Abstract
Primary immunodeficiencies comprise a group of inborn errors of immunity that display significant clinical and genetic heterogeneity. Next-generation sequencing techniques and predominantly whole exome sequencing have revolutionized the understanding of the genetic and molecular basis of genetic diseases, thereby also leading to a sharp increase in the discovery of new genes associated with primary immunodeficiencies. In this review, we discuss the current diagnostic yield of this generic diagnostic approach by evaluating the studies that have employed next-generation sequencing techniques in cohorts of patients with primary immunodeficiencies. The average diagnostic yield for primary immunodeficiencies is determined to be 29% (range 10–79%) and 38% specifically for whole-exome sequencing (range 15–70%). The significant variation between studies is mainly the result of differences in clinical characteristics of the studied cohorts but is also influenced by varying sequencing approaches and (in silico) gene panel selection. We further discuss other factors contributing to the relatively low yield, including the inherent limitations of whole-exome sequencing, challenges in the interpretation of novel candidate genetic variants, and promises of exploring the non-coding part of the genome. We propose strategies to improve the diagnostic yield leading the way towards expanded personalized treatment in PIDs.
Highlights
Primary immunodeficiencies (PIDs) are a group of inborn errors of immunity, caused by germline mutations that affect different parts of the immune system
next-generation sequencing (NGS)-based sequencing approaches such as whole exome sequencing (WES) have been instrumental in the diagnosis of monogenic diseases such as PIDs, giving an insight into the underlying molecular disease mechanisms of immune defects [1, 5, 19, 37]
The heterogeneous nature of phenotypes seen in PID patients, combined with the influence of exposure to external factors, complicates the genetic diagnosis of these patients
Summary
Primary immunodeficiencies (PIDs) are a group of inborn errors of immunity, caused by germline mutations that affect different parts of the immune system. PIDs are associated with a broad range of symptoms, including recurrent infections, autoimmunity, autoinflammation, allergies, and malignancy [1] The diagnosis of these disorders is both hampered by the heterogeneous clinical presentation, genetic heterogeneity, and. The advent of next-generation sequencing (NGS) has revolutionized the field of sequencing technologies, enabling high throughput sequencing with continuously decreasing costs and wide-spread use in both clinical and research settings. The application of these generic and unbiased techniques have enabled an exponential increase in the identification of novel genes for PIDs, predominantly through the application of whole exome sequencing (WES) [2–4]. Functional testing in PID patients is minimally invasive and often required to demonstrate a possible functional defect for variants of uncertain significance (VUS)
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