Primary antibody deficiencies in Turkey: molecular and clinical aspects

Abstract

Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n = 4), CD40L (n = 1), ICOS (n = 1), IGHM (n = 1), and TCF3 (n = 1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2-10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.

Genetic Evaluation of the Patients with Clinically Diagnosed Inborn Errors of Immunity by Whole Exome Sequencing: Results from a Specialized Research Center for Immunodeficiency in Türkiye

“…Within the PAD cohort, genetic causality was determined in a mere 15.6% of cases (10 patients). This notably diminished diagnostic yield in Primary Antibody Deficiencies is in concordance with prior regional studies conducted by Fırtına S et al [ 84 ]. In contrast, patients with probable Mendelian susceptibility to mycobacterial diseases and chronic granulomatous disease (CGD) demonstrated significantly higher diagnostic rates, with near-complete success in CGD patients.…”

Genetic evaluation of the patients with clinically diagnosed inborn errors of immunity by whole exome sequencing: Results from a specialized research center for immunodeficiency in Türkiye

“…Within the primary antibody de ciency cohort, genetic causality was determined in a mere 15.6% of cases (10 patients). This notably diminished diagnostic yield in Primary Antibody De ciencies is in concordance with prior regional studies conducted by Fırtına S et al [25]. In contrast, patients with probable Mendelian susceptibility to mycobacterial diseases and chronic granulomatous disease demonstrated signi cantly higher diagnostic rates, with nearcomplete success in CGD patients.…”

Integrative Analysis of the TNFRSF13B Variants in Common Variable Immune Deficiency

“…TNFRSF13B variants were screened by next-generation sequencing. Patients' characteristics and targeted-panel workflow were previously reported [14,15]. TNFRSF13B variants were filtered and included in the study according to passed filter quality (>Q30) and read depth (>50X) scores.…”

“…In addition, some specific variants cause the downregulation of TACI expression but not a complete loss, promotes autoimmune diseases with CVID phenotype can be given as another example of modifying effects of TNFRSF13B variants [13] (Figure 1). Our group previously screened 24-CVID associated genes (including TNFRSF13B gene) in pediatric and adult primary antibody deficiency/ common variable immune deficiency (PAD/CVID) 80 patients in total but no pathogenic TNFRSF13B variants were detected [14]. In this study, we aimed to estimate the impact of all (benign/likely benign/variant unknown significance) TNFRSF13B variants in CVID/PAD patients via re-analyses of a custom designed next-generation sequencing panel data.…”