Use of Genetic Testing for Primary Immunodeficiency Patients

Abstract

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

“…The characterization of PIDassociated genes is expected to significantly contribute to define the molecular events governing immune system development and will provide new insights into the pathogenesis of PIDs. Molecular genetic testing is also a useful tool for the diagnosis of PIDs in atypical cases (6,10). Despite the progress in the genetic characterization of PIDs, many patients still lack a molecular diagnosis.…”

“…The application of Next Generation Sequencing (NGS) to PIDs has been a revolution and it has accelerated the discovery and identification of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity (7,8,(14)(15)(16). Targeted gene-panel sequencing (17)(18)(19)(20)(21), whole exome sequencing (WES) (22,23) or whole genome sequencing (WGS) (24) approaches can rapidly identify candidate gene variants in an increasing number of genetically undefined diseases (17,24) and are widely used in several laboratories for the diagnosis of PIDs (10). WGS also offers the opportunity to find causative variants in the structural regions of a given gene.…”

Primary Immunodeficiency

“…Genetic testing plays a critical role in patients with PID in confirming diagnosis, predicting the prognosis, assessing the influences of genotype-phenotype associations, and family planning [50,51]. Besides, early and accurate molecular diagnosis is vital for guiding the selection of appropriate treatment including genetic therapy.…”

“…Several molecular tests are available in identifying the genetic defects of PIDs, such as chromosomal analysis, fluorescence in situ hybridization, chromosomal microarray, single gene by Sanger sequencing, gene panels by massively parallel, whole exome, and genome by next-generation sequencing [52]. The selection of these assays should consider their inherent advantages and limitations [50,53]. The summary of these tests is shown in Table 6.…”

“…There is no specific algorithm for genetic testing in patients with PID as individual's genetic mutation is often unique, the technology, cost, and the assay turnaround time are constantly changing, and each molecular method has inherent advantages and limitations. Practically, two or more approaches are often used together to achieve an optimal diagnosis [50]. For example, single gene Sanger sequencing is considered to be not only a simple and reliable assay for testing patients with known monogenic mutations of PID or their family members, but it can also serve as a tool for confirming the genetic variants detected by whole exome sequencing.…”