Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus

Abstract

Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

“…EMSA assay is ongoing to assess the capacity of TCF3 protein to bind DNA target sequences. In these twin patients we also previously found by Sanger sequencing a mutation in TNFRSF13B gene already described to be associated to CVID (50).…”

Assessing Disease Severity in Common Variable Immunodeficiency Disorders (CVID) and CVID-Like Disorders

“…The CDSS correlates with the clinical phenotypes in both kindreds (Figures 1 , 2 ). As can be seen in the first family, the digenic proband has the highest CDSS, consistent with the epistatic interactions of the TNFRSF13B /TACI and TCF3 mutations ( 7 ). Her son carrying only the TCF3 mutation has a higher score than other family members bearing either homozygous or heterozygous mutations of the TNFRSF13B /TACI gene.…”

“…We have recently discovered new genetic defects in two NZ families with CVID-like disorders. In the first family, we have confirmed the existence of quantitative epistasis in humans ( 7 ). Epistasis is the non-linear, synergistic interaction of two or more genetic loci either leading to a much more severe disorder or a novel phenotype ( 8 , 9 ).…”

“…In this family, the synergistic interaction of TNFRSF13B /TACI and TCF3 mutations resulted in a severe immunodeficiency and systemic lupus erythematosus (SLE) in the proband (Figure 1 ). Other members of the family who have various permutations of the two mutated genes had a milder phenotype, which was reflected in their in vitro B cell differentiation and antibody production studies ( 7 ).…”

“…CDSS, CVID disease severity score; CS, clinical score. The CS was suggested as means of determining eligibility for SCIG/IVIG but we have used it as a surrogate marker of disease severity ( 5 , 7 , 11 ).…”