Common Variable Immunodeficiency
Common Variable Immunodeficiency
CVID encompasses the largest group of symptomatic primary immunodeficiencies, with an estimated incidence between 1:10,000 and 1:50,000. There are regional differences in incidence, with CVID being a rare diagnosis among Asians and Afro-Americans. There is no gender predisposition and the age of onset is usually in the second to third decade of life, although a smaller group of patients already manifests CVID in childhood, and, in general, CVID may occur at any age.
In contrast to most other primary immunodeficiencies, more than 90% of documented CVID patients are lacking a definite molecular genetic diagnosis or other causal explanation for their disease. Only 10 to 20% of CVID patients have a positive family history, while most cases occur sporadically. Four out of five 'CVID families' show autosomal dominant inheritance. In some larger pedigrees, individuals with selective IgA deficiency (sIgAD), CVID and intermediate forms can be observed side by side. This finding and cases of progression from sIgAD towards CVID indicate a possible common genetic predisposition. Autosomal recessive CVID is rarely seen in Europe and North America but is more frequent in regions and ethnic groups with higher rates of consanguinity.
Genetic linkage analysis of large collections of familial CVID/sIgAD patients or singular large pedigrees with multiple CVID/sIgAD cases revealed possible genetic loci on chromosome 4q, chromosome 6 and chromosome 16q. These early genome-wide microsatellite-marker studies found the strongest association with the HLA region; they were recently confirmed by a genome-wide single nucleotide polymorphism (SNP) genotyping array approach in several hundred CVID patients. This study also revealed several structural chromosomal abnormalities unique to CVID and many novel candidate genes significantly associated with CVID or its clinical complications.
In a minority of patients with CVID, distinct molecular genetic defects have been identified. These genes associated with a CVID phenotype are ICOS (inducible costimulator),TACI (transmembrane activator and calcium-modulating cyclophilin ligand interactor),CD19,BAFF-R,CD81,CD20,CD21 and LRBA (lipopolysaccharide responsive beige-like anchor protein). These defects are very rare, however, only occurring in single cases or single families and adding up to less than 3% of CVID patients. The exceptions are TACI mutations, which are seen in up to 10% of CVID cases but occur also in 1% of the healthy population, and thus must be regarded as disease modifiers rather than disease-causing gene defects.
The currently known monogenetic defects associated with CVID are summarized in Table 2. These mono-genetic defects affect only very few patients, but do provide important prototypic disease models by indicating weak points in terminal B-cell differentiation.
Epidemiology
CVID encompasses the largest group of symptomatic primary immunodeficiencies, with an estimated incidence between 1:10,000 and 1:50,000. There are regional differences in incidence, with CVID being a rare diagnosis among Asians and Afro-Americans. There is no gender predisposition and the age of onset is usually in the second to third decade of life, although a smaller group of patients already manifests CVID in childhood, and, in general, CVID may occur at any age.
Genetics of Common Variable Immunodeficiency
In contrast to most other primary immunodeficiencies, more than 90% of documented CVID patients are lacking a definite molecular genetic diagnosis or other causal explanation for their disease. Only 10 to 20% of CVID patients have a positive family history, while most cases occur sporadically. Four out of five 'CVID families' show autosomal dominant inheritance. In some larger pedigrees, individuals with selective IgA deficiency (sIgAD), CVID and intermediate forms can be observed side by side. This finding and cases of progression from sIgAD towards CVID indicate a possible common genetic predisposition. Autosomal recessive CVID is rarely seen in Europe and North America but is more frequent in regions and ethnic groups with higher rates of consanguinity.
Genetic linkage analysis of large collections of familial CVID/sIgAD patients or singular large pedigrees with multiple CVID/sIgAD cases revealed possible genetic loci on chromosome 4q, chromosome 6 and chromosome 16q. These early genome-wide microsatellite-marker studies found the strongest association with the HLA region; they were recently confirmed by a genome-wide single nucleotide polymorphism (SNP) genotyping array approach in several hundred CVID patients. This study also revealed several structural chromosomal abnormalities unique to CVID and many novel candidate genes significantly associated with CVID or its clinical complications.
In a minority of patients with CVID, distinct molecular genetic defects have been identified. These genes associated with a CVID phenotype are ICOS (inducible costimulator),TACI (transmembrane activator and calcium-modulating cyclophilin ligand interactor),CD19,BAFF-R,CD81,CD20,CD21 and LRBA (lipopolysaccharide responsive beige-like anchor protein). These defects are very rare, however, only occurring in single cases or single families and adding up to less than 3% of CVID patients. The exceptions are TACI mutations, which are seen in up to 10% of CVID cases but occur also in 1% of the healthy population, and thus must be regarded as disease modifiers rather than disease-causing gene defects.
The currently known monogenetic defects associated with CVID are summarized in Table 2. These mono-genetic defects affect only very few patients, but do provide important prototypic disease models by indicating weak points in terminal B-cell differentiation.
Source...