ORIGINAL RESEARCH article
Front. Immunol.
Sec. Primary Immunodeficiencies
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1638544
Contribution of next generation sequencing to the diagnosis of inborn errors of immunity in a pediatric cohort
Provisionally accepted- 1Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, National Autonomous University of Mexico, México City, Mexico
- 2Genomics, Genetics and Bioinformatics Laboratory, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
- 3Department of Clinical Allergy and Immunology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
- 4Instituto Nacional de Pediatria, Mexico City, Mexico
- 5Department of Genetics, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
- 6Genomic, Genetics and Bioinformatics Laboratory, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
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Inborn errors of immunity (IEI) number more than 500 diseases, with most affected patients being children. Their precise diagnosis is hampered by overlapping phenotypes, and by their ample and varied phenotypic spectrum. We analysed the contribution of next generation sequencing to the diagnosis of IEI in a cohort of 157 children in a referral hospital in Mexico City. Following the classification of the International Union of Immunological Societies (IUIS), patients were assigned to an IEI group before sequencing, or to an "undefined" group, if it was not possible to assign them to any of them. Patients were again classified in the IUIS groups after sequencing. The diagnostic yield was 32.48%. Before sequencing, the largest group was comprised by patients that could not be assigned to a specific IUIS group (38.35% of the cohort), while after sequencing the largest group was made by the patients where no likely molecular diagnosis was found (67.52% of the cohort). Patients that were assigned to an IUIS group were confirmed to have a disease of that same group in 31.25% of the cases, while in 10.42% the molecular diagnosis corresponded to an immunodeficiency of a different group to the one initially suggested. In 18.03% of the children that could not be assigned to an immunodeficiency group before sequencing, a molecular diagnosis was reached after sequencing. In the patients that remained without a molecular diagnosis, the possibility of new IEI genes was explored by analysing the variants, first in a curated set of immune related genes, and then across the whole exome. However, after filtering the variants, by frequency, predicted consequence, and known biology, no new IEI candidate genes were identified. This results underscore the large impact of next generation sequencing for the correct diagnosis of IEI, and also points to the need to better understand their genetic architecture in order to increase the diagnostic yield.
Keywords: inborn errors of immunity (IEI), Whole exome sequencing (WES), Molecular diagnosis, novel genes, International Union of Immunological Societies (IUIS), diagnostic yield, Children
Received: 30 May 2025; Accepted: 04 Aug 2025.
Copyright: © 2025 Godinez-Zamora, Baeza-Capetillo, Saucedo-Ramírez, Del Rio-Navarro, Espinosa-Padilla, Morán-Barroso and Aguirre-Hernández. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jesús Aguirre-Hernández, Genomic, Genetics and Bioinformatics Laboratory, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
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