Web: | mayocliniclabs.com |
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Email: | mcl@mayo.edu |
Telephone: | 800-533-1710 |
International: | +1 855-379-3115 |
Values are valid only on day of printing. |
Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of primary B-cell deficiencies and related disorders
Patients with B cell immunodeficiency disorders who may have other clinical presentations, besides the humoral immune defect, such as inflammatory bowel disease, autoimmunity, or other as indicated above
Establishing a diagnosis of a B-cell deficiency or related disorder, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved
Identifying variants within genes known to be associated with increased risk for disease features allowing for predictive testing of at-risk family members
This test includes next-generation sequencing and supplemental Sanger sequencing to test for variants in the AICDA, BLNK, BTK, CD79A, CD79B (B29), CARD11, CD19, CD27, CD40, CD40LG, CD81, CR2 (CD21), CXCR4, GATA2, ICOS, IGHM, IGLL1 (Lambda5), IKZF1 (IKAROS), LRBA, LRRC8A, MALT1, MS4A1 (CD20), NFKB2, PIK3R1, PIK3CD, PLCG2, PRKCD, RNF168, SH2D1A, TCF3 (E47), TNFRSF13B (TACI), TNFRSF13C, TNFSF12 (TWEAK), and UNG genes.
Identification of a pathogenic variant may assist with prognosis, clinical management, familial screening, and genetic counseling.
The PMS2 gene will be performed on whole blood or DNA submitted samples only at an additional charge via Sanger Sequencing and MLPA when clinical history of defective immunoglobulin class switching is provided.
Due to lower concentration of DNA yielded from alternate specimen sources, _PMS2 cannot be performed on any sample type other than whole blood or DNA extracted from whole blood.
For skin biopsy or cultured fibroblast specimens, fibroblast culture and cryopreservation testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Primary B-cell disorders/humoral immunodeficiencies are characterized by an insufficient number of B-cells or impaired functioning/differentiation of B-cells. B-cell disorders account for approximately two-thirds of all genetic primary immunodeficiency disorders (PIDD) and may result in decrease or dysfunction of one or more isotypes of immunoglobulin, leading to increased susceptibility to infection, particularly bacterial infections such as sinopulmonary infections, gastrointestinal infections, otitis, skin infections, and conjunctivitis. In the absence of infection, patients may be asymptomatic and, thus, difficult to diagnose. In addition, primary B-cell disorders may result in lymphoproliferative disorders or be associated with autoimmune (AI) manifestations, including AI cytopenias, AI endocrine disorders, and AI enteropathy among others.
There are several PIDD that also have an associated T-cell and/or other cellular immunodeficiency, in addition to the B-cell defects.
In some disorders with agammaglobulinemia or hypogammaglobulinemia, patients may have reduced numbers of B-cells, resulting in a severe reduction in all antibody isotypes. Often, they present in the first few years of life with recurrent bacterial infections, a severe life-threatening bacterial infection (ie, meningitis, sepsis), and decreased lymphoid tissue (ie, small adenoids, tonsils, and lymph nodes in X-linked agammaglobulinemia, due to Bruton tyrosine kinase [BTK] gene mutations). Inheritance can be either X-linked (eg, due to variants in BTK), or autosomal recessive (eg, IGHM, CD79A, CD79B, IGLL1, BLNK, LRRC8A, and PIK3R1). B-cell lymphopenia with hypogammaglobulinemia can also be observed in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), which results from pathogenic gain-of-function variants in the CXCR4 gene. These patients also have severe peripheral neutropenia (ANC <500) with evidence of myelokathexis (neutrophil retention) in the bone marrow. In addition to recurrent infections (sinopulmonary, urinary tract, omphalitis, deep soft tissue abscesses, skin), patients are also susceptible to warts and condyloma acuminata due to human papillomavirus (HPV) infection.
