Genetic testing should be routinely done in the diagnosis of CVID - PowerPoint Presentation

Slide1

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

Slide2

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 ageAbsent or poor response to vaccinesDefined causes of hypogammaglobulinemia have been excluded Clinical heterogeneity, lack of specific genetic/ phenotypic classification

Slide3

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Slide4

Complications

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

Slide5

Non-infectious complication

Lung disease (30%) Restrictive

GLILD (10%), BOOP

Obstructive

Bronchiectasis (10-20%), asthmaNeoplasia: 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

Slide6

Survival: Infectious vs Non Infectious

Autoimmune, Inflammatory

Complications

Infectious 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.

Slide7

CVID Genetics

Monogenic cause identified in 2-10% of CVID patientsEpigenetic mechanisms also contribute to disease and phenotype

Bogaert

et al. J Med Genet. 2016

Slide8

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.

Slide9

Challenges

CostAccessibilityInterpretation

Slide10

Cost

Genomic approaches can cost $1000sVariation between lab pricing and insurance policiesGene Panels/Targeted vs Whole Exome

Cost decreasing with improvement in technologies

Slide11

Genetic Panels

Invitae PID Panel (201 genes), CVID Panel

Blueprint Genetics

PID Panel (274 genes)

Slide12

Invitae – PID Panel

Slide13

Invitae – CVID Panel

Slide14

Blueprint Genetics -- 274 Genes

ACD ACP5 ACTB ADA ADAM17 ADAR AICDA AIRE AK2 AP3B1 ARPC1B

ATM BACH2 BCL10 BCL11B BLM BLNK BTK C1QA C1QB C1QC C1S

C2 C3 CARD11 CARD14 CARD9 CASP10 CASP8

CD19 CD247 CD27 CD3DCD3E CD3G CD40 CD40LG CD46 CD55 CD59 CD70 CD79A CD79B

CD81

CD8A CDCA7 CEBPE CECR1 CFB CFD CFH CFI CFP CFTR CHD7

CIITA CLCN7 CLPB COLEC11 COPA CORO1A

CR2

CSF2RA CSF2RB CSF3R CTC1

CTLA4

CTPS1 CTSC CXCR4 CYBA CYBB DCLRE1C DDX58 DGKE DKC1 DNAJC21

DNMT3B DOCK2 DOCK8 ELANE EPG5 ERCC6L2 EXTL3 FADD FAS FASLG FERMT3

FOXN1 FOXP3 G6PC3 G6PD GATA2 GF1 GINS1 HAX1 HELLS HYOU1

ICOS

IFIH1 IFNAR2 IFNGR1 IFNGR2 IGLL1 IKBKB IKZF1 IL10 IL10RA IL10RB IL12B

IL12RB1 IL17RA IL17RC IL1RN

IL21

IL21R

IL2RA IL2RG IL36RN IL7R IRAK4

IRF2BP2

IRF8 ISG15 ITGB2 ITK JAGN1 JAK1 JAK3 KRAS LAMTOR2 LAT

LCK LIG4 LPIN2

LRBA

LYST MAGT1 MALT1 MAP3K14 MASP1 MEFV MKL1

MOGS MRE11A MSN MTHFD1 MVK MYD88 MYO5A NBN NCF1 NCF2 NCF4

NCSTN

NFKB1

NFKB2

NFKBIA NHEJ1 NHP2 NLCR4 CLRP1 NLRP12 NLRP3 NOD2

NOP10 NRAS NSMCE3 OFD1 ORAI1 OTULIN PARN PEPD PGM3 PIGA

PIK3CD

PIK3R1

PLCG2

PMS2 PNP POLE POLE2 PRF1

PRKCD

PRKDC PSENEN PSMB8

PSTPIP1

PSTPIP1

PTPRC RAB27A

RAC2

RAG1 RAG2 RASGRP1 RBCK1 RECQL4 RFX5

FRXANK RFXAP RHOH RLTPR RMRP RNASEH2A RNASEH2B RNASEH2C RNF168 RNF31 RNU4ATAC RORC RPSA RTEL1 SAMD9 SAMD9L SAMHD1 SBDS SERPING1 SH2D1A SLC29A3 SLC35C1

SLC37A4 SLC46A1 SLC7A7 SMARCAL1 SMARCD2 SP110 SPINK5 SRP72 STAT1 STAT2

STAT3

STAT5B STIM1 STK4 STX11 STXBP2 TAP1 TAP2 TAPBP TBX1 TCF3 TCN2

TERC TERT TFRC THBD TINF2 TMC6 TMC8 TMEM173 TNFAIP3

TNFRSF13B

TNFRSF1A

TNFRSF4 TRAF3IP2 TREX1 TRNT1 TTC7A TYK2 UNC119 UNC13D UNC93B1 UNG USB1

USP18 VPS45 WAS WDR1 WIPF1 WRAP53 XIAP ZAP70 ZBTB24 ZNF341

Slide15

Genetic Panels

Invitae

PID Panel (201 genes), CVID Panel

$ 100 to 250Blueprint Genetics PID Panel (274 genes) $ 450 to 900 Exome Proband

: $ 1500

Trio: $ 2400

Slide16

Accessibility

Broadly commercially available and accepted for diagnosisInsurance restrictionsGeneticist orders

Interpretation

Improving technology

Slide17

Benefits

ManagementPrognosisGenetic CounsellingIdentify new gene and Database

Slide18

Management

Targeted therapeutics for non infectious manifestation in CVID, this approach will improve management of patients with more severe phenotypesMonitoring for complications and malignancyUsing Prophylactic Antibiotics

Abatacept

: LRBA and CTLA4

Leniolisib: PI3 Kinase

Slide19

Prognosis

Clinical course predictionAtypical presentations

Genetic Counselling

Family members, Family Planning

Rate of recurrence by knowing the inheritance pattern

Slide20

Stem Cell Transplantation

HSCT indicated or notRisk of GVHD reactions rate higher in certain mutations or notPrognosis

Has shown positive results in patients with LRBA and CTLA4

Slide21

Stem Cell Transplantation

Wehr

, et al. J Allergy

Clin

Immunol 2015;135-988-97

Slide22

Stem Cell Transplantation

Slide23

Refrences

Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3K

δ

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, 

Maciej

 

Cabanski

, 

Aniket

D. Joshi, Stefan de Buck, Julie 

Doucet

, 

Danilo

 

Guerini

, Christoph 

Kalis

, Ilona 

Pylvaenaeinen

, Nicolas 

Soldermann

, 

Anuj

 

Kashyap

, 

Gulbu

 

Uzel

, 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 immunodeficiency

Claudia

Wehr

,

MD,a

Andrew R.

Gennery

,

MD,b

Caroline

Lindemans

, MD,

PhD,c

Ansgar

Schulz,

MD,d

Manfred

Hoenig

,

MD,d

Reinhard

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,n

Sigune

Goldacker

,

MD,a

Lorena

Regairaz

,

MD,o

Serap

Aksoylar

,

MD,p

Omur

Ardeniz

,

MD,q

Marco

Zecca

,

MD,r

Przemyslaw

Zdziarski

, MD,s Isabelle

Meyts

,

MD,t

Susanne

Matthes

-Martin,

MD,u

Kohsuke

Imai,

MD,v

Chikako

Kamae

,

MD,w

Adele Fielding,

MD,x

Suranjith

Seneviratne

,

MD,y

Nizar

Mahlaoui

, MD,

MSc,

MPH,z

Mary A.

Slatter

,

MD,aa

Tayfun

G€ung€or

,

MD,j

Peter D. Arkwright,

MD,bb

Joris

van

Montfrans

,

MD,cc

Kathleen

E. Sullivan, MD,

PhD,dd

Bodo

Grimbacher

,

MD,a

Andrew Cant,

MD,b

Hans-

Hartmut

Peter,

MD,a

Juergen

Finke,

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

Mutation

Bianca

Tesi

& Peter

Priftakis

& Fredrik

Lindgren

& Samuel C. C.

Chiang & Nikolaos

Kartalis

& Alexandra

Löfstedt

& Esther

Lörinc

& Jan-

Inge

Henter

& 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?

Delfien

J A

Bogaert

,

Melissa

Dullaers

,

Bart N

Lambrecht

, Karim

Y

Vermaele

,

Elfride

De

Baere

,

Filomeen

Haerynck

Morbidity and mortality in common variable immune deficiency over 4

decades

Elena

S.

Resnick,

Erin L.

Moshier

,

James H.

Godbold,and

Charlotte

Cunningham-Rundles