X-Linked Hyper IgM Syndrome via the CD40LG Gene

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).

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).

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).