Hyper IgM Syndrome via the AICDA Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1761 AICDA$580.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 AICDA$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

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).


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).

Testing Strategy

Our DNA sequencing test involves bidirectional Sanger sequencing of the entire AICDA gene plus ~20bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test#100) or pair of exons (Test#200) in patients and relatives of patients or to confirm research results.

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).


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


Name Inheritance OMIM ID
Immunodeficiency With Hyper IgM Type 2 605258


Genetic Counselors
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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