Reviews and feature article
Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology

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Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

Section snippets

Genetic tests

Several options are available for clinical genetic testing, each of which bears its own set of advantages and limitations that should be considered when interpreting results. Tests most frequently used by clinicians include individual gene Sanger sequencing (SS), chromosomal microarray analyses (CMAs), targeted gene panels (TGPs), and whole-exome sequencing (WES). Whole-genome sequencing (WGS) is included for discussion as well. A summary of the differences between these genetic tests is

Interpretation guidelines

Novel technologies, such as WES and WGS, are rapidly increasing the number of genes associated with PIDDs, and it has become clear that genetic testing should be used as an essential diagnostic tool in the evaluation of patients with suspected PIDDs.1,3,5 Because an estimated 1 of every 300 nucleotides on average within the human genome will be altered in any subject, the number of variants detected by using genetic testing will increase proportionally with the number of bases sequenced. Most

Use of research and collaboration

Diagnostic yields of NGS in patients with PIDDs range from 15% to 40%, depending on the patient population studied and the sequencing technology used.76 When NGS fails to identify a definitive genetic diagnosis, an important role exists for deeper investigation on a research basis. Research laboratories can (1) perform mechanistic studies necessary to determine the biological effect of candidate variants and (2) perform supplementary genetic analyses when no plausible candidate variants are

Conclusions

Genetic testing remains an essential component of evaluation of patients with PIDDs. Available diagnostic modalities continue to grow, each with its own inherent advantages and limitations that must be considered during assessment of results. Importantly, for PIDDs, functional validation of potential disease-causing genetic candidates remains critical for pathogenic designation. As these necessary studies are being performed, a number of tools and guidelines can be used to assist with

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    Disclosure of potential conflict of interest: I. K. Chinn receives royalties from Wolters Kluwer (UpToDate). K. Chen is on the advisory board for Takeda/Shire. A. Kumanovics receives royalties from Wolters Kluwer (UpToDate). J. W. Leiding is a consultant for Horizon Pharma and CSL Behring. J. S. Orange is on the advisory board for ADMA Biosciences; is a consultant for Takeda/Shire, CSL Behring, and Grifols; is a speaker for Takeda/Shire; and receives royalties from Wolters Kluwer (UpToDate). C. D. Platt receives royalties from Wolters Kluwer (UpToDate). J. M. Puck also receives royalties from Wolters Kluwer (UpToDate) and has a family member who receives financial compensation from Invitae. N. Romberg receives royalties from Wolters Kluwer (UpToDate) and support from the Jeffrey Modell Foundation. K. E. Sullivan is a board member and consultant for the Immune Deficiency Foundation and receives royalties from Wolters Kluwer (UpToDate) and Elsevier. T. K. Tarrant is on the advisory board and speakers’ panel for Thermo Fisher Scientific. T. R. Torgerson is on the data safety and monitoring board for Takeda/Shire and is a consultant for CSL Behring, Takeda/Shire, Grifols, ADMA Biosciences, and UCB Pharma. J. E. Walter is a consultant and speaker for Takeda/Shire, CSL Behring, and X4 Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest.

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