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X-Linked Hyper IgM Syndrome via the CD40LG 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
CD40LG 81404 81404,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8707CD40LG81404 81404,81479 $990 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.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

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

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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


Genetic Counselors


  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Hyper IgM syndrome (HIGM) is a disorder characterized by recurrent bacterial respiratory infections, neutropenia, thrombocytopenia, anemia and failure to thrive. Approximately one in 500,000 males is affected with the X-linked form of the disease (HIGM1) with symptoms appearing by four years of age. In severe cases, central nervous system infections, liver disease, chronic diarrhea, lymphoma and gastrointestinal cancer development are life-threatening complications. Disease results from 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). Three 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. Stem cell transplantation is the only curative option (Tomizawa et al 2004; Levy et al. 1997; Davies and Thrasher 2010). Genetic testing is helpful in differential diagnosis of HIGM1 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).


HIGM1 is inherited in an X-linked manner through mutations in the CD40LG gene. HIGM can also be inherited in an autosomal recessive manner through mutations in the AICDA, CD40, or UNG genes. There is a fourth autosomal recessive form of HIGM (termed HIGM4) where the underlying genetic defect is still unknown. To date, almost 200 pathogenic mutations have been found within the CD40LG gene. Mutations are found throughout the coding region, but are more common in the TNF-homology domain at the terminal exon (Johnson et al. 2013). Nonsense, small insertions, small deletions, and splicing mutations leading to frameshift and early termination are found in about two-thirds of cases (Notarangelo et al.1996; Gilmour et al. 2003). Missense mutations are found in about 25% of cases throughout the gene either disrupting CD40 receptor binding, core packaging, or trimer formation. Patients with missense mutations typically have normal CD40 ligand surface expression following CD4 T-cell stimulation, but impaired protein function (Seyama et al. 1998). Gross deletions occur in less than 5% of cases (Schuster A et al. 2005; Lee et al. 2005). One report has identified a missense mutation, c.-119A>C, within the promoter region as causative for HIGM1 (Van Hoeyveld et al. 2007). The CD40LG gene encodes the CD40 ligand found on the surface of activated CD4+ helper T cells. This membrane bound ligand binds to the CD40 receptor present on B-cells to trigger immunoglobulin class switching and immune cell activation to ward off infections (Etzioni and Ochs 2004).

Clinical Sensitivity - Sequencing with CNV PGxome

X-linked HIGM through mutation in the CD40LG gene is responsible for about 70% of cases of HIGM (Etzioni and Ochs 2004). In patients with absence of CD40 ligand expression, mutations in the CD40LG gene were found in 20 of 21, and 11 of 12 patients affected with X-linked HIGM (Gilmour et al. 2003; Prasad et al. 2005). Analytical sensitivity is 95% for detection of pathogenic variants by Sanger sequencing (Johnson et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the CD40LG 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. 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).

Indications for Test

Individuals with recurrent respiratory infections within the first years of life, heightened IgM, and decreased IgG and IgA antibody levels indicative of HIGM. Ideal candidates have a known family history for the disease and flow cytometry analysis indicating impaired CD40 ligand expression post-CD4 T-cell activation (Johnson et al. 2013).


Official Gene Symbol OMIM ID
CD40LG 300386
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Immunodeficiency With Hyper Igm Type 1 XL 308230

Related Test

Hyper IgM Syndrome Panel


  • Davies EG, Thrasher AJ. 2010. Update on the hyper immunoglobulin M syndromes. Br. J. Haematol. 149: 167–180. PubMed ID: 20180797
  • Etzioni A, Ochs HD. 2004. The hyper IgM syndrome--an evolving story. Pediatr. Res. 56: 519–525. PubMed ID: 15319456
  • Gilmour KC, Walshe D, Heath S, Monaghan G, Loughlin S, Lester T, Norbury G, Cale CM. 2003. Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM. MP, Mol. Pathol. 56: 256–262. PubMed ID: 14514918
  • 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(ฎ), 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
  • Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gomez L, Sanders EA, Tabone MD, et al. 1997. Clinical spectrum of X-linked hyper-IgM syndrome. J. Pediatr. 131: 47–54. PubMed ID: 9255191
  • Notarangelo LD, Peitsch MC, Abrahamsen TG, Bachelot C, Bordigoni P, Cant AJ, Chapel H, Clementi M, Deacock S, Saint Basile G de, Duse M, Espanol T, et al. 1996. CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. Immunol. Today 17: 511–516. PubMed ID: 8961627
  • Prasad ML, Velickovic M, Weston SA, Benson EM. 2005. Mutational screening of the CD40 ligand (CD40L) gene in patients with X linked hyper-IgM syndrome (XHIM) and determination of carrier status in female relatives. J. Clin. Pathol. 58: 90–92. PubMed ID: 15623492
  • Schuster A, Apfelstedt-Sylla E, Pusch CM, Zrenner E, Thirkill CE. 2005. Autoimmune retinopathy with RPE hypersensitivity and “negative ERG” in X-linked hyper-IgM syndrome. Ocul. Immunol. Inflamm. 13: 235–243. PubMed ID: 16019685
  • Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. 1998. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood 92: 2421–2434. PubMed ID: 9746782
  • Tomizawa D, Imai K, Ito S, Kajiwara M, Minegishi Y, Nagasawa M, Morio T, Nonoyama S, Mizutani S. 2004. Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience. Am. J. Hematol. 76: 33–39. PubMed ID: 15114594
  • Van Hoeyveld E, Zhang P-X, Boeck K De, Fuleihan R, Bossuyt X. 2007. Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. Immunology 120: 497–501. PubMed ID: 17244160


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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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