OP0055 LACC1 MUTATION IN MULTIPLE CONSANGUINEOUS FAMILIES CAUSING REFRACTORY JUVENILE IDIOPATHIC ARTHRITIS (2024)

Abstract

Background: Juvenile idiopathic arthritis (JIA); the most common arthropathy in children; is hypothesized to be triggered by many factors including genetic susceptibility[1]. Several reports have underlined inherited variants underlying JIA phenotype[2]. Of those, genetic variants in LACC1 were associated with familial JIA with different phenotypes[3-5].

Objectives: To report the clinical and genetic presentation of a novel LACC1 variant in multiple affected patients with JIA from a large consanguine extended family.

Methods: The patients were identified through our JIA Genomics Cohort. The cohort’s aim is to analyze relevant genetic variants in JIA. Informed consent was obtained (IRB# DOH/CVDC/2022/248). Whole exome sequencing (WES) was performed. The genetic findings were analyzed in the context of the clinical presentation and were confirmed using sanger sequencing.

Results: Genetic analysis via WES revealed a hom*ozygous LACC1 variant at c.658G>A (p. Asp220Asn) in four JIA related patients that is classified as variant of unknow significance (VUS). Figure 1 demonstrates the family pedigree highlighting the affected patients and their heterozygous carrier relatives. LACC1 variant c.658G>A (p. Asp220Asn) is a rare novel variant not reported previously in the literature or any public databases (1000 Genomes, ExAC, GnomAD, or Exome Variant Server). In silico pathogenicity prediction tools predicted damaging effect of the variant (PolyPhen2: Damaging 1, SIFT: Damaging 1, PhyloP: Conserved 8.40, GERP++: Conserved 16.34, CADD: uncertain: 28.8). Clinical and laboratory features are presented in Table 1. All four patients have non-systemic seronegative JIA phenotype with different severities. Patient 3 has alopecia and psoriasis confirmed on skin biopsy. Patient 4 has persistent bilateral lower limb lymphedema, a unique feature that was reported in connection with LACC1 mutations[3,4]. Patients 3 and 4 had poor response to treatment and notable recurrent pneumonias on tocilizumab.

Conclusion: LACC1 genetic variants contribute to a monogenic of JIA. This study supports prior literature linking LACC1 mutations to inherited and refractory type of JIA with different phenotypes. Aside from refractory arthritis, one patient also presented with persistent lymphedema in line with what has been reported in the literature[3,4].

Acknowledgements: NIL.

Disclosure of Interests: None declared.