A number sign (#) is used with this entry because of evidence that immunodeficiency-99 with hypogammaglobulinemia and autoimmune cytopenias (IMD99) is caused by homozygous mutation in the CTNNBL1 gene (611537) on chromosome 20q11. One such patient has been reported.

Immunodeficiency-99 with hypogammaglobulinemia and autoimmune cytopenias (IMD99) is an autosomal recessive immunologic disorder characterized by the onset of recurrent sinopulmonary infections in early childhood. Laboratory studies reveal hypogammaglobulinemia with decreased memory B cells that show impaired class-switch recombination (CSR) and decreased somatic hypermutation (SHM). Due to abnormal antibody production and impaired self-tolerance, patients may develop autoimmune cytopenias, such as thrombocytopenia, or autoimmune features, such as vitiligo. There are also defects in the T-cell compartment (Kuhny et al., 2020).

Kuhny et al. (2020) reported a 15-year-old girl, born of unrelated Colombian parents, with a history of recurrent sinopulmonary infections who presented at 2 years of age with idiopathic thrombocytopenic purpura (ITP). Other features included growth delay and later onset of vitiligo and lymphadenopathy. Laboratory studies showed severe hypogammaglobulinemia, no specific antibody responses, persistent lymphopenia of both B and T cells, and absence of switched memory B cells. Most of the B cells expressed IgM. A lymph node biopsy showed distorted and irregularly shaped follicles, follicular hyperplasia, and expanded germinal centers. This correlated with an increase in peripheral autoimmune/autoreactive B cells subsets. There was also a decreased frequency of regulatory T cells (Tregs) and increased levels of follicular helper-like T cells. T cells showed poor proliferative responses to PHA.

The transmission pattern of IMD99 in the family reported by Kuhny et al. (2020) was consistent with autosomal recessive inheritance.

In a 15-year-old girl with IMD99, Kuhny et al. (2020) identified a homozygous missense mutation in the CTNNBL1 gene (M466V; 611537.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies of patient peripheral blood cells and B cells engineered to carry the M466V mutation using CRISPR/Cas9 technology showed that the mutant protein was expressed, but was less stable compared to wildtype. The mutation significantly decreased the interaction of CTNNBL1 and AICDA (605257), resulting in impaired nuclear import and decreased nuclear localization of AICDA compared to controls. Patient memory B cells showed impaired class-switch recombination (CSR) with most of the B cells expressing IgM. There was also a significant decrease in somatic hypermutation (SHM) in patient cells: the average number of mutations in VH transcripts from patient B cells was 6.7 compared to 18.2 in healthy donors. Similar defects in SHM were observed in cultured B cells transfected with the M466V mutation, and these defects could be rescued by expression of wildtype CTNNBL1. The findings indicated that CTNNBL1 plays an important role in regulating AICDA-dependent antibody diversification in humans.