Agammaglobulinemia Panel

Agammaglobulinemia is an immunodeficiency due to defects in B-cell maturation. While the exact incidence of agammaglobulinemia is unknown, a study of the United States registry of patients with X-linked agammaglobulinemia estimates the incidence to be ~1 in 380,000 live births (~1 in 200,000 male births) (Winkelstein et al. 2006. PubMed ID: 16862044). Patients with agammaglobulinemia present with recurrent bacterial infections including Haemophilus influenza, Strephtococcus pneumoniae, and staphylococci due to loss of antibody mediated immune responses. Common sites of infection include skin, respiratory tract, gastrointestinal tract, and joints. Severe infections can be life threatening due to empyema, meningitis, and sepsis. Infections typically occur after the first few months of life as maternal immunoglobulins are protective (Conley and Howard. 2011. PubMed ID: 20301626). Symptoms primarily occur in the first two years of life although ~10% of cases have delayed onset with immunodeficiency not being apparent until after ten years of age. Bimonthly gammaglobulin transfusions are the mainstay treatment with affected individuals receiving heightened antibiotic regimen to ward off pathogens during infection (Quartier et al. 1999. PubMed ID: 10228295).

Genetic testing is helpful in the differential diagnosis of agammaglobulinemia from other immunodeficiency syndromes such as common variable immunodeficiency and Omenn syndrome, infectious diseases, malignancies, and drug induced agammaglobulinemia (Conley and Howard. 2011. PubMed ID: 20301626; Conley et al. 1999. PubMed ID: 10600329).

This test includes genes identified through literature, OMIM, and HGMD searches that have a reported association with a severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells (agammaglobulinemia) (Bousfiha et al. 2018. PubMed ID: 29226301; Picard et al. 2018. PubMed ID: 29226302; Tangye et al. 2020. PubMed ID: 31953710).

Primary agammaglobulinemia is most commonly inherited as an X-linked trait. X-linked agammaglobulinemia (XLA) represents about 85-95% cases of agammaglobulinemia via pathogenic variants in the BTK gene. Variants in BTK may be inherited with ~40% of XLA cases having a previously affected family member, or they may occur de novo (Winkelstein et al. 2006. PubMed ID: 16862044). There is one report of a heterozygous female with XLA, however, the majority of female carriers are asymptomatic (Takada et al. 2004. PubMed ID: 12958074). While the disease is fully penetrant, no clear genotype-phenotype correlation has been established (Väliaho et al. 2006. PubMed ID: 16969761; Holinski-Feder et al. 1998. PubMed ID: 9445504). To date, over 700 different pathogenic variants in the BTK gene have been reported with no single variant representing more than 3% of XLA cases (Conley et al. 2005. PubMed ID: 15661032; Lindvall et al. 2005. PubMed ID: 15661031; Väliaho et al. 2006. PubMed ID: 16969761). Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations. Large deletions, duplications, and rearrangements are present in less than 8% of XLA cases (Conley and Howard. 2011. PubMed ID: 20301626; Conley et al. 1998. PubMed ID: 9545398; Kanegane et al. 2001. PubMed ID: 11742281).

Autosomal recessive and autosomal dominant forms of agammaglobulinemia have also been documented. Autosomal recessive forms of the disease are due to pathogenic variants in the BLNK, CD79A, CD79B, IGHM, IGLL1, PIK3CD, PIK3R1, SH2D1A, and SLC39A7 genes. Autosomal dominant forms of the disease have been associated with pathogenic variants in the LRRC8A and TOP2B genes. Agammaglobulinemia via pathogenic variants in the TCF3 gene may be inherited in an autosomal recessive or autosomal dominant manner. In addition, variants in these genes may arise de novo. Causative variants may include missense, nonsense, splicing, regulatory, or copy number alterations. Autosomal recessive forms of agammaglobulinemia represent ~10% of cases and autosomal dominant forms of disease are less commonly reported.

The majority of products of the genes in this panel are involved in the development, maturation, and function of immune cells, specifically of B cells. In addition, the products of genes in this panel are involved in DNA regulation during transcription and in zinc transportation.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

X-linked agammaglobulinemia (XLA) accounts for ~85-95% of cases of agammaglobulinemia in males through pathogenic variants in the BTK gene. Large deletions, duplications, and rearrangements are present in less than 8% of XLA cases (Conley and Howard. 2011. PubMed ID: 20301626; Conley et al. 1998. PubMed ID: 9545398; Kanegane et al. 2001. PubMed ID: 11742281).

Autosomal recessive and autosomal dominant forms of agammaglobulinemia through pathogenic variants in either the BLNK, CD79A, CD79B, IGHM, IGLL1, LRRC8A, PIK3CD, PIK3R1, SH2D1A, SLC39A7, TCF3, and TOP2B genes represent ~10% of cases in males. The clinical sensitivity of this specific grouping of genes is difficult to estimate. However, in a study of 12 families with IGHM deficiency, gross deletions were detected in four cases (Lopez Granados et al. 2020. PubMed ID: 12370281). Another study determined that ~60% of X-linked lymphoproliferative disease cases are attributed to pathogenic variants in the SH2D1A gene. Large deletions account for ~25% of all reported SH2D1A pathogenic variants (Sumegi et al. 2000. PubMed ID: 11049992). 

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides full coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).