ORIGINAL RESEARCH

Primary Immunodeficiency Diseases: an Updateon the Classification from the International Unionof Immunological Societies Expert Committeefor Primary Immunodeficiency 2015

Capucine Picard1,2& Waleed Al-Herz3,4 & Aziz Bousfiha5 & Jean-Laurent Casanova1,6,7,8,9 &

Talal Chatila10 & Mary Ellen Conley6 & Charlotte Cunningham-Rundles11 &

Amos Etzioni12 & Steven M. Holland13& Christoph Klein14

& Shigeaki Nonoyama15 &

Hans D. Ochs16 & Eric Oksenhendler17,18 & Jennifer M. Puck19& Kathleen E. Sullivan20

&

Mimi L K. Tang21,22,23 & Jose Luis Franco24 & H. Bobby Gaspar25

Received: 20 July 2015 /Accepted: 20 September 2015 /Published online: 19 October 2015# The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract We report the updated classification of primary im-munodeficiencies compiled by the Primary ImmunodeficiencyExpert Committee (PID EC) of the International Union ofImmunological Societies (IUIS). In the two years since the

previous version, 34 new gene defects are reported in this up-dated version. For each disorder, the key clinical and laboratoryfeatures are provided. In this new version we continue to seethe increasing overlap between immunodeficiency, as

J Clin Immunol (2015) 35:696–726DOI 10.1007/s10875-015-0201-1

* H. Bobby Gasparh.gaspar@ucl.ac.uk

1 Laboratory of Human Genetics of Infectious Diseases, NeckerBranch, INSERM UMR1163, Necker Hospital for Sick Children,Paris, France

2 Centre d’étude des déficits immunitaires (CEDI), HôpitalNecker-Enfants Malades, AP-HP, Paris, France

3 Department of Pediatrics, Faculty of Medicine, Kuwait University,Kuwait City, Kuwait

4 Allergy and Clinical Immunology Unit, Department of Pediatrics,Al-Sabah Hospital, Kuwait City, Kuwait

5 Clinical Immunology Unit, Casablanca Children’s Hospital, IbnRochd Medical School, King Hassan II University,Casablanca, Morocco

6 St. Giles Laboratory of Human Genetics of Infectious Diseases,Rockefeller Branch, The Rockefeller University, New York, NY,USA

7 Howard Hughes Medical Institute, New York, NY, USA8 University Paris Descartes, Imagine Institute, Paris, France9 Pediatric Hematology & Immunology Unit, Necker Hospital for Sick

Children, Paris, France10 Division of Immunology, Children’s Hospital Boston, Boston, MA,

USA11 Department of Medicine and Pediatrics, Mount Sinai School of

Medicine, New York, NY, USA

12 Meyer Children’s Hospital-Technion, Haifa, Israel13 Laboratory of Clinical Infectious Diseases, National Institute of

Allergy and Infectious Diseases, Bethesda, MD, USA14 Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University

Munich, Munich, Germany15 Department of Pediatrics, National Defense Medical College,

Saitama, Japan16 Department of Pediatrics, University of Washington and Seattle

Children’s Research Institute, Seattle, WA, USA17 Department of Clinical Immunology, Hôpital Saint-Louis,

Assistance Publique-Hôpitaux de Paris, Paris, France18 Université Paris Diderot, Sorbonne Paris Cité, Paris, France19 Department of Pediatrics, University of California San Francisco and

UCSF Benioff Children’s Hospital, San Francisco, CA, USA20 Division of Allergy Immunology, Department of Pediatrics, The

Children’s Hospital of Philadelphia, Philadelphia, PA, USA21 Murdoch Childrens Research Institute, Melbourne, VIC, Australia22 Department of Paediatrics, University of Melbourne,

Melbourne, VIC, Australia23 Department of Allergy and Immunology, Royal Children’s Hospital,

Melbourne, Australia24 Group of Primary Immunodeficiencies, University of Antioquia,

Medellin, Colombia25 UCL Institute of Child Health, 30, Guilford Street, London WC1N

1EH, UK

manifested by infection and/or malignancy, and immune dys-regulation, as manifested by auto-inflammation, auto-immuni-ty, and/or allergy. There is also an increased number of geneticdefects that lead to susceptibility to specific organisms whichreflects the finely tuned nature of immune defense systems.This classification is the most up to date catalogue of all knownand published primary immunodeficiencies and acts as a cur-rent reference of the knowledge of these conditions and is animportant aid for the genetic and molecular diagnosis of pa-tients with these rare diseases.

Keywords Primary immunodeficiencies . classification .

genetic defects

Background

The International Union of Immunological Societies (IUIS)Expert Committee on Primary Immunodeficiency met inLondon on the 14th and 15th March 2015 to update the clas-sification of human primary immunodeficiencies (PIDs). Thisreport represents the most current and complete catalogue ofknown PIDs. It serves as a reference for these conditions andprovides a framework to help in the diagnostic approach topatients suspected to have PID.

As in previous reports, we have classified the condi-tions into major groups of PIDs and these are now repre-sented in 9 different tables (Tables 1, 2, 3, 4, 5, 6, 7,8 and9). In each table, we list the condition, its genetic defect ifknown and the major immunological and in some condi-tions the non-immunological abnormalities associatedwith the disease. This year we have added the geneOMIM number as well as the phenotype OMIM numberfor ease of reference.

The classification this year differs in a number of waysfrom the previous edition published in 2014. Importantly,each defect is now listed in only one table. The diverseimmunological phenotypes of many conditions imply thata very large number of conditions could very readily belisted in multiple tables. However, with the increasingnumber of identified defects, this would make each tablelarge and cumbersome. For this reason, we chose to listeach defect in one table only and to place it according tothe most pronounced and fundamental defect. For thisreason and as an example, CD40L deficiency is nowfound in Table 1 amongst combined immunodeficiencies,because CD40L is a T cell signaling molecule whose ab-sence leads to both cellular and humoral defects, eventhough it was originally described as an antibody deficien-cy. Although some of our placements may be disputed,the committee came to these decisions after much thoughtand deliberation.

The title of Table 6 has now been slightly changed to‘Defects in intrinsic and innate immunity’ and contains de-fects characterized by susceptibility to specific organisms.For this reason, the MSMDs (Mendelian Susceptibility toMycobacterial Disease) are now in Table 6, having previouslybeen in Table 5 (Phagocytic Disorders).

In previous editions, we have placed an asterisk againstconditions in which 10 or fewer individuals had been de-scribed in the literature. However, this is now felt to be anartificial indicator as, once described, a condition may befound in additional patients but not necessarily reported. Forthis reason, there is no specific indicator of the number ofpatients identified or reported.

There is a growing appreciation of wide phenotypic vari-ability for many of the individual specific gene defects,reflecting not only the variety of mutations within each genebut also host and/or environmental modifying factors that mayimpact the phenotype even between individuals with the samemutation within the same gene. The complexities of theseconditions in terms of clinical and immunological presenta-tion and heterogeneity cannot easily be captured in the limitedspace of a table format. For this reason, the furthest rightcolumn contains the Online Mendelian Inheritance in Man(OMIM) reference for each condition to allow access to asource of greater detail and updated information as to thephenotype.

A number of the new genes included in this edition of theclassification tables are molecules associated not only with theimmune system, but also with more generic cellular functions;such defects result in both immunological and non-immunological abnormalities. In addition, there are a numberof gain-of-function (GOF) mutations identified such as inPIK3CD. In CARD11 and STAT1 for example, there are bothautosomal dominant GOF and autosomal recessive loss offunction variants and these different modes of inheritance inthe same gene lead to different functional consequences andhence different immunological and clinical phenotypes. Theother trend that is increasingly observed is the increase indisorder of immunedysregulation rather than pureimmunodeficiency.

The goal of the IUIS Expert Committee on PrimaryImmunodeficiencies is to increase awareness, facilitate rec-ognition and promote optimal treatment for patients withPrimary Immunodeficiencies. In addition to the currentreport and previous ‘classification table’ publications, thecommittee has also produced a ‘Phenotypic Approach forIUIS PID classification and Diagnosis: Guidelines forClinicians at the Bedside,’ which aims to lead physiciansto particular groups of PIDs starting from clinical featuresand combining routine immunological investigations. Thiswill be further updated to include the newly identifieddefects. Together these contributions will hopefully allowa practical clinical framework for PID diagnosis.

J Clin Immunol (2015) 35:696–726 697

Tab

le1

Immunodeficienciesaffectingcellu

larandhumoralim

munity

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

T− B

+SevereCom

binedIm

munodeficiency(SCID

)

γcdeficiency

Mutationof

IL2R

GDefectinγchainof

receptorsforIL-2,

-4,-7,-9,-15,-21

308380

XL

Markedlydecreased

Normalor

increased

Decreased

Markedlydecreased

NKcells;

300400

JAK3deficiency

Mutationof

JAK3

DefectinJanus

activatingkinase

3600173

AR

Markedlydecreased

Normalor

increased

Decreased

Markedlydecreased

NKcells;

600802

IL7R

αdeficiency

Mutationof

IL7R

ADefectinIL-7

receptor

αchain

146661

AR

Markedlydecreased

Normalor

increased

Decreased

NormalNKcells

608971

CD45

deficiency

Mutationof

PTP

RC

DefectinCD45

151460

AR

Markedlydecreased

Normal

Decreased

Normalγ/δ

Tcells

608971

CD3δ

deficiency

Mutationof

CD3D

DefectinCD3δ,chain

ofTcellantigen

receptor

complex

186790,

AR

Markedlydecreased

Normal

Decreased

NormalNKcells

Noγ/δ

Tcells

615617

CD3ε

deficiency

Mutationof

CD3E

DefectinCD3ε

chain

ofTcellantigen

receptor

complex

186830,

AR

Markedlydecreased

Normal

Decreased

NormalNKcells

Noγ/δ

Tcells

615615

CD3ζ

deficiency

Mutationof

CD3Z

DefectinCD3ζ

chainof

Tcell

antigen

receptor

complex

186780

AR

Markedlydecreased

Normal

Decreased

NormalNKcells

Noγ/δ

Tcells

610163

Coronin-1Adeficiency

Mutationof

CORO1A

Defectivethym

icegress

ofTcells

anddefective

Tcelllocomotion

605000

AR

Markedlydecreased

Normal

Decreased

Detectablethym

usEBV-associatedB-cell

lymphoproliferation

615401

T− B

−SCID

DNArecombinationdefects(for

additionalD

NArepairdefectsseeTable2)

RAG1deficiency

Mutationof

RAG1

DefectiveVDJ

recombination;

defectof

recombinase

activatinggene

(RAG)1

179615

AR

Markedlydecreased

Markedlydecreased

Decreased

601457

RAG2deficiency

Mutationof

RAG2

DefectiveVDJ

recombination;

AR

Markedlydecreased

Markedlydecreased

Decreased

601457

698 J Clin Immunol (2015) 35:696–726

Tab

le1

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

defectof

recombinase

activatinggene

(RAG)2

179616

DCLRE1C

(Artem

is)

deficiency

Mutationof

ARTE

MIS

DefectiveVDJrecombination;

defectin

Artem

isDNA

recombinase-repairprotein

605988

AR

Markedlydecreased

Markedlydecreased

Decreased

Radiationsensitivity

602450

DNAPK

csdeficiency

Mutationof

PRKDC

DefectiveVDJ

recombination;

defectin

DNA

PKcs

Recom

binase

repair

protein

600899

AR

Markedlydecreased

Markedlydecreased

variable

Radiationsensitivity,

microcephalyand

developm

entald

efects

Autoimmunity

andgranulom

a

615966

Cernunnos/XLF

deficiency

Mutationof

Cernunnos

DefectiveVDJ

recombination;

defectin

Cernunnos

611290

AR

Markedlydecreased

Markedlydecreased

Decreased

Radiationsensitivity,

microcephalyand

developm

entald

efects

611291

DNAligaseIV

deficiency

Mutationof

LIG

4DefectiveVDJrecombination;

defectin

DNA

ligaseIV

601837

AR

Markedlydecreased

Markedlydecreased

Decreased

Radiationsensitivity,

microcephalyand

developm

entald

efects

606593

Reticular

dysgenesis,

AK2deficiency

Mutationof

AK2

Defectivematurationof

lymphoidandmyeloid

cells

(stem

celldefect)

Defectinmitochondrial

adenylatekinase

2.103020

AR

Markedlydecreased

Decreased

ornorm

alDecreased

Granulocytopeniaanddeafness

267500

Adenosine

deam

inase

(ADA)deficiency

Mutationof

ADA

AbsentA

DAactivity,elevated

lymphotoxicmetabolites

(dATP,S-adenosylh

omocysteine)

608958

AR

Absentfrom

birth(nullm

utations)

orprogressivedecrease

Absentfrom

birthof

progressivedecrease

Progressivedecrease

Decreased

NKcells,often

with

costochondraljunction

flaring,neurological

features,hearing

impairment,

lung

andliver

manifestations;

partialA

DAdeficiency

may

lead

todelayedor

milder

presentatio

n

102700

Com

binedim

munodeficienciesgenerally

less

profound

than

severecombinedim

munodeficiency

DOCK2deficiency

Mutations

inDOCK2required

forRAC1activ

ation,

actin

polymerization,

T-cellproliferation,

chem

okine-induced

lymphocytemigration

andNK-celld

egranulatio

n603122

AR

Decreased.P

oorresponse

toPH

A.L

owTRECs

Normal

Decreased/N

ormal.

