AB0846 MOLECULAR PROFILING OF AN EASTERN MEDITERRANEAN FAMILY REVEALS NOT ONLY KNOWN BUT ALSO NEW CANDIDATE GENETIC RISK FOR AUTOIMMUNE DISEASES
Authors: B. Firlatan, G. Ayan, S. Noyan, S. Kiraz, M. Alikasifoğlu, O. Karadag
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic autoimmune diseases can present in a highly heterogeneous range of clinical presentations. And the classification of these autoimmune diseases using clinical criteria alone can lead to inaccuracies and leave many patients undiagnosed. Therefore, there is a need to reclassify these diseases using a more refined approach. <h3>Objectives:</h3> This study aimed to evaluate molecular profiling in a family with systemic autoimmune diseases. <h3>Methods:</h3> In the study, whole exome sequencing (WES) was performed using genomic DNA obtained from family members (I-1 and II-6). Candidate variants found as a result of the WES analysis were investigated in other family members via Sanger DNA sequence analysis. <h3>Results:</h3> The clinical and laboratory characteristics of family members are shown in Table 1. The WES results of the proband (II-6) were analyzed for Sjogren's syndrome (SjS) and the presence of a compound heterozygote for the IRF5 gene c.572_601del (p.R191LfsX) (NM_001098629.3) and c.1495C&gt;T (p.L499F) (NM_001098629.3) was determined. These identified alterations were confirmed by Sanger DNA sequence analysis. DNA sequence analysis was performed for the IRF5 gene c.572_601del (p.R191LfsX) and c.1495C&gt;T (p.L499F) using DNA samples from the mother, father and siblings. While the mother (I-2) was found to be heterozygous for the IRF5 gene c.1495C&gt;T (p.L499F), the father (I-1) was found to be heterozygous for the IRF5 gene c.572_601del (p.R191LfsX). II-3 and II-8 were found to be normal for both mutations. II-2 was found to be compound heterozygous for the IRF5 gene c.572_601del (p.R191LfsX) and c.1495C&gt;T (p.L499F). The WES results of I-1 were analyzed for SjS and dermatomyositis (DM). The presence of the RBMS3 gene c.249-7_249-6del (NM_001003793.2) (heterozygous) and the PRDM1 gene c.70G&gt;T (p.V24L) (NM_001198.3) (heterozygous) was detected. II-6, I-2, II-3, and II-8 were heterozygous for the RBMS3 gene c.249-7_249-6del change. II-3 and II-8 were found to be heterozygous for the PRDM1 gene c.70G&gt;T (p.V24L) (Figure 1). <h3>Conclusion:</h3> The IRF5 gene has been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), SjS and inflammatory bowel disease. PRDM1, a transcription factor regulated by IRF5, has been implicated in primary SjS. In addition, RBMS3 is thought to be a new susceptibility gene for primary SjS. Our results suggest that alterations in the IRF5 gene are associated with RA and SjS clinic in family members, while alterations in the PRDM1 and RBMS3 genes are associated with SjS and DM. Incorporating advances in molecular medicine into routine clinical practice could improve the diagnosis of systemic autoimmune diseases. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Funding: This project is financially supported by Society of Hacettepe Rheumatology. <h3>Disclosure of Interests:</h3> <b>None declared.</b>