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  • Test code: 08114
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
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Invitae Hyper IgM Syndrome Panel

Test description

The Invitae Hyper IgM Syndrome Panel analyzes up to 6 genes which are associated with Hyper IgM syndromes. Analysis of these genes may confirm a diagnosis of hyper IgM syndrome in individuals with recurrent respiratory or opportunistic infections and normal to increased levels of immunoglobulin M (IgM), and low IgG and IgA. Identification of disease-causing variants provide accurate risk assessment and carrier status for at-risk relatives.

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Primary panel (3 genes)
Add-on Clinically-overlapping Genes (3 genes)

Pathogenic changes in BTK, IL2RG, and SH2D1A have been reported in males with a hyper IgM phenotype. Given the clinical overlap, clinicians can choose to expand their search. These genes can be added at no additional charge.

BTK IL2RG SH2D1A

Alternative tests to consider

For a broader analysis of the genetics of primary immunodeficiencies:

Hyper IgM syndromes, including:



Gene Disorder Protein name Protein symbol
AICDA AID deficiency activation-induced cytidine deaminase AID
CD40LG CD40 ligand deficiency CD40 ligand CD40LG
UNG UNG deficiency uracil-DNA glycosylase UNG

The most common form of hyper IgM syndrome is HIGM1, caused by mutations in the X-linked CD40LG gene. HIGM1 is characterized by normal to elevated serum IgM levels and reduced IgG and IgA. Most affected individuals develop symptoms in infancy or early childhood. The clinical presentation is variable, although presenting symptoms often include respiratory and opportunistic infections, pneumonia, and failure to thrive due to recurrent diarrhea. Other common findings include neutropenia, anemia, thrombocytopenia, neurologic complications, liver disease including sclerosing cholangitis and cirrhosis, and increased risk of certain malignancies such as liver and biliary tree tumors and Hodgkin lymphoma.

HIGM2 and HIGM5, due to biallelic mutations in AICDA and UNG, respectively, are clinically similar and are characterized by B-cell differentiation abnormalities, recurrent infections, enlargement of the spleen and lymph nodes, and autoimmune and inflammatory disorders. The risk of opportunistic infections and malignancy is lower than in HIGM1.

In a study of 115 unrelated families with HIGM syndromes (PMID 15358621), a mutation in a gene included on this panel was identified in approximately 71% of patients. 67% of families had mutations in CD40LG. AICDA mutations were identified in 4 families (3.5%). Mutations in UNG were rare and are responsible for only a small proportion of HIGM cases.

Hyper IgM syndrome may be inherited in an autosomal recessive or X-linked recessive pattern depending on the gene involved:

Gene Disorder Inheritance
AICDA Hyper IgM syndrome type 2 Autosomal recessive
CD40LG Hyper IgM syndrome type 1 X-linked recessive
UNG Hyper IgM syndrome type 5 Autosomal recessive

Hyper IgM syndromes are rare, making estimates of the frequency of these diseases difficult. It has been estimated that the incidence of X-linked hyper IgM syndrome is at least 1 in 1 million live births in the United States. The other forms of HIGM are rarer.

Diagnostic criteria for X-linked HIGM according to the European Society for Immunodeficiencies:

Assay and technical information

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
AICDA NM_020661.2
BTK NM_000061.2
CD40LG NM_000074.2
IL2RG NM_000206.2
SH2D1A NM_002351.4
UNG NM_080911.2