Poor

antibody

responses

NormalNKnumbers,but

defective

function.Im

paired

interferon

responsesin

hematopoieticand

non-hematopoieticcells

616433

J Clin Immunol (2015) 35:696–726 699

Tab

le1

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

CD40

liganddeficiency

Mutationof

CD40LGDefectsin

CD40

ligand(CD40L;

also

calledTNFS

F5

orCD154)

causedefective

isotypesw

itching

andim

paired

dendritic

cellsignaling

300386

XL

Normal;m

ayprogressivelydecrease

sIgM

+andsIgD

+Bcells

present,

othersurfaceisotype

positiveBcells

absent

IgM

increasedor

norm

al,other

isotypes

decreased

Neutropenia,throm

bocytopenia;

hemolyticanem

ia,biliary

tractand

liver

disease,

opportunistic

infections

308230

CD40

deficiency

Mutationof

CD40

(alsocalled

TNFR

SF5

)Defectsin

CD40

causedefective

isotypesw

itching

andim

paired

dendritic

cellsignaling

109535

AR

Normal

IgM

+andIgD+Bcells

present,

otherisotypes

absent

IgM

increasedor

norm

al,other

isotypes

decreased

Neutropenia,gastrointestinal

andliver/biliarytract

disease,opportunistic

infections

606843

ICOSdeficiency

Mutations

inICOS;

aco-stim

ulatory

moleculeexpressedon

Tcells

604558

AR

Normal

Normal

Low

Recurrent

infections;autoimmunity,

gastroenteritis,m

ayhave

granulom

as

607594

CD3γ

deficiency

Mutationof

CD3G

.DefectinCD3γ

component

oftheTcell

antigen

receptor

complex

186740

AR

Normal,but

reducedTCR

expression

Normal

Normal

615607

CD8deficiency

Mutationof

CD8A

.Defectsof

CD8

αchain,im

portantfor

maturation

andfunctionof

CD8Tcells

186910

AR

AbsentC

D8,norm

alCD4cells

Normal

Normal

ZAP-70

deficiency

Mutationin

ZAP70

intracellular

signalingkinase,acts

downstream

ofTCR

176947

AR

Decreased

CD8,norm

alCD4cells

Normal

Normal

Autoimmunity

insomecases

269840

MHCclassIdeficiency

Mutations

inTA

P1,gene,

causingMHCclass

Inon-expression

170260

AR

Decreased

CD8,norm

alCD4cells;

absent

MHCIexpression

onlymphocytes

Normal

Normal

Vasculitis;p

yoderm

agangrenosum

604571

MHCclassIdeficiency

Mutations

inTA

P2,gene,

causingMHCclass

Inon-expression

170261

AR

Decreased

CD8,norm

alCD4cells;

absent

MHCIexpression

onlymphocytes

Normal

Normal

Vasculitis;p

yoderm

agangrenosum

604571

MHCclassIdeficiency

Mutations

inTA

PBP(tapasin)

gene,causing

MHC

classInon-expression

601962

AR

Decreased

CD8,norm

alCD4cells;

absent

MHCIexpression

onlymphocytes

Normal

Normal

Vasculitis;p

yoderm

agangrenosum

604571

MHCclassIdeficiency

Mutations

inB2M

gene,

causingMHCclass

Inon-expression

109700

AR

Decreased

CD8,norm

alCD4cells;

absent

MHCIexpression

onlymphocytes

Normal

Normal

Sinopulmonaryinfections,cutaneous

granulom

a,hypoproteinemia.

Absentexpressionof

β2m

associated

proteins

likeMHC-I,

CD1a,and

CD1b,C

D1c

onβ2m

-deficientcells

noty

etassigned

MHCclassIIdeficiency

groupA

Mutationin

transcription

factorsforMHCclassII

proteins

(CIITA

gene)

600005

AR

Decreased

CD4cells

AbsentM

HCIIexpression

onlymphocytes

Normal

Normalor

decreased

Failureto

thrive,diarrhea,respiratory

tractinfections

liver/biliary

tractd

isease

209920

700 J Clin Immunol (2015) 35:696–726

Tab

le1

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

MHCclassIIdeficiency

groupB

Mutationin

transcription

factorsforMHCclassII

proteins

RFXANKgene

603200

AR

Decreased

CD4cells

AbsentM

HCIIexpression

onlymphocytes

Normal

Normalor

decreased

Failureto

thrive,diarrhea,

respiratorytractinfectio

nsliver/biliarytractd

isease

209920

MHCclassIIdeficiency

groupC

Mutationin

transcription

factorsforMHCclassII

proteins

RFX5,gene)

601863

AR

Decreased

CD4cells

AbsentM

HCIIexpression

onlymphocytes

Normal

Normalor

decreased

Failureto

thrive,diarrhea,respiratory

tractinfectio

nsliv

er/biliarytract

disease

209920

MHCclassIIdeficiency

groupD

Mutationin

transcriptionfactors

forMHCclassIIproteins

(RFXAPgene

601861

AR

Decreased

CD4cells

AbsentM

HCIIexpression

onlymphocytes

Normal

Normalor

decreased

Failureto

thrive,diarrhea,respiratory

tractinfectio

nsliv

er/biliary

tractd

isease

209920

ITKdeficiency

Mutations

inITKencoding

IL-2

inducibleTcellkinase

required

forTCR-m

ediatedactivation

186973

AR

Progressivedecrease

Normal

Normalor

decreased

EBVassociated

Bcelllymphop-

roliferation,lymphom

aNormalor

decreasedIgG

613011

MAGT1deficiency

Mutations

inMAGT1

,Impaired

Mg+

+flux

leadingto

impaired

TCRsignaling300715

XL

Decreased

CD4cells

reducednumbers

ofRTE,impaired

T-cell

proliferationin

response

toCD3

Normal

Normal

EBVinfection,lymphom

a;viralinfections,respiratory

andGIinfections,

300853

DOCK8deficiency

Mutations

inDOCK8encoding

adedicatorof

cytokinesis

regulatorof

intracellular

actin

reorganisatio

n611432

AR

Decreased;Impaired

Tlymphocyte

proliferation;

Tregdeficiency

andpoor

function

Decreased;low

CD27+mem

ory

Bcells

Low

IgM,increased

IgE

Decreased

NKcells

with

impaired

function,hypereosinophilia,

recurrentinfectio

ns;severe

atopy,extensivecutaneous

viraland

staphylococcal

infections,susceptibility

tocancer.D

efectsin

peripheralBtolerance.

243700

RhoHdeficiency

Mutations

inRHOH–an

atypical

Rho

GTPase

transducing

signalsdownstream

ofvariousmem

branereceptors

602037

AR

Normal

lownaïveTcells

andRTE,restricted

Tcellrepertoireandim

paired

Tcells

proliferationin

response

toCD3stim

ulation.

Normal

Normal

HPV

infection,lymphom

a,lung

granulom

as,m

olluscum

contagiosum,

noty

etassigned

MST

1deficiency

Mutations

inST

K4–aserine/

threoninekinase

604965

AR

Decreased

increasedproportion

ofterm

inaldifferentiatedeffector

mem

orycells

(TEMRA),low

naïveTcells,restricted

Tcellrepertoire

inthe

TEMRApopulationand

impaired

Tcells

proliferation

Decreased

High

Recurrent

bacterial,viral,and

candidal

infections;intermittent

neutropenia;

EBV-drivenlymphoproliferation;

lymphom

a;Congenitalh

eart

disease,autoim

munecytopenias;

HPV

infection.

614868

TCRαdeficiency

Mutations

inTR

AC–essential

component

oftheTcellreceptor

186880

AR

NormalAllCD3Tcells

expressed

TCRγδ(ormay

bebetter

tosay:

TCRαβT-cell

deficiency),im

paired

Tcells

proliferation

Normal

Normal

Recurrent

viral,bacterialand

fungalinfections,immune

dysregulationautoim

munity,

anddiarrhea.

615387

LCKdeficiency

Defectsin

LCK–aproxim

altyrosine

kinase

thatinteractswith

TCR

153390

AR

Normaltotaln

umbersbutC

D4+

T-celllymphopenia,low

Tregnumbers,restricted

Tcellrepertoire

and

impaired

TCRsignaling

Normal

NormalIgGand

IgAandincreased

IgM

Diarrhea,recurrentinfectio

ns,

immunedysregulation

autoim

munity,

615758

MALT

1deficiency

Mutations

inMALT

1–

AR

Normal

Normal

Bacterial,fungaland

viralinfections

615468

J Clin Immunol (2015) 35:696–726 701

Tab

le1

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

acaspase-likecysteine

protease

that

isessentialfor

nuclear

factor-kappa-B

activation

604860

Normalnumberbutimpaired

Tcells

proliferation

Impaired

antibody

response

CARD11

deficiency

Defectsin

CARD11

–actsas

ascaffold

forNF-9B

activity

intheadaptive

immuneresponse

607210

AR

Normalpredom

inance

ofnaive

T-lymphocyte,im

paired

Tcells

proliferation

Normalpredom

inance

oftransitional

Blymphocytes,

Absent/low

Pneum

ocystis

jiroviciipneumonia,

bacterialinfections,

615206

BCL10

deficiency

Mutations

inBCL1

0which

encodestheBcellCLL/

lymphom

a10

proteinthat

form

saheterotrim

erwith

Malt1

andCARDfamily

adaptorsandplaysarole

inNF-kB

signaling

603517

AR

Normalnumbers,low

mem

ory

TandTregs,decreased

proliferationto

antigen

andanti-

CD3

Normalnumber;decreased

mem

oryandsw

itchedB

cells

Low

Recurrent

bacterialand

viralinfections,candidiasis,

gastroenteritis

616098

IL-21deficiency

Mutationin

IL21

605384

AR

Normalnumber.

Normal/lo

wfunctio

nLow

IgGdeficiency

Severeearlyonsetcolitis

615767

IL-21R

deficiency

Defectsin

IL21R–together

with

common

gamma

chainbindsIL-21

605383

AR

AbnormalTcellcytokine

production;

AbnormalTcellproliferation

tospecificstim

uli

Normal

Normalbutimpaired

specificresponses

Suspectibility

tocryptoporidia

andpneumocystis

andcholangitis

615207

OX40

deficiency

Defectsin

OX40

(TNFRSF

4)encoding

aco-stim

ulatory

moleculeexpressedon

activated

Tcells

600315

AR

NormalTcellnumbers;d

ecreased

antig

enspecificmem

oryCD4+

cells

NormalBcellnumbers;

reducedfrequencyof

mem

oryBcells

Normal

Kaposi’s

sarcom

a;im

paired

immunity

toHHV8

615593

IKBKBdeficiency

Defectsin

IKBKB,encoding

IkB2kinase

2,a

component

oftheNF-kB

pathway

603258

AR

NormaltotalT

cells;absentregulatory

and+%

Tcells;impaired

TCR

activ

ation

NormalBcellnumbers;

impaired

BCRactiv

ation;

Decreased

Recurrent

bacterial,viraland

fungalinfections;clinical

phenotypeof

SCID

615592

LRBAdeficiency

Mutations

inLR

BA

(lipopolysaccharide

responsive

beige-like

anchor

protein)

606453

AR

Normalor

decreasedCD4numbers;

Tcelldysregulation

Low

ornorm

alnumbersof

Bcells

Reduced

IIgG

andIgAin

most

Recurrent

infections,inflammatory

boweldisease,autoim

munity;

EBVinfections

614700

CD27

deficiency

Mutations

inCD27

(TNFRSF

7)encoding

TNF-Rmem

ber

superfam

ilyrequired

for

generationandlong-term

maintenance

ofTcellim

munity

186711

AR

Normal

Nomem

oryBcells

Hypogam

ma-

globulinaemia

follo

wingEBV

infection

Clinicalandim

munologicfeatures

triggeredby

EBVinfection,HLH

Aplastic

anaemia,L

ymphom

a,hypogammaglobulinem

ia,

Low

iNKTcells

615122

NIK

deficiency

Mutationin

MAP3K

14,encoding

NIK

(NF-kB

-inducingkinase)

604655

AR

Normalnumber;im

paired

proliferation

inresponse

toantigen

stim

ulation.

