TACI Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece

Abstract

Background and objectives: Monoallelic (heterozygous) or biallelic (homozygous or compound heterozygous) TACI mutations have been reported as the most common genetic defects in patients with common variable immunodeficiency (CVID), which is the most common clinically significant primary immunodeficiency in humans. The aim of our study was to evaluate the prevalence and any correlations of TACI defects in Greek patients with primary antibody deficiencies. Materials and Methods: 117 patients (male/female: 53/64) with CVID (110) and a combined IgA and IgG subclass deficiency (7) with a CVID-like clinical phenotype were enrolled in the study. Genomic DNA was extracted from peripheral blood and the molecular analysis of the TACI gene was performed by PCR (Polymerase Chain Reaction) and sequencing of all 5 exons, including exon–intron boundaries. Results: Seventeen patients (14.5%) displayed TACI defects, four (23.5%) carried combined heterozygous mutations and 13 (76.5%) carried single heterozygous mutations. The most frequently detected mutation was C104R (58.8%), followed by I87N (23.5%) and A181E (11.8%), while R20C, C62Y, P151L, K188M and E236X mutations were present in only one patient each. Patients with TACI defects were more frequently male (p = 0.011) and displayed a benign lymphoproliferation (splenomegaly and lymph node enlargement, p = 0.047 and p = 0.002, respectively), had a history of tonsillectomy (p = 0.015) and adenoidectomy (p = 0.031) and more frequently exhibited autoimmune cytopenias (p = 0.046). Conclusions: Considering that accumulating evidence suggests several CVID patients have a complex rather than a monogenic inheritance, our data further support the notion that TACI mutations, particularly as monoallelic defects, should be primarily considered as susceptibility co-factors and/or modifiers of primary antibody deficiencies.

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece

“…One of our study limitations is the fact that we did not have molecular data for the entire cohort of patients (with the exception of the molecular analysis of CTLA4 gene for all and TNFRSF13B/TACI for the great majority of the enrolled patients [33]. Consequently, we have not performed association studies of the genetic background of affected individuals with the phenotype of their disease.…”

Autoimmune Cytopenias in Common Variable Immunodeficiency Are a Diagnostic and Therapeutic Conundrum: An Update

“…A recent study from Greece reported that monoallelic defects in TACI may act as susceptibility or disease modifying factor in the pathogenesis of CVID. It was, however, observed that patients with CVID with TACI defects had significantly higher risk of autoimmune cytopenia as compared to patients with CVID without any TACI defect ( 61 ). In addition, studies have shown that TACI plays an important role in central B cell tolerance and defects in TACI lead to impaired central B cell tolerance leading to an increased production of autoreactive B cells ( 62 ).…”

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

“…FANCP/SLX4 Fanconi anemia, complementation group P/Structure-Specific endonuclease subunit) Cases 14 and 15 are siblings diagnosed with CVID who carry a pathogenic mutation in TNFRSF13B, which is one of the more common variants found in immune deficiencies 96,97 . The same variant has been found in several other PANS cases (unpublished observations).…”