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Genetic Diagnosis Contributing to Treatment Example of Genetic Diagnosis Contributing to Treatment

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Genetic Diagnosis Contributing to Treatment Example of Genetic Diagnosis Contributing to Treatment 10/30/2013 Disclosures Whole exome sequencing in pediatric patients with rare early onset • None relevant to this discussion immunodysregulatory diseases that present with fever and systemic inflammation Adriana Almeida de Jesus Background Background IL-1a/b IL-1a/b IL-1Ra IL-1Ra IL-1Ra IL-1a/b • Severe and early onset • Hereditary IL-1a/b IL-1Ra DIRA disease suggests a autoinflammatory Nucleus Pro-IL-1b Mendelian disorder diseases TNF, IL-6 RNA PRO IL-1b CAPS PRO IL-1b • Role of IL-1b in the ROS NALP3 • Complex clinical pathogenesis TRAPS ASC Cardinal IL-1b phenotypes and models A IL-1b IL-1b of inheritance CASPASE1 CASPASE1 IL-1b - • Non-response to IL-1 - PRO PRO IL-1b PRO CASPASE1 blocking therapies in CASPASE1 • WES (Whole Exome IL-1b IL-1b some diseases Sequencing) FMF HIDS Monocyte/Macrophage Methods Objectives Total blood DNA Bioinformatics extraction pipeline • To describe the use of WES to investigate the molecular basis of rare diseases presenting with autoinflammatory phenotypes Human exome Integrated capture Agilent workflow V4 exome • To describe the application of WES in translational enrichment kit medicine Quality control Next generation Gender and sequencing family (Illumina relatedness HiSeq2000) checking 1 10/30/2013 Results – Quality Control Results – Demographic Data Parameter Quality Control Coding variants per sample ✓ • 16 patients and their parents (trios); 48 subjects (range) (19,000 – 25,000) • 10 female : 6 male Transition to Transversion ratio ✓ (range) (2.98 – 3.27) • Ethnicity Heterozygous to homozygous ratio ✓ – Caucasian: 81.3% (range) (1.30 to 2.46) Synonymous to nonsynonymous ratio ✓ – Hispanic: 12.5% (range) (0.86 to 0.95) – Other: 6.2% Indel percentage ✓ (range) 1.75 to 2.40 Concordance in two pairs of technical ✓ replicates (%) (97.25) Results – Clinical phenotypes Results – De novo mutations Genetic Findings PSMB8 (T75M) + PSMA3 Analysis Clinical Phenotypes (R233del de novo) heterozygous mutations n=1 CANDLE/CANDLE-like Variant Filtering n=2 Somatic de novo annotation workflow mutation in TREX1 (D255N) n=1 6 disease- PSMA3 related de (digenic model of inheritance in CANDLE) Germline mutation Somatic de novo mutation novo NLRP3 16 patients negative NOMID in NLRP3 (F302L) mutations (somatic) (trios) n=1 n=4 TREX1 De novo mutations in (somatic) genes not previously 3 mutations under evaluation associated with human Undifferentiated disease autoinflammatory n=3 disease n=10 XIAP mutation (N249Kfs*18 - X-linked) n=1 All mutations were confirmed by Sanger sequencing Example of genetic diagnosis contributing to treatment Example of genetic diagnosis contributing to treatment • 3 year-old Caucasian male • Splenectomy at the age of 9 months • Hydrops fetalis with intra utero Anemia + Leukocytosis + blood transfusion Thrombocytosis • Preterm birth (31wk) • Liver biopsy: sinusoidal periportal lymphocytic