Hyper IgM Syndrome via the AICDA 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
8879 AICDA 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8879AICDA81479 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.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hyper IgM syndrome (HIGM) is a disorder characterized by recurrent bacterial respiratory infections due to defective antibody diversification. In severe cases, central nervous infections, liver disease, chronic diarrhea, lymphoma and gastrointestinal cancer development are life-threatening complications. Disease is the result of impaired B-cell function where B-cells fail to be activated by T-cells in response to infection. This leads to a lack of antibody class switching from IgM to IgG and IgA making it more difficult to ward off infection. The majority of patients display high IgM and low IgG and IgA antibody levels (Johnson et al. 2013; Etzioni and Ochs 2004). In some cases, antibody production may appear normal making diagnosis more challenging.

There are several forms of HIGM. The most common form is inherited in an X-linked recessive manner through mutations in the CD40LG gene (HIGM1). Other autosomal recessive forms of HIGM have been described through mutations in the AICDA (HIGM2), CD40 (HIGM3), and UNG (HIGM5) genes. A fourth autosomal recessive form of HIGM is described with no known genetic cause to date (HIGM4). Treatments for HIGM include prophylactic IgG and antibiotics. Patients with HIGM2 typically have milder form of disease, but half also present with lymphoid hyperplasia due to B-cell proliferation in the germinal centers. Stem cell transplantation is the only curative option (Davies and Thrasher 2010). Genetic testing is helpful in differential diagnosis of HIGM2 from other HIGM forms as well as from other autoimmune deficiencies such as ataxia-telangiectasia, Nijmegen breakage syndrome, and common variable deficiency which are phenotypically similar (Johnson et al. 2013).

Genetics

HIGM2 is inherited in an autosomal recessive fashion through mutations in the AICDA gene. HIGM can also be inherited in an autosomal recessive manner through mutations in the CD40, or UNG genes or through an X-linked recessive form with mutations in the CD40LG gene. There is a fourth autosomal recessive form of HIGM (termed HIGM4) where the underlying genetic defect is still unknown. Missense and nonsense mutations resulting in loss of protein activity are the most common causative variants for HIGM2. These mutations occur throughout the coding region of the AICDA gene and represent over half of the cases for HIGM2 (Mu et al. 2012). Splice site alterations, small insertions/deletions, and gross deletions have also been reported (Durandy et al. 2006; Revy et al. 2000; Lee et al. 2005). The AICDA gene encodes the activation-induced cytidine deaminase (AID) which is selectively expressed in B-cells undergoing class switch recombination and somatic hypermutation. Class switch recombination and somatic hypermutation are essential processes for antibody diversification and increasing antigen affinity to ward off infections (Ta et al. 2003).

Clinical Sensitivity - Sequencing with CNV PGxome

In a cohort of patients presenting with Hyper IgM syndrome, mutations in the AICDA gene were identified in 4 of 140 patients (Lee et al. 2005). A separate analysis of patients meeting strict criteria for HIGM2, AICDA mutations were found in 18 of 18 patients (Revy et al. 2000). Analytical sensitivity is >90% as gross deletions have been reported in only a few cases of HIGM2 (Durandy et al. 2006; Lee et al. 2005).

Testing Strategy

This test provides full coverage of all coding exons of the AICDA 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.

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

Individuals with recurrent respiratory infections within the first years of life, heightened IgM, and decreased IgG and IgA antibody levels are candidates. Ideal candidates have a known family history for the disease and flow cytometry analysis indicating normal CD40 ligand expression post-CD4 T-cell activation (Etzioni and Ochs et al. 2004). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in AICDA.

Gene

Official Gene Symbol OMIM ID
AICDA 605257
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Immunodeficiency With Hyper IgM Type 2 AR 605258

Related Test

Name
Hyper IgM Syndrome Panel

Citations

  • Davies EG, Thrasher AJ. 2010. Update on the hyper immunoglobulin M syndromes. Br. J. Haematol. 149: 167–180. PubMed ID: 20180797
  • Durandy A, Peron S, Taubenheim N, Fischer A. 2006. Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants. Human Mutation 27: 1185–1191. PubMed ID: 16964591
  • Etzioni A, Ochs HD. 2004. The hyper IgM syndrome--an evolving story. Pediatr. Res. 56: 519–525. PubMed ID: 15319456
  • Johnson J, Filipovich AH, Zhang K. 2013. X-Linked Hyper IgM Syndrome. 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: 20301576
  • Lee W-I, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD. 2005. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood 105: 1881–1890. PubMed ID: 15358621
  • Mu Y, Prochnow C, Pham P, Chen XS, Goodman MF. 2012. A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants. Journal of Biological Chemistry 287: 28007–28016. PubMed ID: 22715099
  • Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, Catalan N, Forveille M, Dufourcq-Lagelouse R, Gennery A, Tezcan I, Ersoy F, Kayserili H, Ugazio AG, Brousse N, Muramatsu M, Notarangelo LD, Kinoshita K, Honjo T, Fischer A, Durandy A. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102: 565–575. PubMed ID: 11007475
  • Ta V-T, Nagaoka H, Catalan N, Durandy A, Fischer A, Imai K, Nonoyama S, Tashiro J, Ikegawa M, Ito S, Kinoshita K, Muramatsu M, et al. 2003. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunology 4: 843–848. PubMed ID: 12910268

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.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

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

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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