X-linked Agammaglobulinemia via the BTK Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9869 BTK 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9869BTK81406 81406, 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency found in males and is hallmarked by increased susceptibility to bacterial infections due to loss of antibody mediated immune responses. Recurrent otitis, conjunctivitis, skin infections, sinopulmonary infections, and diarrhea are common symptoms. About 60% of males with XLA develop severe infections, with S. pneumoniae and H. influenzae being most common pathogens. Severe infections can be life threatening leading to empyema, meningitis, and sepsis. Infections typically occur after the first few months of life as maternal immunoglobulins are protective (Conley and Howard 2011). Symptoms primarily occur in the first two years of life although 10% have delayed onset with immunodeficiency not being apparent until after ten years of age. XLA affects an estimated 1 in 200,000 males. Bimonthly gammaglobulin transfusions are the mainstay treatment of XLA. XLA individuals with infection often receive heightened antibiotic treatments to counter their lack of humoral immunity to ward off pathogens (Quartier et al. 1999). Agammaglobulinemia may also be inherited in an autosomal recessive manner through mutations in the IGHM, IGLL1, CD79A, CD79B, or BLNK genes. Genetic testing may help in differential diagnosis of XLA from other immune deficiencies and between X-linked and autosomal recessive forms of agammaglobulinemia (Ameratunga et al. 2010).

Genetics

XLA is inherited in an X-linked manner through mutations in the BTK gene. While the disease is fully penetrant, no clear genotype-phenotype correlation has been established (Väliaho et al. 2006; Holinski-Feder et al. 1998). Only one case of agammaglobulinemia in females through mutation in the BTK gene has been reported and was due to skewed X-chromosome inactivation (Takada et al. 2004). To date, over 700 different mutations in the BTK gene have been reported with no single mutation representing more than 3% of XLA cases (Conley et al. 1999; Lindvall et al. 2005; Väliaho et al. 2006). Two thirds of causative variants in BTK result in premature termination due to nonsense, splice site, or frameshift mutations (Tóth et al. 2009; Hashimoto et al. 1996; Velickovic et al. 2004; Väliaho et al. 2006). Missense mutations, found in about 20% of cases, affect protein stability and occur throughout the entire coding region. Large deletions have been reported in about 8% of cases. A deletion of the 3’ end of BTK and neighboring TIMM8A leads to a disorder called Mohr-Tranebjærg syndrome resulting in XLA with deafness-dystonia-optic neuropathy (Richter et al. 2001; Sedivá et al. 2007). De novo mutations occur in about 15% of cases of XLA (Conley and Howard 2011). Substitution mutations within the promoter region are rare, but have been shown to alter transcriptional regulatory elements leading to XLA onset (Rohrer and Conley 1998). Autosomal recessive forms of agammaglobulinemia are known to occur through mutations in the IGHM, IGLL1, CD79A, and BLNK genes. BTK encodes the Bruton agammaglobulinemia tyrosine kinase and is an essential intracellular signaling component for B cell lymphocyte development, differentiation, and activation (Mohamed et al. 2009; Lindvall et al. 2005).

Clinical Sensitivity - Sequencing with CNV PGxome

XLA accounts for 90% of cases of agammaglobulinemia in males through mutation in the BTK gene. Autosomal recessive forms of agammaglobulinemia through mutations in either the IGHM, IGLL1, CD79A, CD79B, or BLNK gene represent 10% of cases in males. Large deletions, duplications, and rearrangements are present in less than 8% of XLA cases (Conley and Howard 2011; Conley et al. 1999; Kanegane et al. 2001).

Testing Strategy

This test provides full coverage of all coding exons of the BTK gene 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 full coverage as >20X NGS reads or Sanger sequencing.

This test also includes coverage of the c.-169T>G variant.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Candidates for testing have recurrent bacterial infections in the first five years of life, low serum immunoglobulin levels (IgG, IgM, and IgA), and less than 2% of normal levels of CD19+ B-cells. The strongest candidates have a family history of the XLA or protein and expression analysis indicating an absence of BTK in white blood cells (Conley et al. 1999). Molecular testing for BTK is especially helpful in determining female carrier status of XLA (Conley and Howard 2011).

