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Invitae Agammaglobulinemia Panel
Test description
The Invitae Agammaglobulinemia Panel analyzes up to 31 genes that are associated with agammaglobulinemia or hypogammaglobulinemia. Genetic testing of these genes is useful to confirm a diagnosis in patients who are suspected of having agammaglobulinemia or hypogammaglobulinemia from clinical symptoms and laboratory findings. This includes recurrent bacterial infections occurring at an early age, small or absent tonsils and lymph nodes on physical examination and very low levels of immunoglobulins and B cells in serum. Identification of disease-causing variants provide accurate risk assessment and carrier status for at -risk relatives.
Genes tested
Primary panel
BLNK BTK CD79A CD79B IGLL1 PIK3R1
Add-on Hypogammaglobulinemia Genes
GATA2 MOGS SH2D1A TRNT1 XIAP
GATA2 deficiency, MOGS-congenital disorder of glycosylation (CDG-IIb), X-linked lymphoproliferative disorder, and TRNT1 can all cause hypogammaglobulinemia. Given the clinical overlap between patients with agammaglobulinemia and hypogammaglobulinemia, analyzing these genes may be appropriate. These genes can be included at no additional charge.
Add-on Common Variable Immunodeficiency Genes
CD27 CR2 CTLA4 DCLRE1C ICOS IL21 IL21R JAK3 LRBA NFKB2 PIK3CD PLCG2 PRKCD RAC2 RAG1 STAT3 STXBP2 TNFRSF13B TNFRSF13C TNFSF12
Patients with CVID can have immunoglobulin levels that look similar to agammaglobulinemia or hypogammaglobulinemia. 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.
Order test
Primary panel (6 genes)
Customized gene selection (0 included, 0 excluded)
BLNK BTK CD79A CD79B IGLL1 PIK3R1
Add-on Hypogammaglobulinemia Genes (5 genes)
Customized gene selection (0 included, 0 excluded)
GATA2 deficiency, MOGS-congenital disorder of glycosylation (CDG-IIb), X-linked lymphoproliferative disorder, and TRNT1 can all cause hypogammaglobulinemia. Given the clinical overlap between patients with agammaglobulinemia and hypogammaglobulinemia, analyzing these genes may be appropriate. These genes can be included at no additional charge.
GATA2 MOGS SH2D1A TRNT1 XIAP
Add-on Common Variable Immunodeficiency Genes (20 genes)
Customized gene selection (0 included, 0 excluded)
Patients with CVID can have immunoglobulin levels that look similar to agammaglobulinemia or hypogammaglobulinemia. 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 DCLRE1C ICOS IL21 IL21R JAK3 LRBA NFKB2 PIK3CD PLCG2 PRKCD RAC2 RAG1 STAT3 STXBP2 TNFRSF13B TNFRSF13C TNFSF12
Alternative tests to consider
For a broader analysis of genes associated with primary immunodeficiency:
Clinical information
Disorders tested
| Gene | Disorder | Protein name | Protein symbol |
| BLNK | BLNK deficiency | B-cell linker protein | BLNK |
| BTK | BTK deficiency | Bruton agammaglobulinemia tyrosine kinase | BTK |
| CD79A | Igα deficiency | immunoglobulin-associated alpha | Ig-alpha |
| CD79B | Igβ deficiency | immunoglobulin-associated beta | Ig-beta |
| IGLL1 | λ5 deficiency | lambda-5 | IGL5 |
| PIK3R1 | PI3KR1 deficiency, PI3KR1 loss of function | p85-alpha protein | p85-alpha |
Clinical subtypes
Agammaglobulinemia and isolated hormone deficiency
Clinical description
Agammaglobulinemia causes undetectable immunoglobulins (antibodies) while hypogammaglobulinemia causes reduced level of all serum immunoglobulins due to a defect in the production of functional B-lymphocytes.
Patients affected with agammaglobulinemia usually present early onset periodic bacterial infections, most commonly, respiratory tract and gastrointestinal tract infections. These infections can be severe, life-threatening bacterial infections such as sepsis, meningitis, pneumonia, empyema. Although most viral infections run a typical course in patients with agammaglobulinemia, enteroviral infections are typically severe and can be life-threatening.