PolycloncalV

βrepertoires

Decreased

totalp

eripheral

Bcellandsw

itched

mem

oryBcells

Hypogam

ma-

globulinaemia

Recurrent

bacterial,viraland

Cryptosporidium

infections.

Low

NKcellnumberand

defectiveNKcellactiv

ation

Not

yet

assigned

CTPS1

deficiency

Mutationin

CTPS1,encoding

CTPsynthase

1,essential

forlymphocyteproliferation

123860

AR

Normalor

decreasednumber

Normalor

decreasedproliferation

Normal/lo

wnumber

Normal/highIgG

Recurrent/chronicviralinfectio

nsspecially

EBVandVZV,

bacterialinfections,E

BV-driven

B-celln

on-H

odgkin

lymphom

a

615897

702 J Clin Immunol (2015) 35:696–726

Tab

le1

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedFeatures

Phenotype

OMIM

number

Omennsyndrome

Hypom

orphicmutations

inRAG1,

RAG2,Artem

is,IL7

RA,R

MRP,

ADA,D

NALigase

IV,IL2

RG,

AK2,or

associated

with

DiGeorge

syndrome;somecaseshave

nodefinedgene

mutation

Present;restricted

Tcellrepertoire

andim

paired

functio

nNormalor

decreased

Decreased,except

forincreasedIgE

Erythroderm

a,eosinophilia,

adenopathies,

hepatosplenomegaly

603554

Totaln

o.of

genesin

Table1:

49

New

genesadded:

DOCK2,B2M

,IL2

1,MAP3K

14,C

TPS1

Notes:Infantswith

SCID

who

have

maternalTcellengraftm

entmay

have

allogeneic

Tcells

presenteven

innorm

alnumbers,butthat

donotfunctio

nnorm

ally;thesecells

may

causeautoim

mune

cytopenias

orgraftv

ersushostdisease.Hypom

orphicmutations

inseveralo

fthegenesthatwhenaffected

bynullmutations

causeSC

IDmay

resultin

Omennsyndrome(O

S),or“leaky”SCID

oraless

profound

combinedim

munodeficiencyor

CID

phenotype.BothOSandleakySCID

canbe

associated

with

>300autologous

Tcells/uLof

peripheralbloodandreducedrather

than

absent

proliferative

responses;Individualswith

partially

defective,or

leaky,mutations

aregenerally

moremild

lyaffected

comparedwith

thosewith

typicalS

CID

caused

bynullmutations.A

spectrum

ofclinicalfindings

includingtypicalSCID

,OS,leakySCID

,CID

,granulomas

with

Tlymphopenia,autoimmunity

andCD4+

Tlymphopeniacanbe

foundinan

allelic

seriesof

RAG1andotherS

CID

associated

genes.RAC2

deficiency

isadisorderof

leukocytemotilityandisreported

inTable5;however,one

patientwith

RAC2deficiency

hadabsentTcellreceptor

excision

circles(TRECs)by

newborn

screening,though

Tcell

numbersandmito

genresponseswerenotimpaired.F

oradditio

nalsyndrom

icconditionswith

Tcelllymphopenia,suchas

DNArepairdefects,cartilage

hairhypoplasia,IKAROSdeficiency

andNEMO

syndrome,seeTables

2and6;

however,itshouldbe

notedthatindividualswith

themostseveremanifestatio

nsof

thesedisorderscouldhave

clinicalsignsandsymptom

sof

SCID

UNC119deficiency

hasbeen

removed

from

thisversionof

theclassificatio

ntables,astheUNC119variantreportedpreviously

hasbeen

identifiedas

apolymorphism

inunaffected

individuals(G

orska

MM,A

lam

R.A

mutationin

thehuman

Uncoordinated

119gene

impairsTCRsignalingandisassociated

with

CD4lymphopenia.B

lood.2

012Feb9;119(6):1399–406.

doi:10.1182/blood-2011-04-

350686.E

pub2011

Dec

19).See

Erratum

(Blood.2014Jan16;123(3):457)

XLX-linkedinheritance,

ARautosomal

recessiveinheritance,

AD

autosomal

dominantinheritance,

SCID

severe

combinedim

munedeficiency,EBVepsteinbarrvirus,Ca+

+calcium,MHC

major

histocom

patib

ility

complex,R

TErecent

thym

icem

igrants,HPVhuman

papillo

mavirus

J Clin Immunol (2015) 35:696–726 703

Tab

le2

Com

binedim

munodeficiencieswith

associated

orsyndromicfeatures

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

numbergene

locus

Inheritance

CirculatingTcells

Circulatin

gB

cells

Serum

IgAssociatedfeatures

OMIM

number

Phenotype

1.Congenitalthrom

bocytopenia

Wiskott-Aldrich

syndrome(W

AS)

Mutations

inWAS;

cytoskeletaland

immunologicsynapsedefectaffecting

haem

atopoietic

stem

cellderivatives

301000

XL

Progressivedecrease,A

bnormal

lymphocyteresponses

toanti-CD3

Normalnumbers

Decreased

IgM:antibody

topolysaccharides

particularly

decreased;

oftenincreased

IgAandIgE

Throm

bocytopeniawith

smallp

latelets;

eczema;lymphom

a;autoim

mune

disease;IgAnephropathy;

bacterial

andviralinfections.X

Lthrombocytopenia

isamild

form

ofWAS,

andXL

neutropeniaiscaused

bymissense

mutations

intheGTPase

binding

domainof

WASP

300392

WIP

deficiency

Mutations

inWIPF1;

cytoskeletal

andim

munologicsynapse

defectaffectinghaem

atopoietic

stem

cellderivatives

602357

AR

Reduced,D

efectivelymphocyte

responsesto

anti-CD3

Low

Normal,exceptfor

increasedIgE

Recurrent

infections;eczem

a;thrombocytopenia.WAS-likephenotype.

614493

2.DNArepairdefects(otherthan

thosein

Table1)

Ataxia-telangiectasia

Mutations

inATM

;disorderof

cellcyclecheck-point

andDNAdouble-strand

breakrepair

607585

AR

Progressivedecrease,abnormal

proliferationto

mitogens

Normal

Often

decreasedIgA,

IgEandIgG

subclasses;increased

IgM

monom

ers;

antibodiesvariably

decreased

Ataxia;telangiectasia;p

ulmonary

infections;lym

phoreticularand

othermalignancies;increased

alphafetoproteinandincreased

radiosensitivity;chrom

osom

alinstability

208900

Nijm

egen

breakage

syndrome

Hypom

orphicmutations

inNBS1

(Nibrin);d

isorderof

cellcycle

checkpoint

andDNA

double-strand

breakrepair

602667

AR

Progressivedecrease

Variablyreduced

Often

decreasedIgA,IgE

andIgGsubclasses;

increasedIgM;

antibodiesvariably

decreased

Microcephaly;

bird-likeface;lym

phom

as;

solid

tumors;increasedradiosensitivity;

chromosom

alinstability

251260

Bloom

syndrome

Mutations

inBLM

(RECQL3

);encoding

DNAhelicase

RecQprotein-like3helicase

604610

AR

Normal

Normal

Reduced

Shortstature;b

irdlikeface;sun-

sensitive

erythema;marrow

failure;leukemia;lym

phom

a;chromosom

alinstability

210900

Immunodeficiencywith

centromericinstability

andfacialanom

alies

(ICF1

)

Mutations

inDNAmethyltransferase

DNMT3

B(ICF1

)resulting

indefectiveDNAmethylation602900;

AR

Decreased

ornorm

al;responses

toPH

Amay

bedecreased

Decreased

ornorm

alHypogam

maglobulinem

ia;

variableantibodydeficiency

Facialdysm

orphicfeatures;

macroglossia;bacterial/opportunistic

infections;m

alabsorption;

cytopenias;

malignancies;multiradial

configurations

ofchromosom

es1,9,

16;n

oDNAbreaks

242860

Immunodeficiencywith

centromericinstability

andfacialanom

alies

(ICF2

)

Mutations

inZB

TB24

(ICF2

)614064

AR

Decreased

ornorm

al;

Responses

toPH

Amay

bedecreased

Decreased

ornorm

alHypogam

maglobulinem

ia;

variableantibodydeficiency

Facialdysm

orphicfeatures;m

acroglossia;

bacterial/opportunisticinfections;

malabsorption;

cytopenias;

malignancies;multiradial

configurations

ofchromosom

es1,9,16;

614069

PMS2

deficiency

Mutations

inPMS2,resultingi

nClass

Switchrecombination

deficiency

dueto

impaired

mismatch

repair

600259

AR

Normal

Reduced

Bcells,

switcheda

ndnon-sw

itched

Low

IgGandIgA,

elevated

IgM,

abnorm

alantibody

responses

Recurrent

infections;café-au-lait

spots;lymphom

a,colorectal

carcinom

a,braintumor

276300

RNF1

68deficiency

Mutations

inRNF168,

resulting

indefectiveDNA

double-strand

breakrepair(RID

DLE

syndrome)612688

AR

Normal

Normal

Low

IgG,IgM

,or

lowIgA

Shortstature;m

ilddefectof

motor

control

toataxia;n

ormalintelligenceto

learning

difficulties;mild

facial

dysm

orphism

tomicrocephaly;

increasedradiosensitivity

611943

MCM4deficiency

Mutations

inMCM4(m

inichrom

osom

emaintenance

complex

component

4)gene

involved

inDNA

replicationandrepair

AR

Normal

Normal

Normal

Viralinfections

(EBV,H

SV,V

ZV)

Adrenalfailure

Shortstature

Low

NKcells

609981

704 J Clin Immunol (2015) 35:696–726

Tab

le2

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

numbergene

locus

Inheritance

CirculatingTcells

Circulatin

gB

cells

Serum

IgAssociatedfeatures

OMIM

number

Phenotype

602638

3.Thymicdefectswith

additionalcongenitalanomalies

DiGeorgesyndrome*

Contiguous

gene

deletionin

chromosom

e22q11.2or

mutationof

agene

within

thisdeletionregion,T

BX1,

encoding

atranscription

factor

criticalfor

developm

ent

ofthym

usandadjacent

embryonicstructures

602054

Denovo

haplo-insufficiency

(majority)or

AD;

phenocopies

may

have

otheras

yetundefined

genetic

lesions

Decreased

ornorm

al;5

%have

<1500CD3Tcells/uL

inneonatalperiod

Normal

Normalor

decreased

Hypoparathyroidism,conotruncalcardiac

malform

ation,velopalatalinsufficiency,

abnorm

alfacies,intellectuald

isability

andotherabnorm

alities;o

ften

with

3Mbinterstitiald

eletionin

22q11.2

(orrarely

with

intragenicmutationof

TBX1,deletionin

10p)

188400

CHARGEsyndrome

dueto

CHD7defects

Variabledefectsof

thethym

usandassociated

Tcell

abnorm

alities,often

dueto

deletions

ormutations

intranscriptionregulatorCHD7,

608892

Denovo

haplo-insufficiency

(majority)or

AD

Decreased

ornorm

al;

response

toPH

Amay

bedecreased

Normal

Normalor

decreased

Colobom

a,heartanomaly,choanalatresia,

mentalretardation,genitaland

ear

anom

alies;someareSC

ID-likeand

have

lowTRECs

214800

CHARGEsyndrome

dueto

SEMA3E

defects

Variabledefectsof

thethym

usandassociated

Tcellabnorm

alities,

oftendueto

deletions

ormutations

intranscription

regulator,or

semaphorinSE

MA3E

608166

Denovo

haplo-insufficiency

(majority)or

AD

Decreased

ornorm

al;response

to PHAmay

bedecreased

Normal

Normalor

decreased

Colobom

a,heartanomaly,choanalatresia,

mentalretardation,genitaland

ear

anom

alies;someareSC

ID-like

andhave

lowTRECs

214800

Wingedhelix

deficiency

(nude)

