Common Variable Immune Deficiency (CVID) Panel

Common Variable Immune Deficiency (CVID) is the most common primary immune deficiency affecting one in ~25,000 births. CVID is hallmarked by impaired B cell differentiation and antibody production, namely IgG and IgA. CVID is primarily diagnosed via exclusion of other primary immune disorders, however, recurrent bacterial infections after two years of age, poor response of vaccines, decreased IgG and IgA are indicative of CVID (Conley et al. 1999. PubMed ID: 10600329). About half of CVID patients also present with decreased serum IgM. CVID is a heterogeneous disorder affecting multiple organ systems with symptoms ranging from autoimmune disease, chronic lung disease, bronchiectasis, gastrointestinal disease, malabsorption, granulomatous disease, liver disease, and/or lymphoma (Resnick et al. 2012. PubMed ID: 22180439; Conley et al. 2009. PubMed ID: 19302039). Due to the highly variable clinical presentation of CVID, median diagnostic delay is 4.1 years with 20% of patients being diagnosed before 20 years of age. The majority of patients with CVID are diagnosed between the ages of 20-45 years old (Gathmann et al. 2014 PubMed ID: 24582312). Genetic testing is helpful in differential diagnosis from other immundeficiencies including agammaglobulinemia, B-cell and T-cell deficiencies, complement deficiencies, and other primary and secondary immundeficiencies (Conley et al. 2009. PubMed ID: 19302039).

In about 75% of CVID, a molecular diagnosis is not found. This is due to the multifactorial etiology of CVID including both genetic and environmental factors. Autosomal dominant CVIDs occur through pathogenic variants in the TNFRSF13B, IRF2BP2, NFKB1, NFKB2, VAV1 and IKZF1 genes. Autosomal recessive CVIDs occur through pathogenic variants in the ICOS, IL21, CD81, MS4A1, NFKB2, CR2, LRBA, TNFRSF13C, SKIC3/TTC37, or CD19 genes (Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302). About 20% of CVID cases are due to pathogenic variants in the TNFRSF13B gene with ~90% of these cases being sporadic. Two missense variants, c.310T>C (p.Cys104Arg) and c.542C>A (p.Ala181Glu) are most commonly found and represent about 80% of all TNFRSF13B-related CVID cases (Salzer et al. 2009. PubMed ID: 18981294).

Other disorders that have phenotypic overlap with CVID include autoimmune lymphoproliferative syndrome III, Trichohepatoenteric syndrome 1, and congenital disorder of glycosylation type IIb which are all autosomal recessive disorders due to pathogenic variants in the PRKCD, SKIC3 and MOGS genes respectively (Picard et al. 2018. PubMed ID: 29226302).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

In a study of 50 patients with Common Variable Immune Deficiency, a genetic diagnosis was found in 15 cases. Pathogenic variants were identified in the TNFRSF13B (14%), NFKB1 (10%), STAT3 (6%), CTLA4 (4%), PIK3CD (2%), IZKF1 (2%), LRBA (4%), and STXBP2 (2%) genes (Maffucci et al. 2016. PubMed ID: 27379089). Gross deletions in the CD19, ICOS, VAV1, and LRBA genes have been reported in a few cases (Kanegane. 2007. PubMed ID: 17882224; Grimbacher. 2003. PubMed ID: 12577056; Capitani. 2012. PubMed ID: 23058036; Johnson. 2017. PubMed ID: 28473463; Burns. 2012. PubMed ID: 22981790).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).