#618963
Table of Contents
Alternative titles; symbols
Immunodeficiency-69 (IMD69) is an autosomal recessive disorder characterized by increased susceptibility to disseminated mycobacterial infection, including after BCG (bacille Calmette-Guerin) vaccination. Affected individuals develop fever, hepatosplenomegaly, leukocytosis, and thrombocytosis during the acute infection. There appears to be normal immunologic function against other pathogens, including viruses and bacteria. Immunologic work-up shows normal parameters, but patient T and NK cells fail to produce gamma-interferon (IFNG) when stimulated in vitro (summary by Kerner et al VSports手机版. , 2020). .
IMD69 is a form of mendelian susceptibility to mycobacterial disease (MSMD) (see, e. g. , IMD27A; 209950) V体育安卓版.
Kerner et al. (2020) reported 2 children from a large consanguineous kindred of Lebanese descent who developed disseminated mycobacterial disease following BCG vaccination in early infancy. Clinical features included prolonged fever and hepatosplenomegaly; 1 patient developed a maculopapular rash. Laboratory studies showed leukocytosis, anemia, thrombocytosis, and elevated liver enzymes. One patient was treated with recombinant gamma-interferon. However, she later developed features of hemophagocytic lymphohistiocytosis (HLH) with fever, splenomegaly, pancytopenia, high ferritin (see 134790), and increased triglycerides. Mutations in known HLH genes were excluded, and no infectious agent was identified V体育ios版. She underwent hematopoietic bone marrow transplant at 3 years of age, but died soon thereafter. The second patient, who was a first cousin of the first patient, had a similar early disease course after BCG vaccination and was successfully treated with antimycobacterial medications. Other immunologic parameters in the patients were normal, and antibody testing indicated that both patients had been exposed to bacteria and viruses, including respiratory syncytial virus (RSV), herpes, and opportunistic bacteria, but neither developed significant disease with these organisms. .
The transmission pattern of IMD69 in the family reported by Kerner et al. (2020) was consistent with autosomal recessive inheritance VSports最新版本. .
In 2 patients from a large consanguineous kindred of Lebanese descent with IMD69, Kerner et al. (2020) identified a homozygous frameshift mutation in the IFNG gene (147570. 0005). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed decreased levels of IFNG mRNA compared to controls, suggesting some mRNA decay of the mutant transcript V体育平台登录. The predicted truncated protein, if expressed, would lack the C-terminal domain and likely be nonfunctional. In vitro functional expression studies of patient T cells and cells transfected with the mutation showed impaired IFNG production when stimulated and impaired induction of HLA-DR compared to controls, consistent with a complete loss of IFNG function. These cellular defects could be partially rescued by expression of wildtype IFNG. .
Alternative titles; symbols
ORPHA: 699618; DO: 0112006; MONDO: 0033541;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q15 | ?Immunodeficiency 69, mycobacteriosis | 618963 | Autosomal recessive | 3 | IFNG | 147570 |
A number sign (#) is used with this entry because of evidence that immunodeficiency-69 (IMD69) is caused by homozygous mutation in the IFNG gene (147570) on chromosome 12q15. One such family has been reported V体育2025版.
Immunodeficiency-69 (IMD69) is an autosomal recessive disorder characterized by increased susceptibility to disseminated mycobacterial infection, including after BCG (bacille Calmette-Guerin) vaccination. Affected individuals develop fever, hepatosplenomegaly, leukocytosis, and thrombocytosis during the acute infection. There appears to be normal immunologic function against other pathogens, including viruses and bacteria VSports. Immunologic work-up shows normal parameters, but patient T and NK cells fail to produce gamma-interferon (IFNG) when stimulated in vitro (summary by Kerner et al. , 2020). .
IMD69 is a form of mendelian susceptibility to mycobacterial disease (MSMD) (see, e VSports app下载. g. , IMD27A; 209950).
Kerner et al. (2020) reported 2 children from a large consanguineous kindred of Lebanese descent who developed disseminated mycobacterial disease following BCG vaccination in early infancy. Clinical features included prolonged fever and hepatosplenomegaly; 1 patient developed a maculopapular rash. Laboratory studies showed leukocytosis, anemia, thrombocytosis, and elevated liver enzymes. One patient was treated with recombinant gamma-interferon. However, she later developed features of hemophagocytic lymphohistiocytosis (HLH) with fever, splenomegaly, pancytopenia, high ferritin (see 134790), and increased triglycerides. Mutations in known HLH genes were excluded, and no infectious agent was identified. She underwent hematopoietic bone marrow transplant at 3 years of age, but died soon thereafter. The second patient, who was a first cousin of the first patient, had a similar early disease course after BCG vaccination and was successfully treated with antimycobacterial medications. Other immunologic parameters in the patients were normal, and antibody testing indicated that both patients had been exposed to bacteria and viruses, including respiratory syncytial virus (RSV), herpes, and opportunistic bacteria, but neither developed significant disease with these organisms.
The transmission pattern of IMD69 in the family reported by Kerner et al. (2020) was consistent with autosomal recessive inheritance.
In 2 patients from a large consanguineous kindred of Lebanese descent with IMD69, Kerner et al. (2020) identified a homozygous frameshift mutation in the IFNG gene (147570.0005). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed decreased levels of IFNG mRNA compared to controls, suggesting some mRNA decay of the mutant transcript. The predicted truncated protein, if expressed, would lack the C-terminal domain and likely be nonfunctional. In vitro functional expression studies of patient T cells and cells transfected with the mutation showed impaired IFNG production when stimulated and impaired induction of HLA-DR compared to controls, consistent with a complete loss of IFNG function. These cellular defects could be partially rescued by expression of wildtype IFNG.
Kerner, G., Rosain, J., Guerin, A., Al-Khabaz, A., Oleaga-Quintas, C., Rapaport, F., Massaad, M. J., Ding, J.-Y., Khan, T., Ali, F. A., Rahman, M., Deswarte, C., and 18 others. Inherited human IFN-gamma deficiency underlies mycobacterial disease. J. Clin. Invest. 130: 3158-3171, 2020. [PubMed: 32163377] [Full Text: https://doi.org/10.1172/JCI135460]
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