AAB:syndrom

icSC

IDDefectsin

forkhead

boxN1transcription

factor

encoded

byFOXN1

600838

AR

Markedlydecreased

Normal

Decreased

Alopecia;naildystropphy;severeinfections

abnorm

althym

icepithelium,

impaired

Tcellmaturation

601705

4.Im

mune-osseousdysplasias

Cartilagehairhypoplasia

Mutations

inRMRP(RNase

MRPRNA)Involved

inprocessing

ofmitochondrial

RNAandcellcyclecontrol

157660

AR

Variesfrom

severely

decreased

(SCID

)to

norm

al;impaired

lymphocyteproliferation

Normal

Normalor

reducedantibodies

variably

decreased

Short-lim

beddw

arfism

with

metaphysealdysostosis,

sparse

hair,

bone

marrowfailure,

autoim

munity,susceptibility

tolymphom

aandothercancers,

impaired

spermatogenesis,

neuronaldysplasiaof

theintestine

250250

Schimke

Immunoosseous

Dysplasia

Mutations

inSM

ARCAL1

;involved

inchromatin

remodeling

606622

AR

Decreased

Normal

Normal

Shortstature,spondiloepiphysealdysplasia,

intrauterine

grow

thretardation,

nephropathy;

bacterial,viral,fungal

infections;m

aypresentasSC

ID;b

one

marrowfailure

242900

5.Hyper-IgE

syndromes

(HIES)

AD-H

IES(Job

orBuckley

Syndrome)

Dom

inant-negativeheterozygous

mutations

insignal

transducerandactivator

oftranscriptionSTAT3

102582

AD

Often

denovo

mutation

NormaloverallT

h-17

and

T-follicularhelper

cells

decreased

Normal;reduced

switched

andnon-sw

itched

mem

oryBcells;B

AFF

expression

increased

ElevatedIgE;specific

antibodyproduction

decreased

Distinctivefacialfeatures

(broad

nasal

bridge),bacterialinfections

(boilsand

pulm

onaryabscesses,pneumatoceles)

dueto

S.aureus,aspergillus,

Pneum

ocystis

jirovecii;

eczema,

mucocutaneous

candidiasis,

hyperextensible

joints,osteoporosisandbone

fractures,

scoliosis,retentionof

prim

aryteeth,

aneurysm

form

ation

147060

Com

el-N

etherton

syndrome

Mutations

inSP

INK5resulting

inlack

oftheserine

protease

inhibitorLEKTI,expressed

inepithelialcells

605010

AR

Normal

Switchedand

non-sw

itched

Bcells

arereduced

ElevatedIgEandIgA

Antibodyvariably

decreased

Congenitalichthyosis,bamboohair,

atopicdiathesis,increased

bacterialinfections,failureto

thrive

256500

PGM3deficiency

AR

CD8andCD4Tcells

may

bedecreased

Reduced

Bandmem

ory

Bcells

615816

J Clin Immunol (2015) 35:696–726 705

Tab

le2

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

numbergene

locus

Inheritance

CirculatingTcells

Circulatin

gB

cells

Serum

IgAssociatedfeatures

OMIM

number

Phenotype

Mutations

inphosphoglycomutase3

(PGM3)

associated

with

aglycosylationand

atopy

172100

Normalor

elevated

Ig’s,elevatedIgE;

eosinophilia

Severeatopy,autoim

munity,bacterial

andviralinfections,cognitive

impairment,hypomyelination

6.Dyskeratosiscongenita

(DKC)with

bone

marrowfailureanddysfunctionaltelom

eremaintenance

XL-D

KCdueto

Dyskerindeficiency

Mutations

inDKC1encoding

dyskerin

300126

XL

Progressivedecrease

Progressivedecrease

Variablehypogammag-

lobulinem

iaIntrauterine

grow

thretardation,

microcephaly,naildystrophy,

recurrentinfections,digestivetract

involvem

ent,pancytopenia,

reducednumberandfunctionof

NK

cells.A

severephenotypewith

developm

entald

elay

andcerebellar

hypoplasiaisknow

nas

Hoyeraal-

Hreidarsson

Syndrome(H

HS)

305000

AR-D

KCdueto

nucleolar

proteinfamily

Amem

ber2(N

HP2

)deficiency

Mutations

inNOLA

2(NHP2),

component

oftheH/ACA

ribonucleo-protein

complex

606470

AR

Decreased

Variable

Variable

Pancytopenia,sparsescalphairand

eyelashes,prom

inentperiorbital

telangiectasia,hypoplastic/dysplastic

nails

613987

AR-D

KCdueto

nucleolar

proteinfamily

Amem

ber3

(NHP3

)or

NOP1

0deficiency

Mutationin

NOLA

3(NOP10,

PCFT),a

component

oftheH/ACAribonucleo-

proteincomplex

606471

AR

Decreased

Variable

Variable

Pancytopenia,sparsescalphairand

eyelashes,prom

inentp

eriorbital

telangiectasia,hypoplastic/

dysplasticnails

224230

AR-D

KCdueto

regulatorof

telomereelongation(RTEL1)

deficiency

Mutationin

RTE

L1encoding

regulatorof

telomere

elongationhelicase

1(RTEL1)

608833

ADor

AR

Decreased

Variable

Variable

Pancytopenia,sparsescalphairand

eyelashes,prom

inentp

eriorbital

telangiectasia,hypoplastic/dysplastic

nails.M

aypresentasHHS

615190

AD-D

KCdueto

TERC

deficiency

Mutationin

TERCencoding

telomerase

RNAcomponent

602322

AD

Variable

Variable

Variable

Reticularhyperpigmentationof

theskin,

dystrophicnails,osteoporosis

prem

alignant

leukokeratosisof

the

oralmucosa,palmarhyperkeratosis,

anem

ia,pancytopenia.May

presentasHHS

127550

AD-D

KCdueto

TERT

deficiency

Mutationin

TERTencoding

telomerasereverse

transcriptase187270

ADor

AR

Variable

Variable

Variable

Reticularhyperpigmentationof

the

skin,dystrophicnails,osteoporosis

prem

alignant

leukokeratosis

oftheoralmucosa,palm

arhyperkeratosis,anemia,pancytopenia.

ADversionismilderthan

theAR

versionwhich

canresembleHHS

613989

AD-D

KCdueto

TIN

F2deficiency

Mutationin

TINF2encoding

telomeraseinteracting

fac tor

2604319

AD

Variable

Variable

Variable

Reticularhyperpigmentationof

the

skin,dystrophicnails,osteoporosis

prem

alignant

leukokeratosis

oftheoralmucosa,palm

arhyperkeratosis,

anem

ia,pancytopenia.May

presentasHHS

613990

AD/AR-D

KCduetoTPP

1deficiency

Mutationin

adrenocorticaldysplasia

homolog

(ACD)encoding

TPP

1affectingtheTELpatch

domainresulting

infailureto

recruittelom

eraseto

telomers

609377

AD/AR

Variable

Variable

Variable

Reticularhyperpigmentationof

theskin,

dystrophicnails,osteoporosis

leukoplakia

oftheoralmucosa,carcinom

a,leukem

iapalm

arhyperkeratosis,anemia,

pancytopenia.M

aypresentasHHS

AR-D

KCdueto

DCLRE1B

deficiency

Mutationin

DCLRE1B

/SNM1/

APO

LLO:D

NA

CROSS

-LIN

KREPA

IRPR

OTEIN

1B609683

AR

dyskeratosiscongenita

and

Hoyeraal-Hreidarsson

(HH)syndrome

616353

AR

616353

706 J Clin Immunol (2015) 35:696–726

Tab

le2

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

numbergene

locus

Inheritance

CirculatingTcells

Circulatin

gB

cells

Serum

IgAssociatedfeatures

OMIM

number

Phenotype

AR-D

KCdueto

PARN

deficiency

Mutationin

PARN,P

OLY

ADENYLATE-

SPECIFIC

RIBONUCLEASE

604212

7.Defectsof

Vitamin

B12

and

Folatemetabolism

Transcobalamin

2(TCN2)

deficiency

Mutationin

TCN2;

encoding

atransporterof

cobalamin

into

bloodcells

613441

AR

Normal

Variable

Decreased

Megaloblasticanaemia,

pancytopaenia,ifuntreated

forprolongedperiodsresults

inmentalretardation

275350

SLC46A1/PC

FTdeficiency

causinghereditary

folatemalabsorbtion

Mutationin

SLC46A1,

encoding

aproton

coupledfolatetransporter

AR

Variablenumbersand

activationprofile

Variable

Decreased

Megaloblasticanaemia,failureto

thrive,ifuntreatedf

orprolongedperiodsresults

inmentalretardation

229050

611672

Methylene-tetrahydrofolate

dehydrogenase

1(M

THFD

1)deficiency

Mutations

inenzymeencodedby

MTH

FD,essential for

processing

single-carbon

folatederivatives

AR

Low

Low

Decreased

Megaloblasticanaemia,failure

tothrive,neutropenia,s

eizures,mentalretardation

601634

172460

8.Anhidrotic

ectoderm

aldysplasia

with

immunodeficiency(EDA-ID)

(EDA-ID.N

EMO/IKBKGdeficiency

Mutations

ofNEMO(IKBKG),

amodulator

ofNF-κB

activation

Defectsin

IKBKG,encodingNEMO,

acomponent

oftheNF-κB

pathway

Mutations

ofNEMO(IKBKG),

amodulator

ofNF-κB

activation

300248

XL

Normalor

decreased;

poor

CRactivation

function

Normal

Low

Bmem

oryBcells

Decreased;p

oorspecific

antibodyresponses,

absent

antibodyto

polysaccharide

antigens

anhidroticectoderm

aldysplasia

+specificantibodydeficiency

(lackof

Abresponse

topolysac-

charides)+variousinfections

(mycobacteriaandpyogens)

Various

infections

(bacteria,

mycobacteria,virusesandfungi);

colitis,E

DA(not

inallp

atients);

conicalteeth,variabledefectsof

skin

pigm

entation,monocyte

dysfunction

300291,

300584,

300301

300640

EDA-IDIK

BAgain

offunctionmutation

Gainof

functionmutationin

IKBA

(NFKIAB),encoding

IκBα,a

component

oftheNF-κB

pathway

Gain-of-functionmutationof

IKBA,resultingin

impaired

activationof

NF-κB

164008

AD

NormaltotalT

cells;;

impaired

TCRactivation

NormalBcellnumbers;

impaired

BCR

activation;

Decreased;p

oorspecific

antibodyresponses,

absent

antibodyto

polysaccharide

antigens

Various

infections

(bacteria,

mycobacteria,virusesandfungi);

colitis,E

DA(not

inallp

atients);

variabledefectsof

skin,hairandteeth,

Tcellandmonocytedysfunction

Anhidrotic

ectoderm

aldysplasia+Tcell

defect+variousinfections:R

ecurrent

bacterial,viraland

fungalinfections;

612132

9.Calcium

channeld

efects

ORAI-Ideficiency

Mutationin

ORAI1,a

Ca+

+

release-activated

channel

(CRAC)modulatory

component

610277

AR

Normal;d

efectiveTCR

mediatedactiv

ation

Normal

Normal

Autoimmunity,anhydrotic

ectoderm

icdysplasia,non-progressivemyopathy

612782

STIM

1deficiency

Mutations

inST

IM1,astromal

interactionmolecule1

605921

AR

Normal;d

efectiveTCR

mediatedactiv

ation

Normal

Normal

Autoimmunity,anhydrotic

ectoderm

aldysplasia,non-progressivemyopathy

612783

10.O

therdefects

Hepaticveno-occlusive

disease

with

immunodeficiency

(VODI)

Mutations

innuclearbody

proteinencodedby

SP110

604457

AR

Normal(decreased

mem

oryTcells)

