Clinical Utility of Whole Exome Sequencing and Targeted Panels for the Identification of Inborn Errors of Immunity in a Resource-Constrained Setting.

Clair Engelbrecht,Mardelle Schoeman,Deepthi Raju Abraham,Michael Urban,Brigitte Glanzmann,Marlo Möller,Richard Glashoff,Monika Esser,Ansia Van Coller,Brandon Paarwater,Craig Kinnear,Helena Cornelissen

doi:10.3389/fimmu.2021.665621

Abstract

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

Highlights

Primary immunodeficiency disorders (PIDs) are a group of genetically heterogeneous inborn errors of immunity (IEI), which lead to a predisposition to the development of autoimmune and inflammatory diseases, lymphoproliferation and infection [1,2,3,4,5]
We report on molecular results, diagnoses and alterations in clinical management in patients with suspected IEIs, tested within the South African state healthcare system
next generation sequencing (NGS) is becoming the gold standard for confirming diagnoses in patients with suspected IEIs [12, 15] with our detection rates being comparable to other published studies [14, 16]

Summary

Introduction

Primary immunodeficiency disorders (PIDs) are a group of genetically heterogeneous inborn errors of immunity (IEI), which lead to a predisposition to the development of autoimmune and inflammatory diseases, lymphoproliferation and infection [1,2,3,4,5]. The diagnostic workup for a suspected IEI is shifting from only detailed clinical evaluations of the patient, to include a number of laboratory tests which may include targeted gene screening and immunological assays. Given that most IEIs are monogenic, genetic testing has become an important modality for providing an accurate and definitive diagnosis, altering management and aiding genetic counselling [11,12,13]. This said, the identification of a disease-associated variant in a suspected case of IEI can be challenging with many cases having no single causative variant identified and large genotype-phenotype variation reported [14,15,16]

Methods

Results

Conclusion