Introduction: The latest release (2022) of the IUIS lists 485 different inborn error of immunity (IEI) diseases, with the addition of 55 genes, compared to the previous release. However, the diagnostic yield for IEI cohorts is on average 30%, and new IEI genes continue to be reported, this suggests that there is still ample room for the discovery of new IEI genes. In this context we decided to search for new candidate genes in a cohort of undiagnosed IEI patients.
Methods: Whole exome sequencing data was analysed in a group of 55 patients, fulfilling the criteria for an IEI, and with no molecular diagnosis after examining known IEI genes. Initially, variants were examined in 4412 candidate genes, selected according to GO annotations or position in protein-protein interaction networks. This was followed by the analysis of all variants in the coding exome. Variants were analysed considering all possible modes of inheritance, and genes were prioritized according to the similarities between their known phenotypic associations and the patient’s phenotypes.
Results: The relevance of the phenotypic association of variants in 270 candidate genes was established. Eleven of these genes were prioritized due to their functions. Upon filtering by frequency in public databases, and the predicted impact of the variants, five genes fulfilled our criteria to be considered candidates of interest due to their characteristics and functions. Conclusion: Results from other groups studying large cohorts of patients, managed to discover a very small number of new genes. This suggests that in addition to novel genes and a monogenic architecture, the combination of rare and common variants may be involved in causing some IEI. The molecular causes of these diseases is not yet fully understood.