Normal(decreased

mem

oryBcells)

Decreased

IgG,IgA

,IgM;absentg

erminal

centersandtissue

plasmacells

Hepaticveno-occlusive

disease;

Susceptibility

toPneum

ocystis

jirovecip

neum

onia,C

MV,candida;

thrombocytopenia;hepatosplenomegaly;

cerebrospinalleukodystropy

235550

Facialdysm

orphism,

immunodeficiency,

livedo,shortstature

(FILS)

syndrome

Mutationin

POLE

1;DefectiveDNAreplication

174762

AR

Low

naïveTcells;d

ecreased

Tcellproliferation

Low

mem

oryBcells

Decreased

IgM

and

IgG;L

ackof

antibodies

topolysaccharide

antig

ens

Mild

facialdysm

orphism

(malarhypoplasia,

high

forehead),livedo,shortstature;

recurrentu

pperandlowerrespiratory

tractinfections,recurrent

pulm

onary

infections

andrecurrentm

eningitis

615139

J Clin Immunol (2015) 35:696–726 707

Tab

le2

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

numbergene

locus

Inheritance

CirculatingTcells

Circulatin

gB

cells

Serum

IgAssociatedfeatures

OMIM

number

Phenotype

Immunodeficiencywith

multipleintestinalatresias

MutationinTT

C7A

(tetratricopeptide

repeat(TPR

)domain7A

)protein,

ofunkownfunction

609332

AR

Variable,butsom

etim

esabsent

Normal

Decreased

Multipleintestinalatresias,often

with

intrauterine

polyhydram

nios

and

earlydemise;somewith

SCID

phenotype

243150

Vicisyndrom

edueto

EPG

5deficiency

Mutations

inEPG5encoding

ectopic

P-granules

autophagyprotein

5,involved

intheform

ationof

autolysosomes

required

forautophagy

AR

Profound

depletionof

CD4+

cells

Defective

Decreased

(particularly

IgG2)

Agenesisof

thecorpus

callosum,cataracts,

cardiomyopathy,skin

hypopigm

entation,

cleftlip/palate,recurrentinfections,

chronicmucocutaneous

candidiasis

242840

615068

Purine

nucleoside

phosphorylase

(PNP)

deficiency

Mutationof

PNPleadingto

absent

PNP,Tcellandneurologic

defectsfrom

elevated

toxic

metabolites,especially

dGTP

164050

AR

Progressivedecrease

Normal

Normalor

decreased

Autoimmunehaem

olyticanem

ia,

neurologicalim

pairment

613179

HOIL1deficiency

Mutationof

HOIL1/RBCK1,

encoding

acomponent

ofthe

linearubiquitinationchain

assemblycomplex

LUBAC,

resulting

inim

paired

activationof

NF-κB

610924

AR

Normalnumbers,

Normal,but

decreased

mem

oryBcells

Poor

antibodyproduction

topolysaccharide

antig

ens

Bacterialinfections

(pyogens),

autoinflam

mation.am

ylopectinosis

615895

HOIP

deficiency

Mutationof

HOIP1(/RNF31),

encoding

acomponent

ofthe

linearubiquitinationchain

assemblycomplex

LUBAC,

resulting

inim

paired

activationof

NF-κB

612487

AR

Normalnumbers

Normal,but

decreased

mem

oryBcells

decreased

Bacterialinfections

(pyogens),

autoinflam

mation.Amylopectinosis,

Lymphangiectasia

Not

yet

assigned

Hennekam-lym

phangiectasia-

lymphedem

asyndrome

Mutationof

CCBE1:

(COLLAGEN

ANDCALCIU

M-BIN

DIN

GEGFDOMAIN

-CONTA

ININ

GPR

OTEIN

1)612753

AR

Low

/variable

Low

/variable

decreased

Lymphangiactasiaandlymphedem

awith

facialabnorm

alities

andother

dysm

orphicfeatures

235510

STAT5b

deficiency

Mutations

inSTAT5

Bsignal

transducerandtranscription

factor,essentialfor

norm

alsignalingfrom

IL-2

and

15,key

grow

thfactorsforT

andNKcells,aswellasother

cytokines

604260

AR

Modestly

decreased

Normal

Normal

Growth-hormoneinsensitive

dwarfism

,dysm

orphicfeatures,eczem

a,lymphocyticinterstitialp

neum

onitis,

autoim

munity

245590

Totaln

o.of

genesin

Table2:

45

New

genesadded:

TPP1,DCLRE1B

,PARN,C

CBE1,HOIP1,EPG5

Notes:T

andBcellnumberand

functio

ninthesedisordersexhibita

widerangeofabnorm

ality

;the

mostseverelyaffected

casesmeetdiagnostic

criteriaforS

CID

orleakySC

IDandrequireim

munesystem

restoringtherapysuch

asallogeneichematopoieticcelltransplantation

*Alth

ough

TBX1deletio

nsareem

phasized,dataarelackingthatdemonstratethatisolated

TBX1haploinsufficiency

(affectin

gsolelythegene

andnone

ofthesurrounding22q11.2region)explicitlycauses

Tcellor

immunologicdeficiency

inhumans

708 J Clin Immunol (2015) 35:696–726

Tab

le3

Predom

inantly

antib

odydeficiencies

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Serum

IgAssociatedfeatures

Phenotype

OMIM

number

1.Severereductionin

allserum

immunoglobulin

isotypes

with

profoundly

decreasedor

absentBcells

BTKdeficiency

Mutations

inBTK

,acytoplasmictyrosine

kinase

activated

bycrosslinking

oftheBCR

300300

XL

Allisotypes

decreasedin

majority

ofpatients;somepatientshave

detectableim

munoglobulins

Severebacterialinfectio

ns;n

ormal

numbersof

pro-Bcells

300755

μheavychaindeficiency

Mutations

inμheavychain(IGHM);essential

component

ofthepre-BCR

147020

AR

Allisotypes

decreased

Severebacterialinfections;n

ormal

numbersof

pro-Bcells

601495

λ5deficiency

Mutations

inλ5

(IGLL

1);p

arto

fthesurrogate

light

chainin

thepre-BCR

146770

AR

Allisotypes

decreased

Severebacterialinfections;n

ormal

numbersof

pro-Bcells

613500

Igαdeficiency

Mutations

inIgα(CD79A);partof

thepre-BCR

andBCR112205

AR

Allisotypes

decreased

Severebacterialinfections;n

ormal

numbersof

pro-Bcells

112205

613501

Igβdeficiency

Mutations

inIgb(CD79B);partof

thepre-BCR

andBCR

147245

AR

Allisotypes

decreased

Severebacterialinfections;n

ormal

numbersof

pro-Bcells

612692

BLNKdeficiency

Mutations

inBLN

K;a

scaffold

proteinthat

bindsto

BTK604615

AR

Allisotypes

decreased

Severebacterialinfections;n

ormal

numbersof

pro-Bcells

613502

PI3K

R1deficiency

Mutations

inPIK3R

1;akinase

involved

insignaltransductionin

multiplecelltypes.

Com

pleteloss

ofPI3K

p85-alpharesulting

incompleteloss

ofBcelldevelopm

ent

171833

AR

Allisotypes

decreased

Severebacterialinfections;d

ecreased

orabsent

pro-Bcells

615214

E47

transcriptionfactor

deficiency

Mutations

inTCF3;

atranscriptionfactor

required

forcontrolo

fBcelldevelopm

ent

147141

AD

Allisotypes

decreased

Recurrent

bacterialinfections

Not

yetassigned

Thymom

awith

immunodeficiency

Unknown

None

One

ormoreisotypes

may

bedecreased

Bacterialandopportunistic

infections;

autoim

munity;d

ecreased

number

ofpro-Bcells

Disease

Geneticdefect/Presumed

pathogenesis

Inheritance

Serum

IgAssociatedfeatures

OMIM

number

2.Severereductionin

atleast2

serum

immunoglobulin

isotypes

with

norm

alor

lownumberof

Bcells

Com

mon

variableim

muno-

deficiency

disorders

Unknown

Variable

Low

IgGandIgAand/or

IgM

Clin

icalphenotypes

vary:m

osth

averecurrent

infections,som

ehave

polyclonal

lymphoproliferation,autoim

mune

cytopenias

and/or

granulom

atousdisease

CD19

deficiency

Mutations

inCD19;transmem

braneproteinthat

amplifiessignalthroughBCR107265

AR

Low

IgGandIgAand/or

IgM

Recurrent

infections;M

ayhave

glom

erulonephritis

613493

CD81

deficiency

Mutations

inCD81;transmem

braneprotein

thatam

plifiessignalthroughBCR186845

AR

Low

IgG,low

ornorm

alIgAandIgM

Recurrent

infections;M

ayhave

glom

erulonephritis

613496

CD20

deficiency

Mutations

inCD20;aBcellsurfacereceptor

involved

inBcelldevelopm

entand

plasmacelldifferentiation

112210

AR

Low

IgG,normalor

elevated

IgM

andIgA

Recurrent

infections

613495

CD21

deficiency

Mutations

inCD21;also

know

nas

complem

ent

receptor

2andform

spartof

theCD19

complex

120650

AR

Low

IgG;impaired

anti-pneumococcal

response

Recurrent

infections

614699

TACIdeficiency

Mutations

inTNFRSF

13B(TACI);a

TNFreceptor

family

mem

berfoundon

Bcells

andisa

receptor

forBAFFandAPR

IL604907

ADor

ARor

complex

Low

IgGandIgAand/or

IgM

Variableclinicalexpression

240500

BAFFreceptor

deficiency

Mutations

inTNFRSF

13C(BAFF-R);aTNF

receptor

family

mem

berfoundon

Bcells

andisareceptor

forBAFF

606269

AR

Low

IgGandIgM;

Variableclinicalexpression

613494

TWEAKdeficiency

Mutations

inacytokine

TWEAK(TNFSF

12);

TNF-relatedweakinducerof

apoptosis

602695

AD

Low

IgM

andA;lackof

anti-

pneumococcalantibody

Pneumonia,bacterialinfections,w

arts;

thrombocytopenia.neutropenia

noty

etassigned

NFK

B2deficiency

Mutations

inNFKB2;

anessentialcom

ponent

ofthenoncanonicalNF-κBpathway

AD

Low

IgGandIgAandIgM;v

ery

lowBcells

insome

Recurrent

infections;adrenal

insufficiency;

ACTHdeficiency;alopecia

615577

MOGSdeficiency

Mutationin

mannosyl-oligosaccharideglucosidase

601336

AR

Severehypogammaglobulinem

ia;

Bacterialandviralinfections;severeneurologic

disease;also

contains

glycosylation

type

IIb(CDG-IIb),

606056

J Clin Immunol (2015) 35:696–726 709

Tab

le3

(contin

ued)

TRNT1deficiency

Mutationin

TRNT1atemplate-

independentR

NApolymeraserequired

forthematurationof

cytosolic

and

mito

chondrialtransferRNAs

(tRNAs)612907

AR

Bcelldeficiency

and

hypogammaglobulin

emia

congenitalsideroblasticanem

ia;

deafness;

developm

entald

elay

616084

TTC37

deficiency

Mutationin

TTC37

gene

614589

AR

Poor

antib

odyresponse

topneumococcalv

accine

Recurrentbacterialand

viralinfectio

ns;

Abnormalhairfindings:trichorrhexis

nodosa

222470

3.Severe

reductionin

serum

IgGandIgAwith

norm

al/elevatedIgM

andnorm

alnumbersof

Bcells

AID

deficiency

Mutations

inAICDAgene

605257

AR

IgGandIgAdecreased;

IgM

increased

Bacterialinfections;enlargedlymph

nodesandgerm

inalcenters

605258

UNGdeficiency

Mutations

inUNG

191525

AR

IgGandIgAdecreased;

IgM

increased

Enlargedlymph

nodesandgerm

inal

centers

608106

INO80

INO80

chromatin

remodeling

complex;m

ildDNArepair

defect610169

AR

IgGandIgAdecreased;