Common variable immunodeficiency (CVID) is the most common adult humoral immunodeficiency disorder with an incidence of approximately 1:25,000 to 1:50,000. CVID may present with frequent and unusual infections during early childhood, adolescence, or adulthood. As per current diagnostic criteria, CVID is not considered in children younger than 4 years of age. In addition, a significant proportion of patients may have autoimmune or inflammatory manifestations, enlarged lymphoid tissues, granulomas, and an increased susceptibility to cancer. These patients typically have normal numbers of B-cells (<5% of CVID patients have less than 1% of B cells, which are considered to be due to early B cell defects), but have impaired terminal differentiation, resulting in decreased levels of IgG and IgA, with or without a decrease in IgM. Over two-thirds of patients have quantitative defects in switched memory B-cells. Some patients may also have quantitative and functional T-cell defects or NK cell deficiency. Patients with decreased naive T-cell numbers are considered to have late-onset combined immunodeficiency (LOCID). Genetic variants have been identified in several genes, including ICOS, TNFRSF13B (TACI), CD19, TNFRSF13C (BAFFR), MS4A1 (CD20), CR2 (CD21), CD81, LRBA, NFKB2, IKZF1 (IKAROS), among others, in a subset of CVID patients. However, the majority of these patients have unknown genetic defects and may have oligogenic or polygenic causes of disease.
Dysgammaglobulinemias including hyper-IgM syndrome and selective antibody deficiencies may also occur where a patient is either lacking a specific immunoglobulin isotype (eg, selective IgA deficiency) or a specific vaccine antibody response (impaired pneumococcal polysaccharide responsiveness) or may have an elevated/normal IgM level. Selective deficiencies (ie, IgA deficiency, IgG deficiency) may be due to variants in genes encoding immunoglobulin heavy or light chains. Selective IgA deficiency (sIgAD) is the most common PIDD with an incidence of 1:200 to 1:1000, depending on the cohort studied. Most patients with sIgAD are asymptomatic though some may have frequent infections. There is also a higher incidence of celiac disease in this group. Most patients with selective antibody deficiencies are treated if they have frequent infections in addition to impaired vaccine antibody responses. Some patients with sIgAD may have autoantibodies to IgA. Hyper IgM syndrome (mostly commonly due to variants in CD40LG but also due to other genes, eg, CD40, AICDA, PI3KCD, UNG) is characterized by an inability to switch from the production of IgM-type antibodies to IgG, IgA, or IgE isotypes. These individuals typically have a normal number of B-cells. Patients with CD40L and CD40 deficiency tend to present with severe opportunistic infections more reminiscent of a cellular immunodeficiency and, therefore, may also be considered as combined immunodeficiencies.
Primary B-cell disorders may also result in lymphoproliferative diseases characterized by dysgammaglobulinemia/hypogammaglobulinemia, persistent or severe complications of Epstein-Barr virus (including hemophagocytic lymphohistiocytosis), and lymphoproliferative disorders (including malignant lymphomas). Lymphomas that are associated with these disorders are typically high-grade B-cell lymphomas, non-Hodgkin type, extranodal, and often involve the intestine. Inflammatory bowel disease has also been associated with some forms. Inheritance of these lymphoproliferative diseases can be X-linked or autosomal recessive. For example, X-linked lymphoproliferative disease (XLP) is due to pathogenic variants in SH2D1A (XLP-1), while autosomal recessive lymphoproliferative syndrome 2 is caused by pathogenic variants in TNFRSF7, which encodes CD27. Some of these lymphoproliferative disorders clinically manifest following infection, especially with Epstein-Barr virus (EBV).
Post-meiotic segregation disorder, due to pathogenic variants in PMS2, leads to defective class switching from IgM and results in low serum IgG and IgA with elevated IgM. Patients also often demonstrate cafe-au-lait macules and are predisposed to several types of malignancy due to Lynch syndrome. PMS2 testing will be performed only for patients who demonstrate defective class switching.
