La genetj tjca al servizio della clinica nelle immunodefj fjcienze - PowerPoint PPT Presentation

La genetj tjca al servizio della clinica nelle immunodefj fjcienze primitj tjve Dr. Boaz Palterer Dipartjmento di Medicina Clinica e Sperimentale Scuola di Specializzazione in Allergologia e Immunologia Clinica Università degli Studi di Firenze FIRENZE 11 – 12 Novembre 2016

Pediatrics; May 1971, VOLUME 47 / ISSUE 5 H. Fudenberg, R. A. Good, H. C. Goodman, W. Hitzig, H. G. Kunkel, I. M. Roitu, F. S. Rosen, D. S. Rowe, M. Seligmann, J. R. Soothill FIRENZE 11 – 12 Novembre 2016

• Incidence ~ 1:10.000 – 1:100.000 • Rare disease… but most frequent symptomatjc PID in adults! • Mendelian Inheritance ~5-25% • However untjll 2012 only rare monogenic forms: ICOS, BAFF-R, CD19, CD20, CD81 • Some common genetjc factors (TACI/TNFRSF13B and MSH5 polymorphisms) • Bimodal peak of incidence (fjrst decade and third decade) • Long diagnostjc delay! (~4-10 years) ESID/PAGID 1999, CVID : • Decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, • Onset of immunodeficiency at greater than 2 years of age • Absent isohemagglutinins and/or poor response to vaccines • Defined causes of hypogammaglobulinemia have been excluded according to a list of differential diagnosis […] The number of potential distinct entities within this group is still unknown, and the diagnosis remains one of exclusion. Monogenic forms have been described, but polygenic inheritance is likely in most. Despite the fact that several monogenic defects underlying apparent CVID have been defined, because of the rarity of each defect and the lack in most cases of significant impact on management, as well as the cost of testing, genetic studies are not considered appropriate for routine use in patients with CVID at this time. FIRENZE 11 – 12 Novembre 2016

Heterogeneous Disease 33-80% ‘’infectjon-only phenotype’’ Vs Neoplastic 20-67% ‘’complicated phenotype’’ Hodgkin and non-Hodgkin Lymphoma Cancer FIRENZE 11 – 12 Novembre 2016

The importance of being complicated ’70: survival 12 years afuer diagnosis = <30% ’90: survival 20 years afuer diagnosis = 64-67% (vs general populatjon 92-94%) 33-80% ‘’infectjon-only phenotype’’ Vs Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and 20-67% ‘’complicated phenotype’’ mortality in common variable immune defjciency over 4 decades. Blood . 2012;119(7):1650-1657. doi:10.1182/blood-2011-09-377945. FIRENZE 11 – 12 Novembre 2016

The long road to phenotyping FIRENZE 11 – 12 Novembre 2016

FIRENZE 11 – 12 Novembre 2016

ESID registry CVID criteria FIRENZE 11 – 12 Novembre 2016

…e la genetica… ? 40 • 35 Mutazioni o polimorfjsmi relatjvamente comuni con scarso signifjcato diagnostjco o prognostjco (TACI) • Mutazioni rarissime 30 Identjfjed CVID genes • Ricerca con studi di singole famiglie, mediante geni candidatj, alterazioni 25 immunologiche evidentj o con studi omozigosità e altri approcci complessi e costosi. • Nella pratjca metodiche di sequenziamento ‘’tradizionali’’: lente e costose 20 15 10 2011; 6 5 2007; 3 2008; 3 2004; 1 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 FIRENZE 11 – 12 Novembre 2016

FIRENZE 11 – 12 Novembre 2016

FIRENZE 11 – 12 Novembre 2016

Cost to sequence a human genome estjmate NGS Sanger sequencing = ~2400$/Mbp Various NGS platgorms = 10 to 0.05$/Mbp FIRENZE 11 – 12 Novembre 2016

Targeted panel VS Whole-exome VS Whole-genome sequencing FIRENZE 11 – 12 Novembre 2016

40 35 30 Identjfjed CVID genes 25 20 15 10 2011; 6 5 2007; 3 2008; 3 2004; 1 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 FIRENZE 11 – 12 Novembre 2016

Expanding and merging of disease phenotypes DCLREC1C / ARTEMIS JAK3 CVID LOCID SCID CID AK2 RAG1 and RAG2 Hum Mol Genet. 2015 Dec 20;24(25):7361-72. doi: 10.1093/hmg/ddv437. Epub 2015 Oct 16. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Volk T 1 , et al. J Investig Allergol Clin Immunol. 2015;25(3):218-20. Common Variable Immunodeficiency or Late-Onset Combined Immunodeficiency: A New Hypomorphic JAK3 Patient and Review of the Literature. Abolhassani H, Cheraghi T, Rezaei N, Aghamohammadi A, Hammarström L. A NOVEL MUTATION IN AK2 RESULTS IN COMMON VARIABLE IMMUNODEFICIENCY R. Hoyos et al. Poster ESID6-0116 Barcelona 2016 FIRENZE 11 – 12 Novembre 2016

