Open AccessDiagnostic Yield and Therapeutic Consequences of Targeted Next-Generation Sequencing in Sporadic Primary Immunodeficiency
Author(s) -
Georgios Sogkas,
Natalia Dubrowinskaja,
Katharina Schütz,
Lars Steinbrück,
Jasper Götting,
Nicolaus Schwerk,
Ulrich Baumann,
Bodo Grimbacher,
Torsten Witte,
Reinhold Schmidt,
Faranaz Atschekzei
Publication year - 2021
Publication title -
international archives of allergy and immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.696
H-Index - 100
eISSN - 1423-0097
pISSN - 1018-2438
DOI - 10.1159/000519199
Subject(s) - primary immunodeficiency , immune dysregulation , immunology , immunodeficiency , medicine , common variable immunodeficiency , immune system , disease , lymphoproliferative disorders , severe combined immunodeficiency , biology , antibody , genetics , lymphoma , gene
Introduction: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the >430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency. Method: We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent’s HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment. Results: tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making. Conclusion: Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.