Hyper IgM Syndrome via the AICDA Gene

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).

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).

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