Inborn errors of immunity: discovery of novel variants and genes involved in their development

ERRA, LORENZO; BRUNELLO FRANCO GINO; FLORES DAIANA; ZAIAT JONATHAN; MARTÍ MARCELO; ALMEJÚN MARÍA BELÉN

Córdoba

Congreso; LXXI REUNIÓN CIENTÍFICA ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI); 2023

SAI

Patients with Inborn Errors of Immunity (IEI) have monogenic defects that lead to immune system dysregulation phenotypes. Advances in molecular genetics and the use of next-generation sequencing, have led to the identification of an increasing number of IEI associated genes.The overall objective of this study is to improve the genetic diagnosis of patients with IEI through comprehensive analysis of exome data performed by our laboratory. Molecular diagnosis is complex because the same clinical phenotype can be caused by mutations in different genes. Additionally, different pathogenic variants in the same locus can cause different forms of IEI.By the end of 2022, in collaboration with AINCA, we conducted massive sequencing on 100 index cases of Argentine patients with IEI and neurological manifestations from different healthcare centers across the country. Bioinformatic analysis of the exome data was performed (fastQ processing, variant prioritization, and association with clinical phenotype). Following ACMG classification standards, this analysis revealed: 18.0% of cases had potentially pathogenic variants in the genes BCL11B, RUNX1, TNFRSF13B, AICDA, while 40.7% had variants of uncertain significance. Within this 40.7%, there are previously reported genes (MAGT1, MSH6, POLE, INO80, TBX1, MST1, RELA, LRBA, RHOG, JAK3, STAT3, CARMIL2, NLRP1), as well as new candidates.We evaluated the coding exonic regions and the exon-intron junctions of genes linked to, or indirectly affect, the immune system function. We also analyzed the copy number variations (CNVs). Our results showed that 77% of the identified variants are located in the coding region while 23% in regulatory regions, CNVs or genes related to epigenetic regulation. This work highlights the importance of a comprehensive analysis of candidate variants directly impacting the percentage of variants found in this cohort compared to the literature for IEI. These results remark the value of collaborative work between researchers and clinical physicians to carry out the NGS analyses. Our findings further support the heterogeneity in monogenic defects of the immune system, emphasizing the non-redundant and fundamental functions of individual genes and proteins in the development and function of host defense.