The Invitae Common Variable Immunodeficiency Panel analyzes up to 32 genes that are associated with common variable immunodeficiency (CVID). Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12
DCLRE1C GATA2 JAK3 RAG1 RAG2 STXBP2
Recently, studies in the literature have reported patients that have been originally diagnosed with CVID, which later turned out to be different primary immunodeficiencies (PMID: 24726394, 25516070, 24996264, 26182690, 26476407, 27379089). Given that patients with these disorders may present with a CVID like phenotype, these genes can be included at no additional charge.
BLNK BTK CD79A CD79B GATA2 IGLL1 MOGS SH2D1A TRNT1 XIAP
Patients with agammaglobulinemia or hypogammaglobulinemia can have immunoglobulin levels that look similar to CVID. Given the clinical overlap between patients with agammaglobulinemia or hypogammaglobulinemia and CVID, analyzing these genes may be appropriate. These genes can be included at no additional charge.
CD27 CR2 CTLA4 ICOS IL21 IL21R LRBA NFKB2 PIK3CD PIK3R1 PLCG2 PRKCD RAC2 STAT3 TNFRSF13B TNFRSF13C TNFSF12
Recently, studies in the literature have reported patients that have been originally diagnosed with CVID, which later turned out to be different primary immunodeficiencies (PMID: 24726394, 25516070, 24996264, 26182690, 26476407, 27379089). Given that patients with these disorders may present with a CVID like phenotype, these genes can be included at no additional charge.
DCLRE1C GATA2 JAK3 RAG1 RAG2 STXBP2
Patients with agammaglobulinemia or hypogammaglobulinemia can have immunoglobulin levels that look similar to CVID. Given the clinical overlap between patients with agammaglobulinemia or hypogammaglobulinemia and CVID, analyzing these genes may be appropriate. These genes can be included at no additional charge.
BLNK BTK CD79A CD79B GATA2 IGLL1 MOGS SH2D1A TRNT1 XIAP
For a broader analysis of the genetics of primary immunodeficiencies:
Gene | Disorder | Protein name | Protein symbol |
CD27 | CD27 deficiency | CD27 antigen | CD27 |
CR2 | CD21 deficiency | CD21 | CD21 |
CTLA4 | CTLA4 deficiency (ALPSV) | Cytotoxic T Lymphocyte antigen 4 | CTLA4 |
ICOS | ICOS deficiency | inducible T-cell costimulator | ICOS |
IL21 | IL-21 deficiency | IL-21 deficiency | IL-21 |
IL21R | IL-21R deficiency | interleukin-21 receptor | IL-21R |
LRBA | LRBA deficiency | lipopolysaccharide responsive beige-like anchor protein | LRBA |
NFKB2 | NFKB2 deficiency | NF-kappa-B, subunit 2 | NFKB2 |
PIK3CD | Activated PI3K-δ | p110-delta protein | p110-delta |
PIK3R1 | PI3KR1 deficiency, PI3KR1 loss of function | p85-alpha protein | p85-alpha |
PLCG2 | PLAID (PLCγ2 associated antibody deficiency and immune dysregulation), Familial cold autoinflammatory syndrome 3, APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation) | phospholipase C gamma 2 | PLCG2 |
PRKCD | PRKC delta deficiency | protein kinase C delta | PRKCD |
RAC2 | Rac 2 deficiency | rho family small GTP-binding protein RAC2 | RAC2 |
STAT3 | AD-HIES (Job or Buckley Syndrome), STAT3 GOF mutations | signal transducer and activator of transcription 3 | STAT3 |
TNFRSF13B | TACI deficiency | transmembrane activator and CAML interactor | TACI |
TNFRSF13C | BAFF receptor deficiency | BAFF receptor | BAFFR |
TNFSF12 | TWEAK deficiency | TNF-related weak inducer of apoptosis | TWEAK |
Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiency syndromes. Although the genetic etiology of most CVID is unknown, an estimated 2 -10% of CVID can be attributed to monogenic causes, the identification of which may help guide treatment and management.