Table 1. Genes included in the B-cell Deficiency/Agammaglobulinemia/Lymphoproliferative Primary Immunodeficiency Gene Panel
GENE SYMBOL (ALIAS) | PROTEIN | OMIM | INCIDENCE | INHERITANCE | PHENOTYPE DISORDER |
AICDA | Single-stranded DNA cytosine deaminase | 605257 | Unknown | AR | Immunodeficiency with hyper IgM, type 2 |
BLNK | B-cell linker protein isoform 1 | 604515 | Unknown | AR | Agammaglobulinemia |
BTK | Tyrosine-protein kinase BTK isoform 1 | 300300 | 1-9/million | XL | X-linked agammaglobulinemia |
CD79A | B-cell antigen receptor complex-associated protein alpha chain isoform 1 precursor | 112205 | Unknown | AR | Agammaglobulinemia |
CD79B (B29) | B-cell antigen receptor complex-associated protein beta chain isoform 1 precursor | 147245 | Unknown | AR | Agammaglobulinemia |
CARD11 | Caspase recruitment domain-containing protein 11 | 607210 | AR/AD | Immunodeficiency 11 (AR), B-cell expansion with NFKB and T-cell anergy (AD) | |
CD19 | B-lymphocyte antigen CD19 isoform 2 precursor | 107265 | Unknown | AR | Common variable immunodeficiency (CVID) 3 |
CD27 (TNFRSF7) | CD27 antigen precursor | 186711 | AR | Lymphoproliferative syndrome 2 (CD27 deficiency) | |
CD40 | Tumor necrosis factor receptor superfamily member 5 isoform 1 precursor | 109535 | Unknown | AR | Immunodeficiency with hyper IgM |
CD40LG | CD40 ligand | 300386 | 2/million males | XL | Immunodeficiency with X-linked hyper IgM |
CD81 | CD81 antigen isoform 1 | 186845 | Unknown | AR | Common variable immunodeficiency (CVID) 6 |
CR2 (CD21) | Complement receptor type 2 isoform 1 precursor | 120650 | Unknown | AR | Common variable immunodeficiency (CVID) 7 |
CXCR4 | C-X-C chemokine receptor type 4 isoform b | 162643 | AD | Myelokathexis, isolated, WHIM syndrome (AD) | |
GATA2 | Endothelial transcription factor GATA-2 isoform 1 | 137295 | AD | Immunodeficiency 21, Emberger syndrome, susceptibility to acute myeloid Leukemia and myelodysplastic syndrome | |
ICOS | Inducible T-cell costimulator precursor | 604558 | Unknown | AR | Common variable immunodeficiency (CVID) 1 |
IGHM | IMMUNOGLOBULIN HEAVY CHAIN CONSTANT REGION MU | 147020 | Unknown | AR | Agammaglobulinemia 1 |
IGLL1 (LAMBDA-5) | Immunoglobulin lambda-like polypeptide 1 isoform a precursor | 146770 | Unknown | AR | Agammaglobulinemia |
IKZF1 (IKAROS) | DNA-binding protein Ikaros isoform 2 | 603023 | AD with incomplete penetrance | Late-onset B-cell PID | |
LRBA | Lipopolysaccharide-responsive and beige-like anchor protein isoform 2 | 606453 | Unknown | AR | Common variable immunodeficiency (CVID) 8 with autoimmunity |
LRRC8A | Volume-regulated anion channel subunit LRRC8A | 608360 | Unknown | AD | Agammaglobulinemia |
MALT1 | Mucosa-associated lymphoid tissue lymphoma translocation protein 1 isoform a | 604860 | AR | Immunodeficiency 12 | |
MS4A1 (CD20) | B-lymphocyte antigen CD20 | 112210 | AR | Common variable immunodeficiency (CVID) 5 | |
NFKB2 | Nuclear factor NF-kappa-B p100 subunit isoform a | 164012 | Unknown | AD | Common variable immunodeficiency (CVID) 10 |
PIK3CD | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform | 602839 | Unknown | AD | Immunodeficiency 14, hyper IgM |
PIK3R1 | Phosphatidylinositol 3-kinase regulatory subunit alpha isoform 1 | 171833 | Unknown | AR | Agammaglobulinemia |
PLCG2 | 1-Phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 | 600220 | Rare | AD | Autoinflammation, antibody deficiency, and immune dysregulation syndrome |
PRKCD | Protein kinase C delta type | 176977 | Unknown | AR | Autoimmune lymphoproliferative syndrome, type III |
RNF168 | E3 ubiquitin-protein ligase RNF168 | 612688 | AR | RIDDLE syndrome | |
