Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes.
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.
Department of Molecular Medicine, Sapienza Medical University, Viale Università 37, 00185 Rome, Italy.
Federica
F
Pulvirenti
Department of Medical Genetics, Policlinico S. Orsola-Malpighi, Medical University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
Roberta
R
Zuntini
Department of Molecular Medicine, Sapienza Medical University, Viale Università 37, 00185 Rome, Italy.
Cinzia
C
Milito
Department of Pediatrics, Policlinico S. Orsola-Malpighi, Medical University of Bologna University of Bologna, Via Pietro Albertoni 15, 10138 Bologna, Italy.
Fernando
F
Specchia
Department of Clinical Medicine and Surgery, Medical University of Naples Federico II, Corso Umberto I 40, 80138 Naples, Italy.
Giuseppe
G
Spadaro
Department of Medical and Molecular Sciences, Torrette Hospital, Medical University of Ancona, Via Conca 71, 60126 Torrette, Italy.
Maria Giovanna
MG
Danieli
Department of Pediatrics, Policlinico S. Orsola-Malpighi, Medical University of Bologna University of Bologna, Via Pietro Albertoni 15, 10138 Bologna, Italy.
Andrea
A
Pession
Department of Molecular Medicine, Sapienza Medical University, Viale Università 37, 00185 Rome, Italy.
Isabella
I
Quinti
Department of Medical Genetics, Policlinico S. Orsola-Malpighi, Medical University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
Simona
S
Ferrari
D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D005817:Genetic Counseling / Q000706:statistics & numerical data; D005820:Genetic Testing / Q000706:statistics & numerical data; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007558:Italy; D008206:Lymphatic Diseases / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; D007070:Immunoglobulin A; D007075:Immunoglobulin M; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein