Genetic testing should be routinely done in the diagnosis of CVID

1. Genetic testing should be routinely done in the diagnosis of CVID M. Hassan Bashir MBBS Allergy and Immunology Fellow Stanford Hospital and Clinics/ Lucile Packard Children’s Hospital

2. Common Variable Immunodeficiency Disease • Marked decrease of IgG and a marked decrease in at least one of the isotypes IgM or IgA • Onset of immunodeficiency at greater than 4 years of age • Absent or poor response to vaccines • Defined causes of hypogammaglobulinemia have been excluded • Clinical heterogeneity, lack of specific genetic/ phenotypic classification

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4. Complications Jolles. JACI in Practice. 2013; Chapel et al. JACI. 2012

5. Non-infectious complication • Lung disease (30%) Restrictive GLILD (10%), BOOP Obstructive Bronchiectasis (10-20%), asthma • Neoplasia: Lymphoma (2-8%), Gastric carcinoma (0.8-1.7%) • Autoimmunity (20%)Cytopenias (ITP, AHA, CD4 lymphopenia) • GI disease: Enteropathy, IBD, focal nodular hyperplasia, atrophic gastritis • Liver Disease: Hepatitis, Nodular Regenerative Hyperplasia

6. Survival: Infectious vs Non Infectious Infectious Complications Autoimmune, Inflammatory Complications E. S. Resnick, E. L.Moshier, J. H.Godbold, andC.Cunningham-Rundles, “Morbidity and mortality in common variable immune deficiency over 4 decades,” Blood, vol. 119, no. 7, pp. 1650–1657, 2012.

7. CVID Genetics • Monogenic cause identified in 2-10% of CVID patients • Epigenetic mechanisms also contribute to disease and phenotype Bogaert et al. J Med Genet. 2016

8. CVID -- Genetics P. Maffucci, C. A. Filion, B. Boisson et al., “Genetic diagnosis using whole exome sequencing in common variable immunodeficiency,” Frontiers in Immunology, vol. 7, article 220, 2016.

9. Challenges • Cost • Accessibility • Interpretation

10. Cost • Genomic approaches can cost $1000s • Variation between lab pricing and insurance policies • Gene Panels/Targeted vs Whole Exome • Cost decreasing with improvement in technologies

11. Genetic Panels • Invitae PID Panel (201 genes), CVID Panel • Blueprint Genetics PID Panel (274 genes)

12. Invitae – PID Panel

13. Invitae – CVID Panel

14. Blueprint Genetics -- 274 Genes ACD ACP5 ACTB ADA ADAM17 ADAR AICDA AIRE AK2 AP3B1 ARPC1BATM BACH2 BCL10 BCL11B BLM BLNK BTK C1QA C1QB C1QC C1SC2 C3 CARD11 CARD14 CARD9 CASP10 CASP8 CD19 CD247 CD27 CD3DCD3E CD3G CD40 CD40LG CD46 CD55 CD59 CD70 CD79A CD79B CD81CD8A CDCA7 CEBPE CECR1 CFB CFD CFH CFI CFP CFTR CHD7CIITA CLCN7 CLPB COLEC11 COPA CORO1A CR2 CSF2RA CSF2RB CSF3R CTC1CTLA4 CTPS1 CTSC CXCR4 CYBA CYBB DCLRE1C DDX58 DGKE DKC1 DNAJC21DNMT3B DOCK2 DOCK8 ELANE EPG5 ERCC6L2 EXTL3 FADD FAS FASLG FERMT3FOXN1 FOXP3 G6PC3 G6PD GATA2 GF1 GINS1 HAX1 HELLS HYOU1 ICOSIFIH1 IFNAR2 IFNGR1 IFNGR2 IGLL1 IKBKB IKZF1 IL10 IL10RA IL10RB IL12BIL12RB1 IL17RA IL17RC IL1RN IL21IL21R IL2RA IL2RG IL36RN IL7R IRAK4IRF2BP2 IRF8 ISG15 ITGB2 ITK JAGN1 JAK1 JAK3 KRAS LAMTOR2 LATLCK LIG4 LPIN2 LRBA LYST MAGT1 MALT1 MAP3K14 MASP1 MEFV MKL1MOGS MRE11A MSN MTHFD1 MVK MYD88 MYO5A NBN NCF1 NCF2 NCF4NCSTN NFKB1NFKB2 NFKBIA NHEJ1 NHP2 NLCR4 CLRP1 NLRP12 NLRP3 NOD2NOP10 NRAS NSMCE3 OFD1 ORAI1 OTULIN PARN PEPD PGM3 PIGA PIK3CDPIK3R1PLCG2 PMS2 PNP POLE POLE2 PRF1 PRKCD PRKDC PSENEN PSMB8PSTPIP1 PSTPIP1 PTPRC RAB27A RAC2 RAG1 RAG2 RASGRP1 RBCK1 RECQL4 RFX5FRXANK RFXAP RHOH RLTPR RMRP RNASEH2A RNASEH2B RNASEH2C RNF168 RNF31 RNU4ATAC RORC RPSA RTEL1 SAMD9 SAMD9L SAMHD1 SBDS SERPING1 SH2D1A SLC29A3 SLC35C1SLC37A4 SLC46A1 SLC7A7 SMARCAL1 SMARCD2 SP110 SPINK5 SRP72 STAT1 STAT2 STAT3STAT5B STIM1 STK4 STX11 STXBP2 TAP1 TAP2 TAPBP TBX1 TCF3 TCN2TERC TERT TFRC THBD TINF2 TMC6 TMC8 TMEM173 TNFAIP3 TNFRSF13B TNFRSF1ATNFRSF4 TRAF3IP2 TREX1 TRNT1 TTC7A TYK2 UNC119 UNC13D UNC93B1 UNG USB1USP18 VPS45 WAS WDR1 WIPF1 WRAP53 XIAP ZAP70 ZBTB24 ZNF341

