Immunodeficiency, Common Variable, 12
A number sign (#) is used with this entry because of evidence that autosomal dominant common variable immunodeficiency-12 (CVID12) is caused by heterozygous mutation in the NFKB1 gene (164011) on chromosome 4q24.
DescriptionCommon variable immunodeficiency-12 is an autosomal dominant primary immunodeficiency characterized by recurrent infections, mainly respiratory, associated with hypogammaglobulinemia. The disorder shows a highly variable age at onset and highly variable disease severity, even within the same family. Some patients have features of autoimmunity (summary by Fliegauf et al., 2015).
For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Clinical FeaturesNijenhuis et al. (2001) reported a family of Dutch origin in which 6 individuals in 3 generations had common variable immunodeficiency. The age at onset of symptoms was highly variable: 1 patient had onset of recurrent respiratory and gastrointestinal tract infections before the age of 2 years, whereas the others were diagnosed as adults, with symptom onset in the thirties or later. Features included recurrent infections and chronic obstructive pulmonary disease. One patient had recurrent skin lesions and inflammatory bowel disease. All patients had reduced serum immunoglobulins with normal B and T cell counts. Ten additional family members had dysgammaglobulinemia without overt CVID, although some showed mild symptoms of immunodeficiency. Finck et al. (2006) followed up on the family reported by Nijenhuis et al. (2001), noting that some patients had isolated IgA deficiency. Fliegauf et al. (2015) followed up on the family reported by Nijenhuis et al. (2001) and Finck et al. (2006), noting that the revised pedigree included 11 patients with overt CVID and 9 with hypogammaglobulinemia, and reported 2 additional unrelated families with a similar disorder. The phenotype was remarkably variable, ranging from moderate to severe hypogammaglobulinemia and recurrent sinus infections to severe CVID and progressive pulmonary disease. Most patients had onset of symptoms as adults, although a few had onset in childhood. Most patients had recurrent sinopulmonary infections, some had skin and/or nail infections, and many also had features of autoimmunity, including thrombocytopenia, autoimmune hemolytic anemia, and alopecia. One patient developed a lymphoma.
InheritanceThe transmission pattern of CVID12 in the family reported by Nijenhuis et al. (2001) was consistent with autosomal dominant inheritance.
MappingBy genomewide linkage analysis of the family with CVID originally reported by Nijenhuis et al. (2001), Finck et al. (2006) found evidence suggestive of a locus on chromosome 4q (peak multipoint lod score of 3.38 at marker D4S423).
Molecular GeneticsIn affected members of 3 unrelated families with autosomal dominant CVID12, Fliegauf et al. (2015) identified 3 different heterozygous mutations in the NFKB1 gene (164011.0001-164011.0003). The mutations in 2 families were found by whole-exome sequencing; the mutation in the third family was found by targeted sequencing of a cohort of families with CVID. Studies of patient cells and in vitro studies of cells transfected with the mutations showed that all mutations resulted in functional haploinsufficiency of the NFKB1 p50 protein. One of the families had previously been reported by Nijenhuis et al. (2001) and Finck et al. (2006).