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.
BLNK BTK CD79A CD79B IGLL1 PIK3R1
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.
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.
BLNK BTK CD79A CD79B IGLL1 PIK3R1
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
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
For a broader analysis of genes associated with primary immunodeficiency:
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
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.
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% |
Agammaglobulinemia is most commonly inherited in an X-linked recessive manner, but can also be inherited in an autosomal recessive manner.
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.
This test may be recommended for patients with:
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 |