Background: Behçet’s syndrome is a chronic multisystem inflammatory disorder characterised by marked clinical heterogeneity, including mucocutaneous, gastrointestinal, and systemic inflammatory manifestations. Although its pathogenesis is complex and multifactorial, genetic factors play a major role, as evidenced by the strong association with the HLA-B*51 haplotype. In paediatric-onset disease, next-generation sequencing has increasingly been used to identify monogenic autoinflammatory conditions that clinically overlap with Behçet’s syndrome, including disorders associated with recurrent fever, aphthous stomatitis, and intestinal inflammation. A pathogenic continuum linking Behçet’s syndrome, PFAPA syndrome, and recurrent aphthous stomatitis has been proposed, supporting the concept of a shared autoinflammatory spectrum.

Objectives: To investigate the genetic basis of paediatric-onset Behçet-like autoinflammatory disease by identifying pathogenic variants in known Behçet mimics and by exploring novel candidate genes.

Methods: Whole-exome sequencing (WES) was performed in probands with paediatric-onset Behçet-like autoinflammatory phenotypes. Variants were prioritised according to predicted functional impact and population frequency. Segregation analysis was conducted by Sanger sequencing in available family members. HLA typing was inferred from WES data using OptiType v1.3.4. Functional effects of candidate variants were assessed using luciferase reporter assays and laser-scanning confocal microscopy.

Results: Rare heterozygous missense variants in MRTFA were identified in three unrelated families and showed partial cosegregation with Behçet-like phenotypes encompassing recurrent fever, mucosal inflammation, and gastrointestinal involvement. The proband of the first family is a 20-year-old woman with recurrent febrile episodes beginning in the first year of life. She underwent tonsillectomy at the age of 2, but the episodes recurred 3 years after the surgery. They are associated with pharyngitis, aphthous stomatitis, abdominal pain, vomiting, and transient elevations in liver enzymes. Treatment with colchicine was ineffective. WES identified a heterozygous MRTFA c.1720G>A p.(Asp574Asn) variant; HLA-B*51 was not detected. The proband of the second family is a 13-year-old girl with monthly episodes of recurrent fever and aphthous stomatitis starting in early childhood. She also presented with IgA deficiency, anti-nuclear antibody positivity (1:1280) and arthralgias involving the ankle, hip, wrist, and lumbosacral region from the age of 2, with ankle ultrasonography showing only mild peroneal tendon sheath distention. WES identified a distinct rare heterozygous missense variant in MRTFA (c.1864G>A p.Asp622Asn). The variant was inherited from the mother, who has Crohn’s disease, recurrent oral and genital aphthosis, and autoimmune thyroiditis. HLA typing could not be performed due to lack of raw sequencing data as the exome sequencing was performed by an external service. The proband of the third family is a 5-year-old boy who developed ulcerative pancolitis at 3 years of age. He also presented with congenital anomalies, including horseshoe kidney, vesicoureteral reflux, and a patent ductus arteriosus. WES identified a heterozygous MRTFA c.718C>A p.(Pro240Thr) variant; HLA-B*51 was not detected. All identified variants were rare in population databases (gnomAD allele frequency ≤2.86×10 ⁻⁴ ). MRTFA encodes myocardin-related transcription factor A, a regulator of actin polymerisation and a co-activator of serum response factor–dependent transcription. Preliminary functional analyses demonstrated that the D574N and D622N MRTFA variants exhibited both increased transcriptional activity and increased nuclear localisation compared with the wild-type protein, consistent with a gain-of-function mechanism.

Conclusions: Rare missense variants in MRTFA may contribute to a spectrum of paediatric-onset Behçet-like autoinflammatory disease characterised by mucocutaneous and gastrointestinal inflammation, independently of HLA-B*51. These preliminary findings expand the phenotypic and genetic landscape of Behçet-like disorders and highlight the relevance of cytoskeletal regulation in autoinflammatory pathogenesis.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.