SH2D1A | SH2 domain-containing protein 1A isoform 1 | 300490 | 1/million males | XL | X-linked lymphoproliferative syndrome |
TCF3 (E47) | Transcription factor E2-alpha isoform E12 | 147141 | AD | Agammaglobulinemia 8 | |
TNFRSF13B (TACI) | Tumor necrosis factor receptor superfamily member 13B | 604907 | Unknown | AD or AR | Common variable immunodeficiency (CVID) 2, immunoglobulin A deficiency |
TNFRSF13C | Tumor necrosis factor receptor superfamily member 13C | 606269 | Unknown | AD or AR | Common variable immunodeficiency (CVID) 4 |
TNFSF12 (TWEAK) | Tumor necrosis factor ligand superfamily member 12 proprotein | 602695 | AD | Low IgM and IgA | |
UNG | Uracil-DNA glycosylase isoform UNG2 | 191525 | Unknown | AR | Immunodeficiency with hyper IgM syndrome, type 5 |
XL=X-linked
An interpretive report will be provided.
Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.
Clinical Correlations:
Some individuals who have involvement of one or more of the genes on the panel may have a variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of primary B-cell deficiency or a related disorder. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
For predictive testing of asymptomatic individuals, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual allows for more informative testing of at-risk individuals.
Technical Limitations:
Next-generation sequencing may not detect all types of genetic variants. The variant detection software has lower detection efficiency for insertion/deletion variants as compared to single nucleotide variants. Therefore, small deletions and insertions greater than 8 nucleotides in length may not be detected by this test. Copy number variations (CNV) are not currently reported for any of the genes on this panel. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. In some cases, DNA variants of undetermined significance may be identified. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. If the patient has had an allogeneic blood or bone marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Reclassification of Variants-Policy:
At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time. Consultation with a healthcare provider, or team of healthcare providers, with expertise in genetics and primary immunodeficiencies, is recommended for interpretation of this result.
A list of benign and likely benign variants detected is available from the lab upon request.
Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of results.
1. Picard C, Gaspar HB, Al-Herz W, Bousfina A, et al: International Union of Immunological Societies: 2017 Primary Immunodeficiency Disease Committee Report on Inborn Errors of Immunity, J Clin Immunol 2018;38:96-128
2. Conley ME, Dobbs AK, Farmer DM, et al: Primary B cell immunodeficiencies: Comparisons and contrasts. Ann Rev Immunol 2009;27:199-277
3. Park MA, Li JT, Hagan JB, et al: Common Variable Immunodeficiency: a new look at an old disease. Lancet 2008;372:489-502
4. Ameratunga R, Brewerton M, Slade C, et al: Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front Immunol 2014;415(5):1-9
5. Schaffer AA, Salzer U, Hammarstrom L, et al: Deconstructing common variable immunodeficiency by genetic analysis. Curr Opin. Genetics and Dev 2007;7:201-212
6. Conley ME: Early defects in B cell development. Curr Opin Allergy Clin Immunol 2002;2:517-522
7. Notarangelo LD, Lanzi G, Peron S, et al: Defects of class-switch recombination. J Allergy Clin Immunol 2006;117:855-864
8. Bousfiha AA, Jeddane L, Ailal F, et al: A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol 2013;33:1078-1087