IgM

increased

Severebacterialinfectio

nsnoty

etassigned

MSH

6MSH

6gene

defectpartof

mismatch

repair[M

MR]machinery);DNA

repairdefect

600678

AR

VariableIgG,d

efects;increased

IgM

insome;norm

alBcells,low

switched

mem

oryBcells;Ig-CSR

and

SHM

defects

Family

orpersonalhistoryof

cancer

noty

etassigned

4.Isotypeor

light

chaindeficiencies

with

generally

norm

alnumbersof

Bcells

Activated

PI3K-δ

Mutationin

PIK3C

D;p110

encoding

forp110

subunito

fPI3K

602839

ADgain

offunctio

nReduced

IgG2andim

paired

antib

ody

topneumococciandhemophilus

Respiratory

infections,bronchiectasis;

autoim

munity

;chronicEBV,

CMVinfection

615513

PI3KR1loss

offunctio

nMutationin

PIK3R

1leadingto

mutations

inp85α

171833

ADloss

offunctio

nof

p85α

(leading

toactiv

ationof

PI3K

-δ–as

above)

AbsentIgA

,low

IgG

EBV,C

MVviremia;g

rowth

retardation

616005

Igheavychainmutations

anddeletio

nsMutationor

chromosom

aldeletio

nat

14q32

AR

One

ormoreIgGand/or

IgA

subclasses

aswellasIgEmay

beabsent

May

beasym

ptom

atic

IGKCdeficiency

Mutations

inKappa

constant

gene

AR

Allim

munoglobulin

shave

lambda

light

chain

Asymptom

atic

147200

Isolated

IgGsubclass

deficiency

Unknown

Variable

Reductio

nin

oneor

moreIgG

subclass

Usuallyasym

ptom

atic;a

minority

may

have

poor

antib

odyresponse

tospecificantig

ensandrecurrent

viral/b

acterialinfections

IgAwith

IgGsubclass

deficiency

Unknown

Variable

Reduced

IgAwith

decrease

inone

ormoreIgGsubclass

Recurrent

bacterialinfectio

ns

Specificantib

ody

deficiency

with

norm

alIg

concentrations

and

norm

alnumbers

ofBcells

Unknown

Variable

Normal

Reduced

ability

toproduceantib

odies

tospecificantig

ens

710 J Clin Immunol (2015) 35:696–726

Tab

le3

(contin

ued)

Transient

hypogammaglobulin

emia

ofinfancywith

norm

alnumbersof

Bcells

Unknown

Variable

IgGandIgAdecreased

Normalability

toproduceantib

odies

tovaccineantig

ens,usually

not

associated

with

significant

infections

CARD11

gainof

functio

nCARD11;scaffoldforNF-kB

activ

ityintheadaptiv

eim

muneresponse;gainof

functio

n

AD

CongenitalB

celllymphocytosis.

HighBcellnumbersdueto

constitutiveNF-κBactiv

ation

Splenomegaly;

lymphadenopathy

607210;

606445

Totaln

o.of

gene

inTable3:

28

New

genesadded:

MOGS,TRNT1

,TTC

37,IN08,M

SH6,PI3KR1AD

Notes:S

everalautosomalrecessivedisordersthatmightpreviouslyhave

been

calledCVID

have

been

addedtoTable3.CD81

isnorm

allyco-expressed

with

CD19

onthesurfaceof

Bcells.A

sforCD19

mutations,m

utations

inCD81

resultin

norm

alnumbersof

peripheralbloodBcells,low

serum

IgGandan

increasedincidenceof

glom

erulonephritis

Com

mon

VariableIm

munodeficiencyDisorders(CVID

)includeseveralclin

icalandlaboratory

phenotypes

thatmay

becaused

bydistinctgenetic

and/or

environm

entalfactors.S

omepatientswith

CVID

andno

know

ngenetic

defecthave

markedlyreducednumbersof

Bcells

aswellashypogammaglobulin

emia.A

lteratio

nsin

TNFRSF

13B(TACI)andTNFRSF

13C(BAFF-R)sequencesmay

represent

diseasemodifying

mutations

rather

than

diseasecausingmutations.A

smallm

inority

ofpatientswith

XLP(Table

4),W

HIM

syndrome(Table

6),ICF(Table

2),V

OD1(Table

2),thymom

awith

immunodeficiency(G

oodsyndrome)

ormyelodysplasiaarefirstseenby

anim

munologistb

ecause

ofrecurrentinfectio

ns,hypogam

maglobulin

emiaandnorm

alor

reducednumbersof

Bcells

XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance;

BTKBrutontyrosine

kinase,B

LNKBcelllin

kerprotein

AID

activ

ation-inducedcytid

inedeam

inase,UNGuracil-DNAglycosylase,Ig(κ)im

munoglobulin

orκlig

ht-chain

type

J Clin Immunol (2015) 35:696–726 711

Tab

le4

Diseasesof

immunedysregulation

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTCells

Circulatin

gB

cells

Functio

nald

efect

AssociatedFeatures

Phenotype

OMIM

number

1.Familialhemophagocytic

lymphohistiocytosis(FHL)syndromes

1.1.FH

Lsyndromes

withouth

ypopigmentation

Perforin

deficiency

(FHL2)

Mutations

inPRF1;

perforin

isamajor

cytolytic

protein

170280

AR

Increasedactivated

Tcells

Normal

Decreased

toabsent

NKandCTL

activities

cytotoxicity

Fever,Hepato-Splenom

egaly(H

SMG),

Hem

ophagocytic

lymphohistiocytosis

(HLH),Cytopenias

603553

(UNC13D/M

unc13-4

deficiency

(FHL3)

Mutations

inUNC13D;required

toprim

evesicles

forfusion

608897

AR

Increasedactivated

Tcells

Normal

Decreased

toabsent

NKandCTL

activities

(cytotoxicity

and/or

degranulation)

Fever,HSM

G,H

LH,C

ytopenias,

608898

Syntaxin

11deficiency,(FH

L4)

Mutations

inST

X11,requiredfor

secretoryvesiclefusion

with

thecellmem

brane

605014

AR

Increasedactivated

Tcells

Normal

Decreased

NKactivity

(cytotoxicity

and/or

degranulation)

Fever,HSM

G,H

LH,C

ytopenias,

603552

STXBP2

/Munc18-2deficiency

(FHL5)

Mutations

inST

XBP2,required

forsecretoryvesiclefusion

with

thecellmem

brane

601717

ARor

AD

Increasedactivated

Tcells

Normal

Decreased

NKandCTLactivities

(cytotoxicity

and/or

degranulation)

Fever,HSM

G,H

LH,C

ytopenias,

613101

SH2D

1Adeficiency

(XLP1

)Mutations

inSH

2D1A

encoding

anadaptorproteinregulating

intracellularsignaling

300490

XL

Normalor

increasedactivated

Tcells

Reduced

Mem

ory

Bcells

partially

defectiveNKcellandCTL

cytotoxicactivity

Clinicalandim

munologicfeatures

triggeredby

EBV

infection:

HLH,lym

phoproliferation,Aplastic

anaemia,lym

phom

a.Hypogam

maglobulinem

ia,absentiNKTcells

308240

XIA

Pdeficiency

(XLP2

)Mutations

inXIAP/B

IRC4

encoding

aninhibitorof

apoptosis

300079

XL

Normalor

Increasedactivated

Tcells;low

/normaliNKT

cells

Normalor

reduced

Mem

oryB

cells

IncreasedTcells

susceptibilitytoapoptosis

toCD95

andenhanced

activation-

inducedcelldeath(A

ICD)

EBVinfection,Sp

lenomegaly,lymphoproliferation

HLH,C

olitis,IBD,hepatitis

Low

iNKTcells

300635

1.2.FH

Lsyndromes

with

hypopigm

entation

Chediak-H

igashi

syndrome

Mutations

inLY

ST,impaired

lysosomaltrafficking

606897

AR

Increasedactivated

Tcells

Normal

Decreased

NKandCTLactivities

(cytotoxicity

and/or

degranulation)

Partialalbinism,recurrent

infections,fever,

HSM

G,H

LH

Giant

lysosomes,neutropenia,cytopenias,

bleeding

tendency,

progressiveneurologicaldysfunction

214500

Griscellisyndrome,type2

Mutations

inRAB27Aencoding

aGTPase

thatprom

otes

dockingof

secretoryvesiclesto

thecellmem

brane

603868

AR

Normal

Normal

Decreased

NKandCTLactivities

(cytotoxicity

and/or

degranulation)

Partialalbinism,fever,H

SMG,H

LH,cytopenias

607624

Hermansky-Pudlaksyndrome,

type

2Mutations

inAP3B

1gene,

encoding

fortheβsubunitof

theAP-3complex

603401

AR

Normal

Normal

Decreased

NKandCTLactivities

(cytotoxicity

and/or

degranulation)

Partialalbinism,recurrent

infections,

pulm

onaryfibrosis

Increasedbleeding,neutropenia,H

LH

608233

Hermansky-Pudlaksyndrome,

type

9Mutations

inPLD

N,encoding

Pallidin,acomponentof

the

biogenesisof

lysosome-related

organellescomplex-1

(BLOC-

1)604310

AR

(Not

assessed;leukopenia)

(Not

assessed,

leukopenia)

Decreased

NKcellcytolytic

activity

Oculocutaneousalbinism

,recurrent

cutaneous

infections,leukopenia,thrombocytopenia

614171

2.Tregulatory

cells

genetic

defects

IPEX,immunedysregulation,

polyendocrinopathy,

enteropathyX-linked

Mutations

inFOXP3,encoding

aTcelltranscriptionfactor

300292

XL

Normal

Normal

Lackof

(and/orim

paired

functionof)

CD4+

CD25

+FO

XP3

+

regulatory

Tcells

(Tregs)

Autoimmuneenteropathy,earlyonsetd

iabetes,

thyroiditis

hemolyticanem

ia,

thrombocytopenia,eczema

ElevatedIgE,IgA

304790

CD25

deficiency

Mutations

inIL2R

A,encoding

IL-2Rαchain,147730

AR

Normalto

decreased

Normal

NoCD4+C25+cells

with

impaired

functionof

Tregs

cells

Lymphoproliferation,autoim

munity.

Impaired

Tcellproliferation

606367

CTLA4deficiency

(ALPSV

)Mutations

inCTL

A4,encoding

CytotoxicTLy

mphocyte

antigen

4,aproteinthat

AD

Decreased

Decreased

Impaired

functionof

Tregcells.

Autoimmunecytopenias,enteropathy,

interstitiallungdisease,

616100

712 J Clin Immunol (2015) 35:696–726

Tab

le4

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTCells

Circulatin

gB

cells

Functio

nald

efect

AssociatedFeatures

Phenotype

OMIM

number

negativelyregulateTcell

receptor

signalingand

Tcellactivation.

123890

extra-lymphoidlymphocyticinfiltrationrecurrent

infections,

STAT3GOFmutations

Mutations

inSTAT3

,encoding

SignalT

ransducerand

activator

3102582

AD

Decreased

Decreased

EnhancedSTA

T3signaling,leadingto

increasedTh17celldifferentiation,

lymphoproliferationandautoim

munity.

Decreased

Tregcellnumbersand

impaired

phenotype

Lymphoproliferation,So

lidorganautoim

munity,

recurrentinfections.

615952

3.Autoimmunity

with

orwith

outlym

phoproliferation

APE

CED(A

PS-1),autoim

mune

polyendocrinopathy

with

candidiasisandectoderm

aldystrophy

Mutations

inAIRE,encodinga

transcriptionregulatorneeded

toestablishthym

icself-

tolerance

607358

AR

Normal

Normal

AIRE-1

serves

ascheck-pointinthe

thym

usfornegativeselectionof

autoreactiveTcells

andfor

generationof

Tregs

Autoimmunity:h

ypoparathyroidism

hypothyroidism

,adrenalinsufficiency,diabetes,gonadaldysfunction

andotherendocrineabnorm

alities,chronic

mucocutaneous

candidiasis,dentalenam

elhypoplasia,alopeciaareata

Enteropathy,P

erniciousanem

ia,

240300

ITCHdeficiency

Mutations

inITCH,anE3

ubiquitin

ligasecatalyzesthe

transferof

ubiquitin

toa

signalingproteins

inthecellincluding

phospholipase

Cγ1(PLCγ1)

606409

AR

Not

assessed

Not

assessed

Itch

deficiency

may

causeim

mune

dysregulationby

affectingboth

anergy

inductionin

auto-reactiveeffector

Tcells

andgenerationof

Tregs

Early-onsetchroniclung

disease(interstitial

pneumonitis)

Autoimmunedisorder(thyroiditis,type

Idiabetes,

chronicdiarrhea/enteropathy,and

hepatitis)

Failureto

thrive,developmentald

elay,dysmorphic

facialfeatures

613385

Tripeptidyl-PeptidaseIIDeficiency

Mutations

inTP

P2,encoding

tripeptidyl-

peptidaseII,serine

exopeptidase

involved

inextralysosom

alpeptidedegradation

190470

AR

Decreased

Decreased

TPP

2deficiency

results

inprem

ature

immunosenescenceandim

mune

dysregulation

Variablelymphoproliferation,severeautoim

mune

cytopenias,hypergammaglobulinem

ia,recurrent

infections,

Not

yet

assigned

3.Autoimmunelymphoproliferativesyndrome

(ALPS

)

ALPS

-FAS

Germinalmutations

inTN

FRSF

6,encoding

CD95/Fas

cell

surfaceapoptosis

receptor**

134637

AD

AR***

IncreasedCD4−CD8−TCRαβ

doublenegative(D

N)T

cells

Normal,low

mem

oryB

cells

ApoptosisdefectFA

Smediated

Splenomegaly,adenopathies,A

utoimmunecytopenias,

increasedlymphom

arisk.

