Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort

Area of Science:

• Immunology
• Genetics

Background:

• Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies.
• PADs are characterized by hypogammaglobulinemia and impaired antibody production.

Purpose of the Study:

• To report the most common monogenic PADs.
• To investigate clinical and immunological differences in patients diagnosed with agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID).

Main Methods:

• Utilized stepwise next-generation sequencing and Sanger sequencing.
• Confirmed mutations in patients diagnosed with agammaglobulinemia, HIgM syndrome, and CVID.

Main Results:

• Identified genetic defects in 550 patients: Bruton's tyrosine kinase (BTK) and μ heavy chain deficiencies in agammaglobulinemia; CD40 ligand and activation-induced cytidine deaminase deficiencies in HIgM syndrome; lipopolysaccharides-responsive beige-like anchor deficiency and atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes in CVID.
• Found significantly higher disease severity in patients with μ heavy chain and CD40 ligand mutations compared to BTK and activation-induced cytidine deaminase mutations.
• Observed higher paralysis rates post-polio vaccination in μ heavy chain deficiency and identified genotype-phenotype correlations for BTK mutations (meningitis, chronic diarrhea) and distinct first presentations for lipopolysaccharides-responsive beige-like anchor deficiency (nonrespiratory) versus Immunodeficiency, Centromeric instability, and Facial dysmorphism (respiratory).

Conclusions:

• Highlights similarities and differences in the clinical and genetic spectrum of common PAD-associated gene defects.
• Provides a comprehensive comparison to aid clinical decision-making.
• Aims to improve prognosis and guide targeted treatment for patients with PADs.