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. 2025 Apr;155(4):1149-1160.
doi: 10.1016/j.jaci.2024.11.030. Epub 2024 Nov 30.

Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for diagnosing inborn errors of immunity

Giuliana Giardino  1 , Gigliola Di Matteo  2 , Silvia Giliani  3 , Simona Ferrari  4 , Vassilios Lougaris  5 , Raffaele Badolato  5 , Francesca Conti  6 , Roberta Romano  1 , Maria Pia Cicalese  7 , Silvia Ricci  8 , Federica Barzaghi  9 , Antonio Marzollo  10 , Cristina Cifaldi  2 , Davide Montin  11 , Lorenzo Lodi  8 , Emilia Cirillo  1 , Baldassarre Martire  12 , Antonio Trizzino  13 , Mayla Sgrulletti  14 , Viviana Moschese  14 , Marika Comegna  15 , Giuseppe Castaldo  15 , Alberto Tommasini  16 , Chiara Azzari  8 , Caterina Cancrini  2 , Alessandro Aiuti  7 , Claudio Pignata  17
Affiliations

Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for diagnosing inborn errors of immunity

Giuliana Giardino et al. J Allergy Clin Immunol. 2025 Apr.

Abstract

Background: Inborn errors of immunity (IEIs) comprise more than 500 different rare congenital disorders of the immune system and are characterized by susceptibility to infection and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High-throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specifics for their application to IEIs.

Objective: The aim of this consensus study was to define the best approach to genetic testing for IEIs.

Methods: A panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated by the Delphi method.

Results: The experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes.

Conclusion: Adherence to guidelines on the use and interpretation of genetic tests for diagnosing IEIs should help limit the inappropriate use of these techniques, thereby reducing the risk of misdiagnosis and patient apprehension regarding inconclusive genetic results.

Keywords: Inborn errors of immunity; Sanger sequencing; consensus; genetic tests; high-throughput sequencing; next-generation sequencing; whole-exome sequencing.

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Conflict of interest statement

Disclosure statement Supported by European Union–Next Generation EU-PNRR M6C2-Investimento 2.1 Valorizzazione e potenziamento della Ricerca Biomedica del SSN (PNRR-MR1-2022-12376594 and PNRR-MR1-2022-12376412). G.G., G.D.M., S.G., V.L., R.B., M.P.C., F.B., E.C., C.C., A.A., and C.P. are part of the European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA, project 739543). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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