TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: BCLGP    
B-Cell Deficiency Primary Immunodeficiency Disorder Panel (34 genes), Next-Generation Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

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.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

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.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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
familial cold autoinflammatory 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

AD=autosomal dominant AR=autosomal recessive

XL=X-linked

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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

Special Instructions Library of PDFs including pertinent information and forms related to the test