Merico et al. (2015) and Sharfe et al. (2015) reported a consanguineous family of Irish descent in which 3 boys had a primary immunodeficiency apparent from earl...
Merico et al. (2015) and Sharfe et al. (2015) reported a consanguineous family of Irish descent in which 3 boys had a primary immunodeficiency apparent from early infancy. All had recurrent upper and lower respiratory infections; 1 had ecthyma gangrenosum and developed a polyarticular arthritis with joint swelling, and another had a urinary tract infection. Immunologic workup showed normal to increased numbers of circulating lymphocytes, with an increased CD4+:CD8+ ratio compared to controls. In vitro studies showed impaired T-cell proliferative responses to multiple antigens, as well as impaired ability to produce specific immunoglobulins, indicating an effect on humoral immunity as well. The findings were consistent with a primary T-cell defect. Total serum immunoglobulin levels were normal, and patients did not show susceptibility to atypical mycobacterial infections. However, the disorder was severe enough to warrant treatment with hematopoietic stem cell transplantation. Sharfe et al. (2015) found that a thymus biopsy from 1 of the patients showed decreased levels of new emigrant T cells from the thymus and decreased T-cell receptor excision circles (TREC), consistent with deficient new T-cell production. Circulating cells from all patients showed low numbers of naive T cells and increased numbers of central memory T cells.
The transmission pattern of IMD53 in the family reported by Merico et al. (2015) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 3 male patients from a consanguineous family of Irish descent with IMD53, Merico et al. (2015) identified a homozygous truncating mutation in the RELB gene (Y397X; 604758.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing, was confirmed by Sanger sequencing, The mutation segregated with the disorder in the family. Patient lymphocytes showed no detectable RELB protein, consistent with a complete loss of function.