Gene

Official Gene Symbol OMIM ID
BTK 300300
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
X-Linked Agammaglobulinemia XL 300755

Citations

  • Ameratunga R, Woon S-T, Neas K, Love DR. 2010. The clinical utility of molecular diagnostic testing for primary immune deficiency disorders: a case based review. Allergy Asthma Clin Immunol 6: 12. PubMed ID: 20529312
  • Conley ME, Howard VC. 2011. X-Linked Agammaglobulinemia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301626
  • Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. 1998. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am. J. Hum. Genet. 62: 1034–1043. PubMed ID: 9545398
  • Conley ME, Notarangelo LD, Etzioni A. 1999. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin. Immunol. 93: 190–197. PubMed ID: 10600329
  • Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H, Tsuge I, Yamadori T, et al. 1996. Identification of Bruton’s tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood 88: 561–573. PubMed ID: 8695804
  • Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Bäckesjö CM, Vihinen M, Hubbard SR, Belohradsky BH, Smith CI, Meindl A. 1998. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics 101: 276–284. PubMed ID: 9445504
  • Kanegane H, Futatani T, Wang Y, Nomura K, Shinozaki K, Matsukura H, Kubota T, Tsukada S, Miyawaki T. 2001. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. J. Allergy Clin. Immunol. 108: 1012–1020. PubMed ID: 11742281
  • Lindvall JM, Blomberg KEM, Väliaho J, Vargas L, Heinonen JE, Berglöf A, Mohamed AJ, Nore BF, Vihinen M, Smith CIE. 2005. Bruton’s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling. Immunol. Rev. 203: 200–215. PubMed ID: 15661031
  • Mohamed AJ, Yu L, Bäckesjö C-M, Vargas L, Faryal R, Aints A, Christensson B, Berglöf A, Vihinen M, Nore BF, Smith CIE. 2009. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol. Rev. 228: 58–73. PubMed ID: 19290921
  • Quartier P, Debré M, Blic J De, Sauverzac R de, Sayegh N, Jabado N, Haddad E, Blanche S, Casanova JL, Smith CI, Deist F Le, Saint Basile G de, et al. 1999. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J. Pediatr. 134: 589–596. PubMed ID: 10228295
  • Richter D, Conley ME, Rohrer J, Myers LA, Zahradka K, Kelecić J, Sertić J, Stavljenić-Rukavina A. 2001. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatr Allergy Immunol 12: 107–111. PubMed ID: 11338284
  • Rohrer J, Conley ME. 1998. Transcriptional regulatory elements within the first intron of Bruton’s tyrosine kinase. Blood 91: 214–221. PubMed ID: 9414287
  • Sedivá A, Smith CIE, Asplund AC, Hadac J, Janda A, Zeman J, Hansíková H, Dvoráková L, Mrázová L, Velbri S, Koehler C, Roesch K, et al. 2007. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J. Clin. Immunol. 27: 640–646. PubMed ID: 17851739
  • Takada H, Kanegane H, Nomura A, Yamamoto K, Ihara K, Takahashi Y, Tsukada S, Miyawaki T, Hara T. 2004. Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood 103: 185–187. PubMed ID: 12958074
  • Tóth B, Volokha A, Mihas A, Pac M, Bernatowska E, Kondratenko I, Polyakov A, Erdos M, Pasic S, Bataneant M, Szaflarska A, Mironska K, et al. 2009. Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study. Mol. Immunol. 46: 2140–2146. PubMed ID: 19419768
  • Väliaho J, Smith CIE, Vihinen M. 2006. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum. Mutat. 27: 1209–1217. PubMed ID: 16969761
  • Velickovic M, Prasad ML, Weston SA, Benson EM. 2004. Identification of the bruton tyrosine kinase (BTK) gene mutations in 20 Australian families with X-linked agammaglobulinemia (XLA). Hum. Mutat. 23: 398–399. PubMed ID: 15024743

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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Requisition Form

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  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

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