NextGen 2024: Genetics in SJIA Session Part 1

NextGen 2024: Genetics in SJIA Session Part 1

• 1. “Clinical Utility of Genetics in Systemic JIA” Randy Q. Cron, MD, PhD University of Alabama at Birmingham NextGen Conference 2024 Washington, D.C.

• 2. Disclosures Randy Q. Cron, M.D., Ph.D. SOBI – investigator initiated clinical trial of anakinra to treat MAS SOBI – advisory board for MAS therapy SOBI – paid speaker/moderator for MEDSCAPE/WebMD Novartis – consultant on switching therapy Pfizer – clinical trial MAS adjudication committee chair Sironax – consultant on RIP1 inhibitor AbbVie – clinical trial MAS adjudication committee member Lilly – paid speaker CareerPhysician – advisory council American Board of Pediatrics - Subboard of Pediatric Rheumatology Springer – royalties on Cytokine Storm Syndrome textbook

• 3. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome Alexei A Grom, Joyce Villanueva, Susan Lee, Ellen A Goldmuntz, Murray H Passo, Alexandra Filipovich. J Pediatr. 2003 Mar;142(3):292-6. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, Grom AA. Arthritis Res Ther. 2005;7(1):R30-7. Grom

• 4. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH, Binstadt BA, Filipovich A, Grom AA. Arthritis Rheum. 2008 Sep;58(9):2892-6. Zhang 9/16 sJIA/MAS patients (57%) vs. 6/73 sJIA without MAS (8.2%) vs. 27/229 healthy controls (12%) Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH, Binstadt BA. Arthritis Rheum. 2008 Feb;58(2):567-70. Binstadt

• 5. Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent macrophage activation syndrome and systemic juvenile idiopathic arthritis Grant S Schulert , Mingce Zhang, Ammar Husami, Ndate Fall, Hermine Brunner, Kejian Zhang, Randy Q Cron, Alexei A Grom. Arthritis Rheumatol. 2018 May 2;70(6):963–970 Zhang

• 6. Vastert PRF1 A91V mutation sJIA/MAS – 20% vs. sJIA no MAS – 10%

• 7. Pt Age Sex Diagnosis Trigger Gene Mutation Amino Acid Change Prior Association Outcome 1 15 M leukemia ? UNC13D 2896 C>T R966W Pt. 6 only Died 2 1.5 M uveitis ? UNC13D 847 A>G I283V 4% AA Alive 3 18 F uveitis ? RAB27A 259 G>C A87P Griscelli-2 Alive 4 9 F ? ? PRF1 272 C>T A91V 3% USA Alive 5 16 F gastroparesis CMV STXBP2 1298 C>T A433V none Died 6 12 M systemic JIA HSV1 UNC13D 2896 C>T R966W Pt. 1 only Alive 7 7 M polyarteritis ? STXBP2 1782 G>A 3’ UTR 6 others Alive 8 1.5 F systemic JIA ? UNC13D 2368 C>T splice site none Alive 9 3 M ? immune deficiency ? UNC13D PRF1 869 C>T 272 C>T S290L A91V one prior 3% USA Alive 10 1 F chronic HepB HepB PRF1 272 C>T A91V 3% USA Alive 11 17 M ? EBV STXPB2 822 G>A A274A none Died 12 8 M ? HHV6 STXBP2 STXBP2 STXBP2 STXBP2 1782 G>A 1782 G>A 1026 C>G 1357 G>A 3’ UTR 3’ UTR non-coding non-coding none none none none Died 13 14 F Sjogren ? STXBP2 STXBP2 1590 G>A -37 delete splice site 5’ UTR 3 others linked Alive 14 1.5 M systemic JIA ? UNC13D 610 A>G M204V seen in HLH Alive 15 1.5 F systemic JIA ? PRF1 272 C>T A91V 3% USA Alive HLH Genetics of MAS Patients at Children’s of Alabama

• 8. Heterozygous FHL gene mutations: 5/14 sJIA/MAS – 36% vs. 4/29 sJIA no MAS – 14% Kaufman

• 9. Role of DOCK8 in Cytokine Storm Syndromes. Zhang M, Cron RR, Chu N, Nguyen J, Gordon SM, Eloseily EM, Atkinson TP, Weiser P, Walter MR, Kreiger PA, Canna SW, Behrens EM, Cron RQ. J Allergy Clin Immunol. 2024. Online ahead of print. Behrens Canna

• 10. Ombrello

• 11. MAS Genetics in Systemic JIA Schulert Lee

• 12. Value of genetic knowledge in sJIA/MAS •IRF5, IL1RN, HLA-DRB1*15 - Ombrello •HLH gene associations (e.g. PRF1, UNC13D) • Potential explanation for diminished NK cell cytolyic function • Risk of recurrence • Genetic counseling • One nucleotide change, even missense, does not necessarily … • Rarity of mutation • Prediction of disruption (e.g. PolyPhen-2) • Prior publication of MAS/HLH association • Test individual mutations in lab (e.g. in vitro)