CVID is a phenotypically variable disorder even among family members with the same mutation(s). Age of onset can range from early infancy to adulthood, with most cases presenting in childhood to the 3rd decade of life. About 34% will present before 10 years of age. Severity is also variable ranging from severe to asymptomatic. CVID is primarily an antibody deficiency. Patients have a marked decrease in serum IgG in combination with a decrease in serum IgA and/or IgM, which result in poor antibody response to vaccines. Other known causes of hypogammaglobulinemia must be excluded in CVID patients. CVID patients often have increased susceptibility to upper respiratory infections, which over time can lead to chronic lung disease such as bronchiectasis, granulomatous lymphocytic interstitial lung disease, and mediastinal lymphadenopathy. Granulomatous disease affects 8 to 22% of patients and can occur in many organs. 25 to 30% of patients with CVID will develop autoimmunity, most commonly autoimmune cytopenias, which may be the presenting feature. Other autoimmunity can include systemic lupus erythematosus, inflammatory bowel disease, Sjögren syndrome, and others. Enteropathy, hepatopathy, splenomegaly, lymphoid hyperplasia may also be present. Approximately 6 to 9% of patients will develop malignancy, most commonly lymphoma, although many other cancer types have been reported at an increased frequency in patients compared to the general population.
The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. An estimated 2 – 10% of CVID is due to monogenic causes. Patients with an earlier age of onset, positive family history, and consanguinity are more likely to have a monogenic cause. This test covers many of the known genetic causes of monogenic CVID. A minimum of 89% of individuals with monogenic CVID are expected to have a pathogenic variant identified in one of the genes on this panel, although exact estimates are unknown.
Gene | Gene attribution % |
---|---|
CD27 | 4.81% |
CR2 | 1.07% |
CTLA4 | 6.42% |
ICOS | 3.74% |
IL21 | 0.53% |
IL21R | 3.21% |
LRBA | 26.74% |
NFKB2 | 5.35% |
PIK3CD | 26.74% |
PIK3R1 | 4.81% |
PLCG2 | 2.14% |
PRKCD | 2.14% |
RAC2 | 0.53% |
STAT3 | unknown |
TNFRSF13B | unknown |
TNFRSF13C | unknown |
TNFSF12 | 0.53% |
Gene | Inheritance |
---|---|
CD27 | Autosomal recessive |
CR2 | Autosomal recessive |
CTLA4 | Autosomal dominant |
ICOS | Autosomal recessive |
IL21 | Autosomal recessive |
IL21R | Autosomal recessive |
LRBA | Autosomal recessive |
NFKB2 | Autosomal dominant |
PIK3CD | Autosomal dominant |
PIK3R1 | Autosomal dominant |
PLCG2 | Autosomal dominant |
PRKCD | Autosomal recessive |
RAC2 | Autosomal recessive |
STAT3 | Autosomal dominant; autosomal recessive for Hyper IgE syndrome |
TNFRSF13B | Autosomal recessive and autosomal dominant |
TNFRSF13C | Autosomal recessive and autosomal dominant |
TNFSF12 | Autosomal dominant |
The prevalence of CVID is estimated at 1 in 10,000 to 1 in 50,000.
For considerations for testing please refer to:
For management guidelines please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
---|---|---|---|
BLNK | NM_013314.3 | ||
BTK | NM_000061.2 | ||
CD27 | NM_001242.4 | ||
CD79A | NM_001783.3 | ||
CD79B | NM_000626.3 | ||
CR2 | NM_001006658.2 | ||
CTLA4 | NM_005214.4 | ||
DCLRE1C | NM_001033855.2 | ||
GATA2 | NM_032638.4 | ||
ICOS | NM_012092.3 | ||
IGLL1 | NM_020070.3 | ||
IL21 | NM_021803.3 | ||
IL21R | NM_021798.3 | ||
JAK3 | NM_000215.3 | ||
LRBA | NM_006726.4 | ||
MOGS | NM_006302.2 | ||
NFKB2 | NM_001077494.3 | ||
PIK3CD | NM_005026.3 | ||
PIK3R1 | NM_181523.2 | ||
PLCG2 | NM_002661.4 | ||
PRKCD | NM_006254.3 | ||
RAC2 | NM_002872.4 | ||
RAG1 | NM_000448.2 | ||
RAG2 | NM_000536.3 | ||
SH2D1A | NM_002351.4 | ||
STAT3 | NM_139276.2 | ||
STXBP2 | NM_006949.3 | ||
TNFRSF13B | NM_012452.2 | ||
TNFRSF13C | NM_052945.3 | ||
TNFSF12 | NM_003809.2 | ||
TRNT1 | NM_182916.2 | ||
XIAP | NM_001167.3 |