Diagnostic Yield and Therapeutic Consequences of Targeted Next-Generation Sequencing in Sporadic Primary Immunodeficiency

Georgios Sogkas; Natalia Dubrowinskaja; Katharina Schütz; Lars Steinbrück; Jasper Götting; Nicolaus Schwerk; Ulrich Baumann; Bodo Grimbacher; Torsten Witte; Reinhold E Schmidt; Faranaz Atschekzei

doi:10.1159/000519199

Diagnostic Yield and Therapeutic Consequences of Targeted Next-Generation Sequencing in Sporadic Primary Immunodeficiency

Int Arch Allergy Immunol. 2022;183(3):337-349. doi: 10.1159/000519199. Epub 2021 Oct 7.

Authors

Georgios Sogkas^{1

2}, Natalia Dubrowinskaja^{1

2}, Katharina Schütz³, Lars Steinbrück⁴, Jasper Götting⁴, Nicolaus Schwerk³, Ulrich Baumann³, Bodo Grimbacher^{2

5

6}, Torsten Witte^{1

2}, Reinhold E Schmidt^{1

2}, Faranaz Atschekzei^{1

2}

Affiliations

¹ Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
² Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hanover, Germany.
³ Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
⁴ Institut of Virology Hannover Medical School, Hannover, Germany.
⁵ Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany.
⁶ DZIF - German Center for Infection Research, Satellite Center Freiburg, Braunschweig, Germany.

Abstract

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.

Keywords: Combined immunodeficiency; Common variable immunodeficiency; Inborn errors of immunity; Primary antibody deficiencies; Primary immunodeficiency; Unclassified antibody deficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
High-Throughput Nucleotide Sequencing
Humans
Immunologic Deficiency Syndromes* / diagnosis
Immunologic Deficiency Syndromes* / genetics
Immunologic Deficiency Syndromes* / therapy
Primary Immunodeficiency Diseases* / diagnosis
Primary Immunodeficiency Diseases* / genetics
Primary Immunodeficiency Diseases* / therapy