infiltrate and vanishing • Neonatal-onset of fever, bile duct syndrome hepatosplenomegaly, purpuric • Skin biopsy: immunocomplex cutaneous rash, periorbital mediated vasculitis H&E erythema, testicular swelling and arthritis. • Fluctuating autoantibodies – ANA • inflammatory markers, liver – Anti-Sm and anti-SSA enzymes, transfusion dependent – Anticardiolipin IgG anemia and severe – Lupus anticoagulant thrombocytopenia – Anti-mitochondrial MPO 2 10/30/2013 Example of genetic diagnosis contributing to treatment WES variants filtering for de novo mutations 60000 40000 900000 35000 800000 ) 50000 l 700000 Coding Variants Called by GATK (21,995) ) l ) m l 30000 / 600000 s m l m / l 40000 / s 500000 25000 e s l l l l c ( e 400000 e 20000 c 30000 c s ( t ( 200000 e l C C 15000 Max MAF < 1% (2,272) e 150000 L t B 20000 a A 10000 l W 100000 P 10000 5000 50000 0 0 0 5 5 8 0 5 0 5 0 5 0 5 0 0 5 0 .5 .0 .5 .8 .0 .5 .0 .5 .0 .5 .0 .0 .5 .0 . Exclude Synonymous (1,551) .0 .5 .8 .0 .5 .0 .0 .5 .0 .5 .0 .5 .0 .0 .5 .0 2 4 4 4 5 1 1 5 6 9 2 4 4 5 2 4 4 5 1 6 7 1 5 6 9 2 4 4 5 4 4 4 5 1 6 6 7 1 5 6 9 2 4 4 5 1 2 2 2 2 3 3 3 3 1 1 1 2 2 2 2 3 3 3 3 1 1 1 1 2 2 2 2 3 3 3 3 Age (months) Age (months) Age (months) Not in Parents (71) 15 80 Not in 60 ) Background ) 10 L / 40 L g Post-splenectomy d Genomes* (5) / m 20 g ( ( 10.0 P b R H 5 7.5 C Steroids + IVIG Prioritization *76 samples processed in the same 5.0 batch as control for technical artifacts 2.5 0 0.0 .5 .5 .8 .0 .5 .0 .0 .5 .0 .5 .0 .5 .0 .0 .5 0 .0 .0 .5 .0 .5 .0 .5 .0 .0 .5 .0 2 4 4 5 1 6 6 7 1 5 6 9 2 4 4 3 8 8 1 5 6 9 2 4 4 5 1 1 1 1 2 2 2 2 3 3 3 1 2 2 2 2 3 3 3 3 Age (months) Age (months) LYN genetic defect Lyn kinase c.1524C>G, p.Y508* Multi-species alignment • Positive and negative Patient regulator of signaling pathways Father Y508* • Inactive state through phosphorylation of a tyrosine residue in the C-terminal Mother Stop-codon gained in the Tyr position Loss of 5 amino acids regulatory (R) domain • up/up Genomic Structure chr8 Lyn mouse sustained 508 activation of Lyn tyrosine kinase in vivo autoimmune 1 2 3 4 5 6 7 8 9 10 11 12 13 disease AA 1-44 45-59 60-95 96-128 129-162 163-212 213-263 264-324 325-350 351-401 402-445 446-512 Translational research Conclusion Constitutive activation of Lyn kinase downstream tyrosine kinases Patient Control • WES led to the discovery of digenic disease inheritance in CANDLE syndrome • WES is a useful tool for the detection of somatic mutations in CAPS • WES can be used as an effective tool in translational research of rare and undiagnosed immunodysregulatory diseases 3 10/30/2013 Acknowledgements NIH NIAMS/OST NCI/POB Funding agencies Zuoming Deng Melinda Merchant Hong-Wei Sun Stephen Brooks NIAID/IPS Susan Moir NIAMS/TADS Raphaela Goldbach-Mansky NCI/LP Yin Liu Richard Lee Gina Montealegre Dawn Chapelle THE MEDICAL UNIVERSITY OF Hanna Kim SOUTH CAROLINA Scott Canna Ana Carolina Xavier Nikki Plass Murray Passo April Brundridge Yan Huang Dona Jones NHGRI Ivona Aksentijevich Daniel Kastner Steve Boyden Afzal Sheik CC/DLM Thomas Fleisher Julie Niemela Sergio Rosenzweig Hyesun Kuehn 4 .
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