Immunodeficiency, Common Variable, 13

A number sign (#) is used with this entry because of evidence that common variable immunodeficiency-13 (CVID13) is caused by heterozygous mutation in the IKZF1 gene (603023) on chromosome 7p12.

Description

Common variable immunodeficiency-13 is an autosomal dominant primary immunodeficiency disorder characterized by recurrent bacterial infections, mainly affecting the respiratory tract, and associated with hypogammaglobulinemia and decreased numbers of B cells. The age at onset of clinical features can range from infancy to adulthood, and some patients may have a mild disorder or even remain clinically asymptomatic (summary by Kuehn et al., 2016).

For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Clinical Features

Goldman et al. (2012) reported a male infant, born prematurely at 33 weeks' gestation, with pancytopenia apparent at birth. During the last week of pregnancy, there was severe polyhydramnios and moderate fetal hydrops. The patient had anemia necessitating transfusions, lymphopenia with decreased granulocytes, and thrombocytopenia. Bone marrow aspiration showed marrow aplasia with absent myelopoiesis. Laboratory studies showed absence of circulating B cells, minimal numbers of NK cells, and an abundance of T lymphocytes. After receiving intravenous Ig, he had decreased IgM. The infant underwent allogeneic bone marrow transplant, but died from complications of the procedure.

Kuehn et al. (2016) reported 29 individuals from 6 unrelated families with CVID13. The probands from the families were first evaluated for immunodeficiency between 3 and 32 years of age after recurrent or severe bacterial infections, often due to Streptococcus pneumoniae. All had hypogammaglobulinemia and decreased numbers of B cells. Additional affected family members were subsequently identified: most had recurrent infections associated with hypogammaglobulinemia, although some were clinically unaffected. None had evidence of increased susceptibility to fungal or viral infections. Assessment of antibodies to vaccine antigens in 8 patients showed that 6 had absence of antibody formation, 1 had progressive loss of antibodies, and 1 had normal titers. Almost all patients had severely decreased numbers of CD19+ B cells, although memory B cells were present. Several patients had an increase in CD8+ T cells with a reversed CD4:CD8 ratio. Bone marrow aspirates from 2 patients showed a marked decrease in pro-B cells and earlier precursors, suggesting an incomplete block in B-cell differentiation. Two children developed B-cell acute lymphoblastic leukemia.

Inheritance

The transmission pattern of CVID13 in the families reported by Kuehn et al. (2016) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In an infant with severe CVID13 manifest as pancytopenia, Goldman et al. (2012) identified a de novo heterozygous missense mutation in the IKZF1 gene (C210Y; 603023.0001). The mutation was found by targeted sequencing of the IKZF1 gene because of the phenotypic similarities of the patient compared to that of the Ikzf1-null mouse (see ANIMAL MODEL). In vitro functional expression studies showed that the mutant protein had decreased DNA-binding affinity to pericentromeric heterochromatin compared to wildtype, consistent with a loss of function.

In affected members of 4 unrelated families with CVID13, Kuehn et al. (2016) identified 4 different heterozygous missense mutations in the IKZF1 gene (603023.0002-603023.0005). Affected individuals in a fifth family with the disorder had a heterozygous intragenic deletion affecting the IKZF1 gene (603023.0006), and affected individuals in a sixth family had a heterozygous larger deletion of chromosome 7 involving 11 genes, including IKZF1. In vitro functional expression studies of the missense mutations showed that all the mutant proteins had abnormal and diffuse localization of mutant IKZF1 within the nucleus, indicating that they did not properly localize to pericentromeric heterochromatin, suggesting functional impairment. Although the missense mutant proteins were able to dimerize with the wildtype protein, there was no evidence for a dominant-negative effect, suggesting haploinsufficiency as the mechanism of pathogenesis.

Animal Model

Mice homozygous for a germline mutation in the Ikaros DNA-binding domain lack not only T and B lymphocytes and natural killer cells, but also their earliest defined progenitors (Georgopoulos et al., 1994). In contrast, the erythroid and myeloid lineages are intact in these mutant mice.