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Background <p>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 <i>LACC1</i>-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 <i>LACC1</i> c.658G&gt;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.</p> Methods <p>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 <i>LACC1</i> variants were analyzed in available in-house datasets.</p> Results <p>Four affected patients with non-systemic seronegative juvenile arthritis of different severities were found to have a novel homozygous mutation in <i>LACC1</i> c.658G&gt;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 <i>LACC1</i> variants showed equivalent distribution in both JIA and non-JIA genetic datasets.</p> Conclusion <p>Characterizing the molecular mechanisms of <i>LACC1</i>-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 <i>LACC1</i> testing into the diagnostic approach for familial or atypical cases.</p>

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A novel LACC1 variant c.658G>A (p. Asp220Asn) in familial juvenile arthritis: identification and functional analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • Hiba Alblooshi,
  • Noor Mustafa,
  • Azeem Abdul Khalam,
  • Anjali Bharathan,
  • Ekhlass Mohammed,
  • Ibrahim Baydoun,
  • Mohammed Tabouni,
  • Mushal Allam,
  • Meera Almansoori,
  • Tabeer Fatima,
  • Najla Aljaberi

摘要

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.