteration. Moshous et al. (2003) also reported an unrelated patient with partial SCID who died at the age of 16 years of liver cirrhosis.
Volk et al. (2015) reported 3 sibs, born of consanguineous Turkish parents, with onset of recurrent respiratory tract infections after the second year of life. Laboratory studies showed low B-cell counts, normal T-cell counts, and reduced IgA; 1 patient also had reduced IgG. The patients were initially diagnosed with an antibody deficiency. Two additional patients from another branch of this family and 7 patients from 4 unrelated consanguineous Turkish families with a similar disorder were also identified. All had decreased numbers of B cells associated with variable antibody deficiencies; most also had mildly decreased numbers of T cells. Whole-exome sequencing identified a homozygous missense mutation in the DCLRE1C gene (T65I; 605988.0014) in the first 3 sibs; this mutation was also found in the 4 unrelated families. The 2 patients from the other branch of the first family were compound heterozygous for T65I and a frameshift mutation (605988.0015). Studies of patient cells showed increased sensitivity to gamma-irradiation. In addition, detailed studies of T-cell subsets showed decreased numbers of circulating naive T cells, increased numbers of terminally differentiated T cells, and reduced proliferation of both CD4+ and CD8+ T cells. These findings were consistent with a diagnosis of SCID, even if subclinical and in the presence of near-normal numbers of circulating T cells. Patient cells showed defective immunoglobulin class-type switching and impaired V(D)J recombination, suggesting that both mutations resulted in hypomorphic alleles. There was wide clinical heterogeneity, even within the same family; respiratory infections were common, but signs of defective T-cell immunity were milder, manifest in some patients as varicella infection and verruca vulgaris. Only 1 patient had significant autoimmune disorders and granulomatous skin infections. Volk et al. (2015) noted the importance of correct diagnosis of SCID in those who present with an apparently isolated antibody deficiency: these patients need to avoid exposure to radiation and to live vaccination; in addition, hematopoietic stem cell transplantation should be considered earlier in these patients.
Cowan et al. (2022) noted that Artemis-deficient SCID is poorly responsive to hematopoietic stem cell transplant since patients have increased sensitivity to alkylating agents typically used as preconditioning for transplant. These authors reported 10 unrelated infants of various ethnic origins with SCID due to biallelic mutations in the DCLRE1C gene who were transfused with autologous CD34+ cells transfected with a lentiviral vector containing wildtype DCLRE1C under control of an endogenous DCLRE1C promoter sequence. Eight patients were free of infection before gene therapy. The median age at infusion of gene-transferred cells was 2.7 months (range 2.3 to 13.3) after pretreatment with low-dose busulfan. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all patients, and 5 of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. T-cell receptor excision circles were detected and their numbers increased in parallel with naive T cells; improvements in TCR diversity were also noted. B cells were detected in all patients at a median of 6 weeks, and 4 patients who were followed for at least 24 months had sufficient B-cell numbers and antibody production. Vector insertion sites showed no evidence of clonal expansion or cancer. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this resolved after reconstitution of T-cell immunity. All 10 patients were alive and healthy after treatment. The findings demonstrated that this treatment protocol resulted in genetically corrected and functional T and B cells in this disease.
By linkage analysis on 14 SCIDA families with 18 affected children, Li et al. (1998) mapped the disease gene to a 6.5-cM interval on chromosome 10p between markers D10S1664 and D10S674 (maximum pairwise lod scores of 4.53 and 4.60, at markers D10S191 and D10S1653, respectively). Multipoint analysis positioned the SCIDA locus between D10S191 and D10S1653, with a peak lod score of 5.10 at D10S191. Strong linkage disequilibrium was found in 5 linked markers spanning the candidate region, suggesting a founder effect with an ancestral mutation that occurred some time before 1300 A.D.
Moshous et al. (2000) performed linkage analysis on several families with RS-SCID, including those reported by Nicolas et al. (1998). The highest lod scores, 8.01 and 7.71, were observed for markers D10S1664 and D10S191, respectively. The authors concluded that the defective genes responsible for RS-SCID and SCIDA were the same.
In 13 patients from 11 families with RS-SCID, Moshous et al. (2001) identified 8 different mutations in the Artemis gene (605988.0001-605988.0008).
Athabaskan-type SCID
Li et al. (2002) identified a founder mutation in exon 8 of the Artemis gene (605988.0009) in 21 Athabaskan-speaking Navajo and Apache Native Americans from the southwestern United States with SCIDA.
Partial SCID
In 3 sibs with partial SCID, Moshous et al. (2003) identified a hypomorphic mutation in the Artemis gene (605988.0010), resulting in a protein with residual activity.
Murphy et al. (1980) reported a high frequency of T-, B- SCID in the Navajo and Jicarilla Apache Indians of the U.S. Southwest, who belong to the Athabascan linguistic group. Based on birth rates and population numbers, the authors estimated the incidence of SCID in this population to be 1 in 3,340. Murphy et al. (1980) postulated a founder effect resulting from population bottlenecks that occurred in the late 1800s and early 1900s after wars with the United States. Jones et al. (1991) estimated the gene frequency of SCID among the Navajo to be 2.1%.
The scid mouse, which shows a similar phenotype to T-, B- SCID, is caused by mutation in the Prkdc gene (600899), which is involved in V(D)J recombination (Bosma et al., 1983; Kirchgessner et al., 1995)
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Li, L., Moshous, D., Zhou, Y., Wang, J., Xie, G., Salido, E., Hu, D., de Villartay, J.-P., Cowan, M. J. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. J. Immun. 168: 6323-6329, 2002. [PubMed: 12055248] [Full Text: https://doi.org/10.4049/jimmunol.168.12.6323]
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