15. Genetic Panels • Invitae PID Panel (201 genes), CVID Panel $ 100 to 250 • Blueprint Genetics PID Panel (274 genes) $ 450 to 900 Exome Proband: $ 1500 Trio: $ 2400

16. Accessibility • Broadly commercially available and accepted for diagnosis • Insurance restrictions • Geneticist orders Interpretation • Improving technology

17. Benefits • Management • Prognosis • Genetic Counselling • Identify new gene and Database

18. Management • Targeted therapeutics for non infectious manifestation in CVID, this approach will improve management of patients with more severe phenotypes • Monitoring for complications and malignancy • Using Prophylactic Antibiotics • Abatacept: LRBA and CTLA4 • Leniolisib: PI3 Kinase

19. Prognosis • Clinical course prediction • Atypical presentations Genetic Counselling • Family members, Family Planning • Rate of recurrence by knowing the inheritance pattern

20. Stem Cell Transplantation • HSCT indicated or not • Risk of GVHD reactions rate higher in certain mutations or not • Prognosis • Has shown positive results in patients with LRBA and CTLA4

21. Stem Cell Transplantation Wehr, et al. J Allergy ClinImmunol 2015;135-988-97

22. Stem Cell Transplantation

23. Refrences • Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisibV. Koneti Rao, Sharon Webster, Virgil A. S. H. Dalm, Anna Šedivá, P. Martin van Hagen, Steven Holland, Sergio D. Rosenzweig, Andreas D. Christ, Birgitte Sloth, MaciejCabanski, Aniket D. Joshi, Stefan de Buck, Julie Doucet, DaniloGuerini, Christoph Kalis, Ilona Pylvaenaeinen, Nicolas Soldermann, AnujKashyap, GulbuUzel, Michael J. Lenardo, Dhavalkumar D. Patel, Carrie L. Lucas and Christoph BurkhartBlood 2017 130:2307-2316; doi: https://doi.org/10.1182/blood-2017-08-801191 • Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiencyClaudia Wehr, MD,a Andrew R. Gennery, MD,b Caroline Lindemans, MD, PhD,cAnsgar Schulz, MD,dManfred Hoenig, MD,dReinhard Marks, MD,e Mike Recher, MD,f Bernd Gruhn, MD,g Andreas Holbro, MD,h Ingmar Heijnen, PhD,i Deborah Meyer, BSc,j Goetz Grigoleit, MD,k Hermann Einsele, MD,k Ulrich Baumann, MD,l Thorsten Witte, MD,m Karl-Walter Sykora, MD,nSiguneGoldacker, MD,a Lorena Regairaz, MD,oSerapAksoylar, MD,pOmurArdeniz, MD,q Marco Zecca, MD,rPrzemyslawZdziarski, MD,s Isabelle Meyts, MD,t Susanne Matthes-Martin, MD,uKohsukeImai, MD,v Chikako Kamae, MD,w Adele Fielding, MD,xSuranjithSeneviratne, MD,y Nizar Mahlaoui, MD, MSc, MPH,zMary A. Slatter, MD,aa Tayfun G€ung€or, MD,j Peter D. Arkwright, MD,bbJoris van Montfrans, MD,cc Kathleen E. Sullivan, MD, PhD,dd Bodo Grimbacher, MD,a Andrew Cant, MD,b Hans-Hartmut Peter, MD,aJuergenFinke, MD,e H. Bobby Gaspar, MD,ee Klaus Warnatz, MD,a and Marta Rizzi, MD, PhD,a on behalf of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiency • Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene MutationBianca Tesi& Peter Priftakis& Fredrik Lindgren & Samuel C. C. Chiang & Nikolaos Kartalis& Alexandra Löfstedt& Esther Lörinc& Jan-IngeHenter & Jacek Winiarski& Yenan T. Bryceson& Marie Meeths Received: 11 August 2015 /Accepted: 21 April 2016 /Published online: 4 May 2016 • Genes associated with common variable immunodeficiency: one diagnosis to rule them all?DelfienJ A Bogaert, Melissa Dullaers, Bart N Lambrecht, Karim Y Vermaele, Elfride De Baere, FilomeenHaerynck • Morbidity and mortality in common variable immune deficiency over 4 decadesElena S. Resnick, Erin L. Moshier, James H. Godbold,andCharlotte Cunningham-Rundles