Clinical Associations of Biallelic and MonoallelicTNFRSF13BVariants in Italian Primary Antibody Deficiency Syndromes

Federica Pulvirenti,Isabella Quinti,Simona Ferrari,Andrea Pession,Giuseppe Spadaro,Roberta Zuntini,Maria Giovanna Danieli,Fernando Specchia,Cinzia Milito

doi:10.1155/2016/8390356

Abstract

We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic-mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B-cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild-type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited.

Highlights

Defects in antibody production predisposing to various types of infections are the hallmark of primary antibody deficiencies (PADs) [1, 2]
Considering only mutations in exons 3 and 4, genetic alterations were found in about 10% of the Common Variable Immunodeficiency Disorders (CVID) patients and in about 5% of the IgA Deficiency (IgAD) patients, significantly more than in the corresponding general population
We found a higher rate of TACI mutations ranging from 11.1% in CVID to 13.4% in symptomatic IgAD

Summary

Introduction

Defects in antibody production predisposing to various types of infections are the hallmark of primary antibody deficiencies (PADs) [1, 2]. The European ESID Registry has defined Working Definitions for Clinical Diagnosis of PAD entities for patients without genetic diagnosis including Common Variable Immunodeficiency Disorders (CVID), the most common symptomatic antibody deficiency, and Selective IgA Deficiency (IgAD). The clinical spectrum of PADs varies between different entities and even within the same entity, ranging from severe disease with a reduced life expectancy, to very mild or even asymptomatic forms. For CVID the clinical phenotype ranges from a poorly symptomatic one to severe phenotypes characterized by high susceptibility to infections, autoimmunity, granulomatous inflammation, lymphoproliferative disorders, and malignancies [3,4,5,6,7,8]

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Results

Conclusion