IgGandAnorm

alor

increased

ElevatedFasL

andIL-10,vitamin

B12

601859

ALPS

-FASL

GMutations

inTN

FSF

6,Fasligand

forCD95

apoptosis

134638

AR

IncreasedDNTcells

Normal

ApoptosisdefectFA

Smediated

Splenomegaly,adenopathies,autoimmunecytopenias,

SLE;

SolubleFasL

isnotelevated

601859

ALPS

-Caspase10

Mutations

inCASP

10,intracellular

apoptosispathway

601762

AD

IncreasedDNTcells

Normal

Defectivelymphocyteapoptosis

Adenopathies,splenomegaly,autoim

munity.

603909

ALPS

-Caspase

8Mutations

inCASP

8,intracellular

apoptosisandactivation

pathways

601763

AR

Slightly

increasedDNTcells

Normal

Defectivelymphocyteapoptosisand

activation

Adenopathies,splenomegaly,Bacterialandviral

infections,

Hypogam

maglobulinem

ia

607271

FADDdeficiency

Mutations

inFA

DDencoding

anadaptormoleculeinteracting

with

FAS,

andprom

oting

apoptosis

602457

AR

IncreasedDNTcells

Normal

Defectivelymphocyteapoptosis

Functionalh

yposplenism,

Bacterialandviralinfections,

Recurrent

episodes

ofencephalopathy

andliver

dysfunction.

613759

PRKCdelta

deficiency

Mutations

inPRKCD,

encoding

amem

berof

theprotein

kinase

Cfamily

criticalfor

regulation

AR

Normal

Low

mem

oryB

cells

and

Elevationof

CD5

Bcells

Apoptoticdefectin

Bcells

Recurrent

infections;E

BVchronicinfection

Lymphoproliferation

SLE-likeautoim

munity

(Nephroticand

antiphospholipid

syndromes)

615559

J Clin Immunol (2015) 35:696–726 713

Tab

le4

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTCells

Circulatin

gB

cells

Functio

nald

efect

AssociatedFeatures

Phenotype

OMIM

number

ofcellsurvival,proliferation

andapoptosis

176977

HypoIgG

4.Im

munedysregulation

with

colitis

IL-10deficiency

Mutations

inIL10,

encoding

IL-10

124092

AR

Normal

Normal

NofunctionalIL-10secretion

Inflam

matoryboweldisease(IBD)Fo

lliculitis,

Recurrent

respiratorydiseases,

Arthritis,

notassigned

IL-10R

αdeficiency

Mutations

inIL10RA,

encoding

IL-10R

1146933

AR

Normal

Normal

Leukocytesno

response

toIL-10

IBD,F

olliculitis,

Recurrent

respiratorydiseases,

Arthritis,Ly

mphom

a

613148

IL-10R

βdeficiency

Mutations

inIL10RB,

encoding

IL-10R

2123889

AR

Normal

Normal

Leukocytesno

response

toIL-10,IL-22,IL-26,IL-28A

,IL-28B

,andIL-29

IBD,F

olliculitis,

Recurrent

respiratorydiseases,

Arthritis,Ly

mphom

a

612567

NFA

T5haploinsufficiency

Hem

izygousdeletionof

NFA

T5604708

AD

Normal

Normal

Decreased

mem

oryBcells

and

plasmablasts

IBD,recurrent

sinopulm

onaryinfections

Not

yet

assigned

5.Ty

pe1Interferonopathies

TREX1deficiency,A

icardi-

Goutieres

syndrome1(A

GS1

)

Mutations

inTR

EX1,encoding

nuclease

involves

inclearing

cellularnucleicdebris

606609

AR

AD*****

Not

assessed

Not

assessed

Intracellularaccumulationof

abnorm

alsingle-stranded(ss)DNAspecies

leadingto

increasedCSF

alpha-IFN

production

Progressiveencephalopathy

Intracranialcalcifications,

Cerebralatrophy,leukodystrophy,

HSM

G,T

hrom

bocytopenia,

Elevatedhepatic

transaminases

Chroniccerebrospinalfluid

(CSF

)lymphocytosis

225750

RNASEH2B

deficiency,A

GS2

Mutations

inRNASE

H2B

,encoding

nuclease

subunit

involves

inclearing

cellularnucleicdebris

610326

AR

Not

assessed

Not

assessed

Intracellularaccumulationof

abnorm

alss-D

NAspeciesleadingto

increased

CSFalpha-IFNproduction

Progressiveencephalopathy

Intracranialcalcifications,

Cerebralatrophy,leukodystrophy,

HSM

G,throm

bocytopenia,

Elevatedhepatic

transaminases

ChronicCSF

lymphocytosis

610181

RNASEH2C

deficiency,A

GS3

Mutations

inRNASE

H2C

,encoding

nuclease

subunit

involves

inclearing

cellularnucleicdebris

610330

AR

Not

assessed

Not

assessed

Intracellularaccumulationof

abnorm

alss-D

NAspeciesleadingto

increased

CSFalpha-IFNproduction

Progressiveencephalopathy

Intracranialcalcifications,

Cerebralatrophy,leukodystrophy,

HSM

G,throm

bocytopenia,

Elevatedhepatic

transaminases

ChronicCSF

lymphocytosis

610329

RNASEH2A

deficiency,AGS4

Mutations

inRNASE

H2A

,encoding

nuclease

subunit

involves

inclearing

cellularnucleicdebris

606034

AR

Not

assessed

Not

assessed

Intracellularaccumulationof

abnorm

alss-D

NAspeciesleadingto

increased

CSFalpha-IFNproduction

Progressiveencephalopathy

Intracranialcalcifications,

Cerebralatrophy,leukodystrophy,

HSM

G,throm

bocytopenia,

Elevatedhepatic

transaminases

ChronicCSF

lymphocytosis

610333

SAMHD1deficiency,A

GS5

Mutations

inSA

MHD1,encoding

negativeregulatorof

the

immunostim

ulatory

DNAresponse

606754

AR

Not

assessed

Not

assessed

Inductionof

thecellintrinsicantiviral

response,apoptosis,and

mitochondrialD

NAdestruction

leadingto

increasedCSF

alpha-IFN

production

Progressiveencephalopathy

Intracranialcalcifications,

Cerebralatrophy,leukodystrophy,

HSM

G,throm

bocytopenia,anem

iaelevated

lactates

ChronicCSF

lymphocytosis,

Skin

vascularitis,mouth

ulcers,arthropathy

612952

ADAR1deficiency,A

GS6

Mutations

inADAR1,encoding

aRNA-specificadenosine

deam

inase

146920

AR

Not

assessed

Not

assessed

Catalyzes

thedeam

inationof

adenosineto

inosinein

dsRNAsubstrates

Markedly

elevated

CSFIFN-alpha

Progressiveencephalopathy

intracranialcalcification,

Severedevelopm

entald

elay,leukodystrophy

615010

Aicardi-G

outieressyndrome7

(AGS7

)IFIH

1606951

AD

Not

assessed

Not

assessed

IFIH

1gene

encodesacytoplasmicviral

RNAreceptor

thatactivates

type

Iinterferon

signalingthrough

theMAVSadaptormolecule

Progressiveencephalopathy

intracranialcalcification,

Severedevelopm

entald

elay,leukodystrophy

615846

Spondyloenchondro-dysplasiawith

immune

dysregulation(SPE

NCD)

Mutations

inACP5,encoding

tartrate-resitant

acid

phosphatase

(TRAP)

171640

AR

Not

assessed

Not

assessed

Upregulationof

IFN-alpha

andtype

IIFN-

stim

ulated

genes

Recurrent

bacterialand

viralinfections,

Intracranialcalcification,

SLE-likeautoim

munity

(Sjögren’ssyndrome,

hypothyroidism

,inflammatorymyositis,

Raynaud’sdiseaseandvitiligo),hem

olytic

anem

ia,throm

bocytopenia,

607944

714 J Clin Immunol (2015) 35:696–726

Tab

le4

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

GeneOMIM

Inheritance

Circulatin

gTCells

Circulatin

gB

cells

Functio

nald

efect

AssociatedFeatures

Phenotype

OMIM

number

skeletaldysplasia,shortstature

STIN

G–associatedvasculopathy,

infantile-

onset

TMEM173encoding

for

STIM

ULATOR

OFIN

TERFE

RONGENES

612374

AR

Not

assessed

Not

assessed

STIN

Gactivates

boththeNF-kappa-Band

IRF3transcriptionpathwaysto

induce

expression

ofIFN-alpha

andIFN-beta

andexerta

potent

antiviraleffect

Severeinfantile-onsetautoinfammatoryvasculopathy,

615934

ADA2deficiency

Mutations

inCECR1;

encoding

ADA2

607575

AR

Not

assessed

Not

assessed

ADAsdeactivateextracellularadenosine

andterm

inatesignalingthrough

adenosinereceptors

Polyarteritis

nodosa,childhood-onset,early-onset

recurrentischemicstroke

andfever

615688

Totaln

o.of

genesin

Table4:

37

New

genesadded:

PLDN,C

TLA

4,TP

P2,NFA

T5,IFIH

1,TM

EM173,CECR1,STAT3(G

OF)

XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,FHLfamilialhemophagocytic

lymphohistio

cytosis,HLH

Hem

ophagocytic

lymphohistio

cytosis,HSM

Ghepato-splenom

egaly,DNdouble-negative,SL

Esystem

iclupuserythematous,IBDinflam

matoryboweldisease,CSF

chroniccerebrospinalfluid

**So

maticmutations

ofTN

FRSF

6causeasimilarphenotype(A

LPS-sFA

S)seeTable9.Germinalmutationandsomaticmutations

ofTN

FRSF

6canbe

associated

insomeALPS-FA

Spatients

***ARALPS

-FASpatientshave

amostsevereclinicalphenotype

****

Somaticmutations

inKRASor

NRAScangive

thisclinicalphenotypeassociated

auto-immuneleukoproliferativedisease(RALD)andarenowincludein

Table9entitledPh

enocopiesof

PID

*****de

novo

dominantT

REX1mutations

have

been

reported

J Clin Immunol (2015) 35:696–726 715

Tab

le5

Congenitald

efectsof

phagocytenumber,functio

n,or

both

Disease

Geneticdefect/

Presum

edpathogenesis

OMIM

gene

Inheritance

Affectedcells

Affectedfunction

Associatedfeatures

Phenotype

OMIM

number

1)Congenitaln

eutropenias

Elastasedeficiency

(SCN1)

Mutationin

ELA

NE:misfolded

proteinresponse,increased

apoptosis

130130

AD

NMyeloid

differentiation

Susceptibility

toMDS/leukem

ia202700

GFI

1deficiency

(SCN2)

Mutationin

GFI1:lossof

repression

ofELANE

600871

AD

NMyeloid

differentiation

B/T

lymphopenia

613107

Kostm

annDisease

(SCN3)

Mutationin

HAX1:

controlo

fapoptosis

605998

AR

NMyeloid

differentiation

Cognitiveandneurological

defectsin

patientswith

defectsin

both

HAX1isoforms,

susceptibility

toMDS/leukem

ia

610738

G6P

C3deficiency

(SCN4)

