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Background Juvenile Idiopathic Arthritis (JIA) represents the most prevalent chronic rheumatic disease in childhood. Its etiology is multifactorial, with growing evidence pointing to a significant genetic contribution to disease susceptibility. Recent genomic studies have identified a range of inherited variants associated with distinct arthritis phenotypes, among which LACC1 -related arthritis has emerged as a notable contributor, particularly in familial cases with variable clinical presentations. In this study, we report the clinical and genetic characterization of a novel LACC1 c.658G>A (p. Asp220Asn) variant identified in multiple affected individuals within a large consanguineous extended family, providing further insights into the genetic underpinnings of familial juvenile arthritis. Methods whole exome sequencing (WES) was performed on affected patients and findings were confirmed using sanger sequencing in family members. In-silico protein modeling was performed for model evaluation and visualization. LACC1 protein expression was measured in isolated and differentiated macrophages from selected patients and their carrier relatives. Allele frequency of LACC1 variants were analyzed in available in-house datasets. Results Four affected patients with non-systemic seronegative juvenile arthritis of different severities were found to have a novel homozygous mutation in LACC1 c.658G>A (p. Asp220Asn). Parents of affected patients were all heterozygous carriers. LACC1 protein expression showed variability, but it was markedly reduced in the index patient with the most severe phenotype. Analysis of allele frequency of other LACC1 variants showed equivalent distribution in both JIA and non-JIA genetic datasets. Conclusion Characterizing the molecular mechanisms of LACC1 -related arthritis may refine the biological taxonomy of JIA. This work contributes to the understanding of monogenic juvenile arthritis forms and supports the integration of LACC1 testing into the diagnostic approach for familial or atypical cases.

Objective The presentation and outcomes of Systemic lupus erythematosus (SLE) are influenced by ethnicity and genetic background. The United Arab Emirates (UAE) is one of the leading countries of SLE per recent reports. In this study, we evaluated the effect of positive family history (FHx) of SLE and autoimmunity on clinical presentations and disease outcomes. Methods A retrospective observational study of patients seen between 2011 till 2023 was conducted. Included patients were those fulfilling the 2019 EULAR/ACR classification criteria. Comparative analyses were conducted between those with familial history of autoimmunity and SLE and those without. Results Out of 279 SLE patients, a total of 241 patients fulfilled the 2019 EULAR/ACR classification criteria and were included in the study. There was positive FHx of autoimmunity in 27% of the study population, and positive FHx of SLE (in first-degree relatives, “familial SLE”) in 14.5% of the study population. Comparisons between positive and negative FHx of autoimmunity/SLE showed younger age at diagnosis in those with positive FHx of autoimmunity ( p -value = < 0.001) and higher frequency of Raynaud’s phenomonen ( p -value = 0.022). Patients with familial SLE were also younger at diagnosis ( p - value = 0.004) and had more mucocutaneous features ( p -value = 0.042). Conclusion The percentage of familial SLE in our UAE study population is 14.5% which is higher than reported in non-Arab study populations. In our study population, patients with familial SLE and familial autoimmunity tend to present earlier, while patients with familial SLE tend to have more mucocutaneous features than those without familial SLE. Clinical trial number Not applicable. Key points In this study population, 14.5% of SLE patients had a first-degree relative with SLE, a percentage higher than in non-Arab populations. Patients with familial SLE had a younger age at diagnosis and more mucocutaneous features. The high burden of familial SLE in our region prompts the investigation of underlying genetic factors linked to SLE development.

ObjectivesTo evaluate the functional impact of a novel DNASE1L3 variant (c.572A>G, p.Asn191Ser) in three families with SLE and hypocomplementaemic urticarial vasculitis (HUV) from the United Arab Emirates.MethodsWhole-exome sequencing was performed on affected patients and findings were confirmed using Sanger sequencing in family members. DNASE1L3 protein expression, secretion and enzymatic activity were assessed in HEK293 cell lines. Plasma smear assay for neutrophil extracellular traps (NETs) was evaluated in patients, family members and healthy control.ResultsA total of seven patients diagnosed with both SLE and HUV were identified from three unrelated families. All affected individuals were found to carry a homozygous c.572A>G, p.Asn191Ser (191S) variant in DNASE1L3. The variant 191S was shown to impact the secretion and activity of DNASE1L3. Patients homozygous for 191S variant had significantly higher burden (p=0.0409) of NET structure in comparison to heterozygous and healthy control.ConclusionsWe functionally evaluated the effect of a novel DNASE1L3 (c.572A>G, p.Asn191Ser) in familial SLE with a consistent pattern of HUV across seven patients. This variant resulted in impaired secretion and enzymatic activity of DNASE1L3 along with increased NETosis in patients with homozygous genotype.