• Elisabet Matas Pérez, Andrea González Torbay, Mario Solis López, Ricardo Cuesta Martín de la Cámara, Carmen Rodríguez Jiménez, Mari Ángeles Mori Álvarez, Julián Nevado Blanco, Carla Gianelli, Carmen Cámara Hijón, Eduardo López Granados, Rebeca Rodríguez Pena, Ángela Del Pozo Mate, and María Bravo García-Morato.
• Immunology Department, La Paz University Hospital, Madrid, Spain.
• Eur. J. Clin. Invest. 2024 Jun 1; 54 (6): e14191e14191.

BackgroundGenetic diagnosis of inborn errors of immunity (IEI) is complex due to the large number of genes involved and their molecular features. Missense variants have been reported as the most common cause of IEI. However, the frequency of copy number variants (CNVs) may be underestimated since their detection requires specific quantitative techniques. At this point, the use of Next Generation Sequencing (NGS) is acquiring relevance.MethodsIn this article, we present our experience in the genetic diagnosis of IEI based on three diagnostic algorithms that allowed the detection of single nucleotide variants (SNVs) and CNVs. Following this approximation, 703 index cases were evaluated between 2014 and 2021. Sanger sequencing, MLPA, CGH array, breakpoint spanning PCR or a customized NGS-based multigene-targeted panel were performed.ResultsA genetic diagnosis was reached in 142 of the 703 index cases (20%), 19 of them presented deletions as causal variants. Deletions were also detected in 5 affected relatives and 16 healthy carriers during the family studies. Additionally, we compile, characterize and present all the CNVs detected by our diagnostic algorithms, representing the largest cohort of deletions related to IEI to date. Furthermore, three bioinformatic tools (LACONv, XHMM, VarSeq™) based on NGS data were evaluated. VarSeq™ was the most sensitive and specific bioinformatic tool; detecting 21/23 (91%) deletions located in captured regions.ConclusionBased on our results, we propose a strategy to guide the molecular diagnosis that can be followed by expert and non-expert centres in the field of IEI.© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

18 keywords...

hide…