77. Monogenic Mimics of Behçet's Disease
Creators: name: Alice Burleigh1, 2
name: Ebun Omoyinmi1
name: Papadopoulou3, Charalampia
name: Despina Eleftheriou1,2,3,
name: Paul Brogan1, 3
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Behçet’s Disease (BD) is a rare autoinflammatory vasculitis with a broad spectrum of symptoms, including oral and genital ulcers, uveitis, skin rashes, arthralgia, and internal organ inflammation. BD is polygenic, and multiple risk alleles across numerous genes have been associated with the disease, the strongest association of which is with HLA-B*51. There is, therefore, no single genetic hallmark of BD, making diagnosis challenging. It has recently been discovered that many rare monogenic diseases can present with symptothat are indistinguishable from BD<sup>1</sup>. It is vital that BD is differentiated from these so-called ‘monogenic mimics’, as the treatments and prognoses can differ. The aim of this study was to undertake whole exome sequencing in an unselected cohort of patients from the UK with clinically diagnosed BD to investigate the possibility of a monogenetic pathogenesis. <strong>Methods:</strong> Patients were recruited from five hospitals in London, Birmingham, and Oxford. The only inclusion criterium was a clinically suspected diagnosis of BD. Patients’ DNA was whole exome sequenced, and analysis performed using three approaches: [A] Rare variants in the ~400 genes of our in-house vasculitis and inflammation panel were manually assessed. [B] Potential disease-causing variants were prioritised based on connection to phenotype using Exomiser<sup>2</sup>. [C] HLA genotype was obtained using OptiType<sup>3</sup>. <strong>Results: </strong>A total of 33 patients were recruited, 13 female, median age 13 yrs, range 3-51 yrs. The genetic analysis for this cohort remains in progress, however of the 18 cases analysed thus far, we have identified nine probable monogenic cases: Four cases of Haploinsufficiency of A20 with five novel <em>TNFAIP3</em> mutations (p. p.G316S, p.S548Dfs, p.M112Tfs, p.C657fs, p.E661Nfs) One case of ISG15 deficiency with a novel homozygous <em>ISG15</em> mutation (p.Q16X) One case of TRAF3 deficiency caused by a dominant <em>TRAF3</em> mutation (p.R118W) Two cases associated with a novel heterozygous <em>MEFV</em> mutation (p.T707I) One case of Tumour necrosis factor receptor associated periodic syndrome (TRAPS) with a pathogenic low penetrance <em>TNFRSF1A</em> mutation (p.R121Q) Of the remaining patients for whom a monogenic cause could not be identified, we classified four as having classical BD, three of which were HLA-B*51 positive, and one patient with Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). The remaining patients remain under analysis, unsolved or classified as having a functional disorder. The functional consequences of the novel mutations discovered in this study are under investigation. <strong>Conclusions:</strong> This work has expanded the genotypic spectrum of autoinflammatory diseases that can mimic BD. The genetic diagnoses made in this study have enabled clinicians to make informed decisions regarding individuals’ treatments and prognoses, highlighting the importance of next generation genetic sequencing in patients with suspected BD. The analysis workflow designed for this study offers a template for which genetic characterisation of BD-like disease could be implemented more routinely, both for identification of monogenic diseases, and for HLA-typing. <strong>Disclosures</strong>: None.