Hyper IgM Syndrome Panel

Hyper IgM syndrome (HIGM) is due to impaired immunoglobulin class switch recombination (CSR) resulting in an increase in IgM and a decreased IgG, IgA and IgE antibody levels. This humoral immunodeficiency leads to recurrent sinopulmonary infections, chronic diarrhea due to Cryptosproidium infection, and neutropenia presenting within the first or second decade of life. In severe cases, patients may also present with, sclerosing cholangitis, chronic arthritis, thrombocytopenia, hemolytic anemia, hypothyroidism, kidney disease and failure to thrive (Davies and Thrasher. 2010. PubMed ID: 20180797; Etzioni and Ochs. 2004. PubMed ID: 15319456; Leven et al. 2016. PubMed ID: 27189378). About 75% of HIGM cases are inherited in an X-linked recessive manner due to pathogenic variants in the CD40LG gene (HIGM1). Three autosomal recessive forms of HIGM have been described through pathogenic variants 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) (Johnson et al. 2013. PubMed ID: 20301576). HIGM may also be present in complex disorders including ataxia telangiectasia, agammaglobulinemia, Nijmegen breakage syndrome, combined immundeficiencies, and common variable immunodeficiency. Treatment for HIGM includes prophylactic IgG and antibiotics. Genetic testing is also helpful in the differential diagnosis of HIGM from other disorders including congenital rubella syndrome, lymphoma and acquired autoimmune diseases (Davies and Thrasher. 2010. PubMed ID: 20180797; Conley et al. 2009. PubMed ID: 19302039).

HIGM1 is inherited in an X-linked manner through pathogenic variants in the CD40LG gene. HIGM can also be inherited in an autosomal recessive manner through pathogenic variants 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. About 75% of HIGM cases to date are due to pathogenic variants in the CD40LG gene (Johnson et al. 2013. PubMed ID: 20301576).

Other syndromes inherited in an X-linked recessive manner that also exhibit increased IgM levels include agammaglobulinemia (BTK), and lymphoproliferative syndrome (SH2D1A). Related autosomal dominant disorders include primary immunodeficiency (PIK3CD) and ectodermal dysplasia (NFKBIA). Autosomal recessive conditions include ataxia telangiectasia (ATM), Nijmegen breakage syndrome (NBN), and ataxia telangiectasia like disorder (MRE11) (Conley et al. 2009. PubMed ID: 19302039).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

In a molecular study of 140 patients presenting with Hyper IgM syndrome (HIGM) based on recurrent and/or severe infections, elevated IgM, and reduced IgA and IgG levels, sequencing of the CD40LG, CD40, NEMO, AICDA, UNG, ICOS, ICOSL, BTK, and SH2D1 genes was performed. Pathogenic variants were found in 103 of 140 patients with pathogenic variants in the CD40LG, AICDA, UNG, NEMO, and BTK genes accounting for 92%, 4%, 1%, 1%, and 3% of cases respectively (Lee et al. 2005. PubMed ID: 15358621). Analytical sensitivity for the CD40, MRE11, NBN, NFKBIA, and PIK3CD genes should be high as all reported variants to date are detectable by sequencing. Gross deletions have been reported in the ATM, AICDA, and CD40LG genes, but represent less than 10% of cases (Gatti and Perlman. 2016. PubMed ID: 20301790; Durandy et al. 2006. PubMed ID: 16964591; Lee et al. 2005. PubMed ID: 15358621; Johnson et al. 2013. PubMed ID: 20301576). SH2D1A deletions have been reported in 25% of cases (Sumegi et al. 2000. PubMed ID: 11049992). Analytical sensitivity is >90% for the BTK gene with large deletions, duplications, and rearrangements being present in less than 8% of XLA cases (Conley et al. 1998. PubMed ID: 9545398; Kanegane et al. 2001. PubMed ID: 11742281).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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).

In addition to the regions described above, this testing includes coverage of the following variants that reside in untranslated or deep intronic regions: ATM: c.2639-384A>G, c.3994-159A>G, and c.5763-1050A>G; BTK: c.-169T>G, c.1567-23A>G; and CD40LG: c.347-915A>T variants.

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).