83. Screening for monogenetic vasculitides: the Great Ormond St Hospital Experience
Creators: name: Ebun Omoyinmi1, 2
name: Despina Eleftheriou1,3,4
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> Next generation genetic sequencing (NGS) is now firmly established as part of the routine diagnostic workup of vasculitis, and has been a disruptive but welcome addition to the diagnostic armamentarium, facilitating precision medicine in this space. The growing number of genes that have been identified to cause monogenic vasculitides and vasculopathies now encompass not only vasculitis but also autoinflammatory conditions with occasional vasculitis, immunodeficiency, and hematologic manifestations (1–4). Genetic vasculopathy mimicking vasculitis are also a concern. We describe diagnostic yield in a cohort of 339 patients referred to our autoinflammation centre of excellence (GOSH-ACE) since 2015. <strong>Methods:</strong> A NGS custom gene panel validated for vasculitis and inflammation (5), and whole-exome sequencing approach with virtual panel analysis was used to screen 339 patients with unknown but suspected autoinflammatory/ vasculitides. Genetic variants present in more than 1% of individuals (1000G and gnomAD databases) were excluded, and the remaining rare variants subsequently classified according to pathogenicity. <strong>Results:</strong> Of the 288 cases with demographics, there were 51% males; median age 13 years, range 1-70 years. Pathogenic or likely pathogenic (class 5 or 4) variants were detected in 119/339 patients (35%). A definite new genetic diagnosis was made in 31/339 cases (9%; Table). Seventy-four/339 patients (22%) had at least 1 class 4 variant requiring further workup to fully establish a true genotype-phenotype correlation. The commonest disease-causing genes (i.e. affecting more than one case in this cohort) with class 5 pathogenic mutations were:<em> ADA2</em>, <em>MEFV, C1QB</em> and <em>TREX1</em> (Table). Vasculopathic mimics of vasculitis included neurofibromatosis and Marfan syndrome. <strong>Conclusions:</strong> NGS is now fully embedded as a routine diagnostic test for vasculitis of the young, with overall diagnostic yield (definite, or possible genetic diagnosis) of 10-22% respectively. Precision medicine is thus now possible for these cases, with profound impact on treatment ranging from no immunosuppression (vasculopathy) to targeted treatment with biologics or hematopoietic stem cell transplantation, and in the future gene therapy. Clinicians should be aware that the diagnostic yield of this approach is profoundly influenced by what genes are included in virtual panel analyses, the pre-test odds of genetic disease in the population tested, and by operator expertise since reporting of genetic results is not yet fully automated. <strong>Disclosures:</strong> None <strong>Table. Class 5 mutations detected resulting in a confirmed genetic diagnosis </strong> Gene ID Variants Clinical diagnosis Number of cases <em>ADA2</em> p.G47R (x2), p.G47W, p.N370K DADA2 4 <em>C1QB</em> p.M95fs, p.G96Afs*49, Complement deficiency 2 <em>C3</em> p.R1042G Complement deficiency 1 <em>C6</em> p.Q274Rfs*45 Complement deficiency 1 <em>CYBA</em> p.P157Q Chronic granulomatous disease 1 <em>FBN1</em> p.R1170H, p.P404Hfs*43 Marfan syndrome 2 <em>GLA</em> p.G271S Fabry disease 1 <em>ISG15</em> p.Q16X Interferonopathy 1 <em>MEFV</em> p.V726A (Het x2), p.S208C (Hom), p.M694V (Hom), p.M694V (Hom) FMF 5 <em>NFI</em> p.Q543X Neurofibromatosis 1 <em>PIK3R1</em> c.336+1G&gt;A SHORT syndrome (AD) 1 <em>PRF1</em> p.A91V (Hom) HLH 1 <em>PSTPIP1</em> p.G403R Autoinflammatory; pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) 1 <em>PTEN</em> p.V217D Cowden syndrome 1 1 <em>RNF213</em> p.D4013N Moyamoya 1 <em>SLC29A3</em> p.F316V (Hom) H-syndrome 1 <em>TMEM173</em> p.C206Y Autoinflammatory; SAVI 1 <em>TNFAIP3</em> p.R271X Autoinflammatory syndrome, A20 deficiency, familial, Behcet-like 1 <em>TRAF3</em> p.R118W Encephalopathy, acute, infection-induced, Herpes-specific, 5 (IIAE5) 1 <em>TREX1</em> p.D18N (x2) AGS (interferonopathy) 2 <em>WAS</em> p.E131K Immune deficiency 1