RAG defj fjciency Omenn syndrome : a disorder of Rag1 and Rag2 genes. Villa A, et. al J Clin Immunol. 1999 Mar;19(2):87-97. Review. Agammaglobulinemia associated to nasal polyposis due to a hypomorphic RAG1 mutation in a 12 years old boy. Cifaldi C, et al. Clin Immunol. 2016 Oct 3. pii: S1521-6616(16)30410-7. doi: 10.1016/j.clim.2016.09.013. [Epub ahead of print] A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency . Abolhassani et al. J Allergy Clin Immunol. 2014 Dec;134(6):1375-80. doi: 10.1016/j.jaci.2014.04.042. RAG1 deficiency may present clinically as selective IgA deficiency . Kato T, et al. J Clin Immunol. 2015 Apr;35(3):280-8. doi: 10.1007/s10875-015-0146-4. Hypomorphic Rag mutations can cause destructive midline granulomatous disease . De Ravin SS, et al. Blood. 2010 Aug 26;116(8):1263-71. doi: 10.1182/blood-2010-02-267583. J Clin Immunol. 2016 Oct;36(7):725-32. doi: 10.1007/s10875-016-0326-x. Epub 2016 Aug 18. Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency. John T 1 , et al. FIRENZE 11 – 12 Novembre 2016

Tumors, DNA repair and radiosensitj tjvity Malignancies are the major cause of death in patjents with adult onset CVID Kaplan-Meier curves for patients with CVID. (1) Cumulative; (2) without cancers; and (3) with cancer complications. Isabella Quinti et al. Blood 2012;120:1953-1954 FIRENZE 11 – 12 Novembre 2016

Tumors, DNA repair and radiosensitj tjvity Immunogenetics. 2011 Jan;63(1):1-11. doi: 10.1007/s00251-010-0483-7. Epub 2010 Oct 12. Altered spectrum of somatic hypermutation in common variable immunodeficiency disease characteristic of defective repair of mutations. Duvvuri B 1 , Duvvuri VR, Grigull J, Martin A, Pan-Hammarström Q, Wu GE, Larijani M. PLoS One. 2010 Aug 18;5(8):e12260. doi: 10.1371/journal.pone.0012260. Unique DNA repair gene variatj tjons and potentj tjal associatj tjons with the primary antj tjbody defj fjciency syndromes IgAD and CVID. Ofger SM 1 , Pan-Hammarström Q, Hammarström L, Harris RS. MLH1, MSH2, MSH5, NBS1, RAD50 FIRENZE 11 – 12 Novembre 2016

Tumors, DNA repair and radiosensitj tjvity Common variable immunodefj fjciency caused by FANC mutatj tjons Y. Sekinaka et al. Poster ESID6-0818 Barcelona 2016 2 Patjents presentjng with adult onset CVID skewed CD45RO+ memory T-cells, absent TRECs and sjKRECs No anemia, thrombocytopenia or neutropenia WES  FANCA and FANCE mutatjons Common variable immunodefj fjciency syndrome associated with BRCA2 mutatj tjon R. Romano et al. Poster ESID6-0540 Barcelona 2016 The patjent was born to fjrst-degree consanguineous parents, with history of cancer and mental retardatjon. Diagnosis of CVID was made at 9 years old of age. Moreover, the patjent showed typical symptoms of Fanconi Anemia-like syndrome, such as short stature, mental and developmental delay FIRENZE 11 – 12 Novembre 2016

Tumors, DNA repair and radiosensitj tjvity Implicazioni nella gestj tjone clinica: • Uso di radiazioni ionizzantj ? • Uso di chemioterapici alchilantj ? Implicazioni prognostj tjche ed etj tjche: • Screening per tumori più stretuo ? • Rischio di tumori nella famiglia ? FIRENZE 11 – 12 Novembre 2016

Autoinfm fmammatj tjon 17 yo, female 32 yo, male 18yo SIgAD  evolutjon to CVID, SLE-like disease Vasculopathy No vasculitjs, chronic infmammatory state Splenomegaly Splenomegaly, aphtosis, enteropathy J Clin Immunol. 2016 Apr;36(3):179-86. doi: 10.1007/s10875-016-0245-x. Epub 2016 Feb 27. Defj fjciency of Adenosine Deaminase 2 Causes Antj tjbody Defj fjciency. Schepp J 1 , et al. CECR1 (Cat Eye Syndrome Critjcal Region Protein 1 ) N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. Epub 2014 Feb 19. Early-onset stroke and vasculopathy associated with mutatj tjons in ADA2. Zhou Q 1 , et al. • Familial Panarteritjs Nodosa • Defjcency of ADA2 Sneddon syndrome • Livedo racemosa Rapid and sustained efg fgect of antj tj-TNF treatment in patj tjents with ADA2 defj fjciency R Caorsi, 1 et al. Pediatr Rheumatol Online J. 2015; 13(Suppl 1): O80. FIRENZE 11 – 12 Novembre 2016

Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon CTLA-4 and LRBA FIRENZE 11 – 12 Novembre 2016

Immunedysregulatj tjon, Autoimmunity and Ly Lymphoproliferatj tjon CTLA-4 defj fjciency or LRBA defj fjciency haploinsuffj ffjciency Autosomal recessive AD with incomplete penetrance FIRENZE 11 – 12 Novembre 2016