Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection.

BACKGROUND: Genetic 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. METHODS: In 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. RESULTS: A 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. CONCLUSION: Based 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.

[Predictive factors for pneumonia in adults infected with the new pandemic A (H1H1) influenza virus]. / Factores predictivos de neumonía en pacientes infectados por el nuevo virus de la gripe A (H1N1) pandémica.

BACKGROUND: On April 2009 a new A (H1N1) influenza virus was identified with a higher incidence of severe outcome in younger people, most of them with pneumonia. The objective of our study was to identify the predictive risk factors of pneumonia in patients with the new A (H1N1) influenza virus infection. METHODS: Prospective cohort study of adults infected with the new A (H1N1) influenza virus, admitted in a universitary hospital, from june 2009 to January 2010. Pneumonia was defined as the presence of any pulmonary infiltrate of any distribution with no other evident cause, in the chest radiography. A comparative analysis was made with patients with A (H1N1) influenza without pneumonia. RESULTS: 281 patients with influenza A (H1N1) were treated. Thirty of them (10.6%) had pneumonia and 11 (3.9%) required intensive care. The global mortality was 0.7%. For the comparative analysis, 42 patients with influenza A (H1N1) without pneumonia were analysed (20 hospitalized and 22 nonhospitalised). In the multivariate analysis, obesity (BMI>30), (OR: 3.8; IC 95%: 0.99-15.0), time since symptom onset until hospital admission (OR 1.34; IC 95% 1.04-1.72), serum C reactive protein levels (OR:1.10; IC 95%: 0.98-1.24) and serum IgG2 levels (OR:1.08; IC 95%: 1.0- 1.01), were identified as independent risk factors for pneumonia. CONCLUSION: Obesity, delay in medical care and higher levels of C reactive protein and IgG2 were predictive factors for pneumonia in adult patients with A (H1N1) influenza infection.