Onset of symptoms is commonly in the first year of life although adult onset presentations have been reported. Most patients will be diagnosed as immunodeficient within the first 5 years of age. However, in some cases, patients won’t be diagnosed till 10 years old or adulthood. Infections caused by H.influenzae and S.pneoumoniae are one of the most frequent episodes seen prior a diagnosis and symptoms may continue after treatment with immunoglobulin replacement therapy. Affected individuals are also susceptible to infections by giardia and mycoplasma.
Clinical sensitivity
Approximately 90 – 92% of patients with agammaglobulinemia are expected to have a pathogenic variant(s) in one of the genes on this panel.
| Gene | % of agammaglobulinemia cases attributed |
|---|---|
| BLNK | <1% |
| BTK | ~85% |
| CD79A | <1% |
| CD79B | <1% |
| IGLL1 | <1% |
| PIK3R1 | <1% |
Inheritance
Agammaglobulinemia is most commonly inherited in an X-linked recessive manner, but can also be inherited in an autosomal recessive manner.
Prevalence/Incidence
The prevalence of X-linked agammaglobulinemia has been estimated to roughly 3 to 6 individuals per 1,000,000 males in all racial and ethnic groups. The prevalence for the autosomal recessive form of agammaglobulinemia has not been established, but is much less frequent than X-linked agammaglobulinemia.
Considerations for testing
This test may be recommended for patients with:
- early onset recurrent bacterial infections
- very low levels of circulating immunoglobulins and B-cells in serum
References
- Plebani, A, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin. Immunol. 2002; 104(3):221-30. PMID: 12217331
- Conley, ME, Howard, V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J. Pediatr. 2002; 141(4):566-71. PMID: 12378199
- Conley, ME, et al. Genetic analysis of patients with defects in early B-cell development. Immunol. Rev. 2005; 203:216-34. PMID: 15661032
- Winkelstein, JA, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006; 85(4):193-202. PMID: 16862044
- Conley, ME, et al. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin. Exp. Immunol. 2008; 152(1):39-44. PMID: 18241230
- Smith, CIE, Berglöf, A. X-Linked Agammaglobulinemia. 2001 Apr 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301626
- Bearden, D, et al. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy. J Allergy Clin Immunol Pract. 2016; 4(6):1059-1065. PMID: 26883540
- Recher, M, et al. Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia. Clin. Immunol. 2013; 146(2):84-9. PMID: 23280491
- Hull, S, et al. Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction. JAMA Ophthalmol. 2016; 134(9):1049-53. PMID: 27389523
- Berglöf, A, et al. Agammaglobulinemia: causative mutations and their implications for novel therapies. Expert Rev Clin Immunol. 2013; 9(12):1205-21. PMID: 24215410
- Zhang, ZY, et al. Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia. Scand. J. Immunol. 2010; 72(5):454-9. PMID: 21039741
Assay
Assay and technical information
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 | ||
| 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 |
Resources
Patient resources
Patient guide: Genetic testing simplifiedReferences
- Bearden, D, et al. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy. J Allergy Clin Immunol Pract. 2016; 4(6):1059-1065. PMID: 26883540
- Berglöf, A, et al. Agammaglobulinemia: causative mutations and their implications for novel therapies. Expert Rev Clin Immunol. 2013; 9(12):1205-21. PMID: 24215410
- Conley, ME, Howard, V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J. Pediatr. 2002; 141(4):566-71. PMID: 12378199
- Conley, ME, et al. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin. Exp. Immunol. 2008; 152(1):39-44. PMID: 18241230
- Conley, ME, et al. Genetic analysis of patients with defects in early B-cell development. Immunol. Rev. 2005; 203:216-34. PMID: 15661032
- Hull, S, et al. Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction. JAMA Ophthalmol. 2016; 134(9):1049-53. PMID: 27389523
- Plebani, A, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin. Immunol. 2002; 104(3):221-30. PMID: 12217331
- Recher, M, et al. Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia. Clin. Immunol. 2013; 146(2):84-9. PMID: 23280491
- Smith, CIE, Berglöf, A. X-Linked Agammaglobulinemia. 2001 Apr 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301626
- Winkelstein, JA, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006; 85(4):193-202. PMID: 16862044
- Zhang, ZY, et al. Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia. Scand. J. Immunol. 2010; 72(5):454-9. PMID: 21039741