Mutationin

G6P

C3:

abolishedenzymatic

activity

ofglucose-6-phosphatase,

aberrant

glycosylation,andenhanced

apoptosisof

NandF

611045

AR

N+F

Myeloid

differentiation,

chem

otaxis,

O2−

production

Structuralh

eartdefects,urogenital

abnorm

alities,

innereardeafness,and

venous

angiectasias

oftrunks

andlim

bs

612541

VPS

45deficiency

(SCN5)

Mutationin

VPS45controls

vesiculartrafficking

610035

AR

N+F

Myeloid

differentiation,

migration

Extramedullary

hematopoiesis,

bone

marrowfibrosis,nephrom

egaly,

615285

Glycogenstoragedisease

type

1bMutationin

G6P

T1:

Glucose-6-

phosphatetransporter1

602671

AR

N+M

Myeloid

differentiation,

chem

otaxis,

O2−

production

Fastinghypoglycem

ia,lactic

acidosis,

hyperlipidem

ia,hepatom

egaly

232220

Cyclic

neutropenia

Mutationin

ELA

NE:m

isfolded

proteinresponse

130130

AD

NDifferentiation

Oscillations

ofotherleukocytes

andplatelets

162800

X-linkedneutropenia/

myelodysplasia

Mutationin

WAS:

Regulator

ofactin

cytoskeleton

(lossof

autoinhibition)

300392

XL,gainof

function

N+M

Mitosis

Monocytopenia

300299

P14/LAMTOR2deficiency

Mutationin

ROBLD3/LA

MTO

R2:

Endosom

aladaptorprotein14

610389

AR

N+L

Mel

Endosom

ebiogenesis

Neutropenia

Hypogam

maglobulinem

ia↓C

D8cytotoxicity

Partialalbinism

Growth

failure

610798

Barth

Syndrome

Mutationin

Tafazzin

(TAZ)

gene:

Abnormallipid

structureof

mitochondrialm

embrane,

defectivecarnitine

metabolism

300394

XL

NMyeloid

differentiation

Cardiom

yopathy,myopathy,

grow

thretardation

302060

Cohen

syndrome

Mutationin

COH1gene:

Pgunknow

n607817

AR

NMyeloid

differentiation

Retinopathy,developmental

delay,facialdysm

orphisms

216550

Clericuziosyndrome

Poikiloderm

awith

neutropenia

Mutationin

C16ORF57

(USB

1),

affectsgenomicintegrity

613276

AR

NMyeloid

differentiation

Poikiloderm

a,MDS

604173

JAGN1deficiency

Mutations

inJA

GN1,regulates

secretorypathway

616012

AR

NMyeloid

differentiation

Som

ewith

abone

phenotype

616022

3-Methylglutaconic

aciduria

Mutations

inCLPB

616254

AR

NMyeloid

differentiation

Microcephaly,hypoglycem

ia,

hypotonia,ataxia,seizures,

cataracts,IU

GR

Not

yetassigned

G-CSFreceptor

deficiency

Mutations

inCSF3

R,the

grow

thfactor

receptor

138971

AR

NMyeloid

differentiation

Poorresponse

toGCSF

162830

Disease

Geneticdefect/

Presum

edpathogenesis

Inheritance

Affectedcells

Affectedfunction

Associatedfeatures

OMIM

number

2.Defectsof

Motility

Leukocyteadhesion

deficiency

type

1(LAD1)

Mutationin

ITGB2:

Bchainfor

adhesion

proteins

CD18/CD11

600065

AR

N+M

+L+NK

Adherence,

Chemotaxis,

Endocytosis,

Delayed

cord

separation,

skin

ulcers

Periodontitis

116920

716 J Clin Immunol (2015) 35:696–726

Tab

le5

(contin

ued)

T/NKcytotoxicity

Leukocytosis

Leukocyteadhesion

deficiency

type

2(LAD2)

Mutationin

SLC35C1:

GDP-Fu

cose

transporter

605881

AR

N+M

Rolling,

chem

otaxis

Mild

LADtype

1features

plus

hh-blood

groupplus

mentaland

grow

thretardation

266265

Leukocyteadhesion

deficiency

type

3(LAD3)

Mutationin

KINDLIN3:

Rap1-activationof

β1-3integrins

607901

AR

N+M

+L+NK

Adherence,chemotaxis

LADtype

1plus

bleeding

tendency

612840

Rac

2deficiency

Mutationin

RAC2:

Regulationof

actin

cytoskeleton

602049

AD

NAdherence,

chem

otaxis

O2−production

Poorwound

healing,leukocytosis

608203

β-actin

deficiency

Mutationin

ACTB

:Cytoplasm

icActin

102630

AD

N+M

Motility

Mentalretardation,shortstature

243310

Localized

juvenile

periodontitis

Mutationin

FPR1:

Formylated

peptidereceptor

136537

AR

NFo

rmylpeptideinduced

chem

otaxis

Periodontitisonly

Not

assigned

Papillon-Lefèvre

Syndrome

Mutationin

CTS

C:C

athepsin

Cactivationof

serine

proteases

602365

AR

N+M

Chemotaxis

Periodontitis,palm

oplantar

hyperkeratosisin

somepatients

245000

Specificgranule

deficiency

Mutationin

C/EBPE:m

yeloid

transcriptionfactor

189965

AR

NChemotaxis

Neutrophilswith

bilobednuclei

245480

Shwachm

an-D

iamond

Syndrome

Mutationin

SBDS:

Defective

ribosomesynthesis607444

AR

NChemotaxis

Pancytopenia,exocrine

pancreatic

insufficiency,chondrodysplasia

260400

3.Defectsof

Respiratory

Burst

X-linkedchronic

granulom

atousdisease

(CGD)

Mutationin

CYB

B:E

lectron

transportp

rotein(gp91phox)

300481

XL

N+M

Killing(faulty

O2−production)

McL

eodphenotypein

patients

with

deletions

extendinginto

thecontiguous

Kelllocus

306400

Autosom

alrecessiveCGD

Mutationin

CYB

A:E

lectrontransport

protein(p22phox)

608508

AR

N+M

Killing(faulty

O2−production)

Infections,autoinflammatory

phenotype

233690

Autosom

alrecessiveCGD

Mutationin

NCF1:

Adapter

protein(p47phox)

608512

AR

N+M

Killing(faulty

O2−production)

Infections,autoinflammatory

phenotype

233700

Autosom

alrecessiveCGD

Mutationin

NCF2:

Activating

protein(p67phox)

608515

AR

N+M

Killing(faulty

O2−production)

Infections,autoinflammatory

phenotype

233710

Autosom

alrecessiveCGD

Mutationin

NCF4:

Activating

protein(p40

phox)

601488

AR

N+M

Killing(faulty

O2−production)

Infections,autoinflammatory

phenotype

613960

4.OtherDefects

GATA

2deficiency

(MonoMACsyndrome)

Mutations

inGATA

2:loss

ofstem

cells

137295

AD

Monocytes+peripheral

DC;low

NKcells

Multilineage

cytopenias

Susceptibility

toMycobacteria,

papillomaviruses,histoplasm

osis,

alveolarproteinosis,

MDS/AML/CMML

614286

614172

Pulm

onaryalveolarproteinosis*

Mutationin

CSF

2RA

306250

Biallelic

mutations

inpseudoautosomalgene

Alveolarmacrophages

GM-CSF

signaling

Alveolarproteinosis

300770

Totaln

o.of

genesin

Table5:

31

New

genesadded:

JAGN1,CLB

P,CSF

3R

J Clin Immunol (2015) 35:696–726 717

Tab

le6

Defectsin

IntrinsicandInnateIm

munity

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

gene

Inheritance

AffectedCell

FunctionalD

efect

AssociatedFeatures

Phenotype

OMIM

Num

ber

1.MedelianSu

sceptib

ility

tomycobacterialdisease(M

SMD)

IL-12andIL-23

receptor

β1chain

deficiency

Mutationin

IL12RB1:

IL-12andIL-23

receptor

β1chain

601604

AR

L+NK

IFN-γ

secretion

Susceptib

ility

toMycobacteria

andSalmonella

614891

IL-12p40

deficiency

Mutationin

IL12B:

subunitp

40of

IL12/IL23

161561

AR

MIFN-γ

secretion

Susceptib

ility

toMycobacteria

andSalmonella

614890

IFN-γ

receptor

1deficiency

Mutationin

IFNGR1:

IFN-γRlig

and

bindingchain

107470

AR

M+L

IFN-γ

binding

andsignaling

Susceptib

ility

toMycobacteria

andSalmonella

209950

IFN-γ

receptor

1deficiency

Mutationin

IFNGR1:

IFN-γRlig

and

bindingchain

107470

AD

M+L

IFN-γ

binding

andsignaling

Susceptib

ility

toMycobacteria

andSalmonella

615978

IFN-γ

receptor

2deficiency

Mutationin

IFNGR2:

IFN-γRaccessory

chain

147569

AR

M+L

IFN-γ

signaling

Susceptib

ility

toMycobacteria

andSalmonella

614889

STAT1deficiency

(ADform

)Mutationin

STAT1

(losto

ffunctio

n)600555

AD

M+L

IFN- γsignaling

Susceptib

ility

toMycobacteria,

Salmonella

614892

Macrophagegp91

phox

deficiency

Mutationin

CYB

B:

Electrontransport

protein(gp91

phox)

300481

XL

Mϕonly

Killing(faulty

O2−production)

Isolated

susceptib

ility

tomycobacteria

300645

IRF8

-deficiency

(ADform

)Mutationin

IRF8:

IL12

production

byCD1c

+MDC

601565

AD

CD1c+MDC

Differentiatio

nof

CD1c+MDC

subgroup

Susceptib

ility

toMycobacteria

614893

Tyk2

deficiency

Mutationin

TYK2

176941

AR

Normal,but

Multip

lecytokine

signalingdefect

Normal

Susceptib

ility

tointracellularbacteria

(Mycobacteria,Salm

onella),

fungiand

viruses

(+/−)ElevatedIgE

611521

ISG15

deficiency

Mutationin

ISG15

147571

AR

IFNγdefectproduction

Susceptib

ility

toMycobacteria(BCG)

Brain

calcification

616126

RORcdeficiency

Mutationin

RORC

602943

AR

L+NK

lack

offunctio

nal

RORγTprotein:

IFNγdefectproduction

completeabsenceof

IL-17A

/F-producing

Tcells

mycobacteriosisandcandidiasis

Not

yetassigned

2.Epiderm

odysplasiaverruciformis

EVER1deficiency

Mutations

ofTM

C6

605828

AR

Keratinocytes

and

leukocytes

EVERproteins

may

beinvolved

inthe

regulatio

nof

cellu

lar

zinc

homeostasisin

lymphocytes

HPV

(group

B1)

infections

and

cancer

oftheskin

(typicalEV)

226400

718 J Clin Immunol (2015) 35:696–726

Tab

le6

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

gene

Inheritance

AffectedCell

FunctionalD

efect

AssociatedFeatures

Phenotype

OMIM

Num

ber

EVER2deficiency

Mutations

ofTM

C8

605829

AR

Keratinocytes

and

leukocytes

EVERproteins

may

beinvolved

intheregulatio

nof

cellu

larzinc

homeostasis

inlymphocytes

HPV

(group

B1)

infections

and

cancer

oftheskin

(typicalEV)

226400

WHIM

(Warts,H

ypogam

maglo-

bulin

emia,infectio

ns,M

yelokathexis)

syndrome

Gain-of-function

mutations

ofCXCR4,the

receptor

for

CXCL12

162643

AD

Granulocytes+

Lymphocytes

Increasedresponse

oftheCXCR4chem

okine

receptor

toits

ligand

CXCL12

(SDF-1)

warts/Hum

anPapillo

mavirus

(HPV

)infection

Neutropenia

Reduced

Bcellnumber

Hypogam

maglobulin

emia

193670

4.Predispositio

nto

severe

viralinfectio

n

STAT1deficiency

Mutations

ofSTAT1

600555

AR

TandNKcells

and

monocytes

STAT1-dependent

IFN-α,and

-βresponse

Severeviralinfectio

nsMycobacterialinfection

613796

STAT2deficiency

Mutations

ofSTAT2

600556

AR

TandNKcells

STAT2-dependent

IFN-α,and

-βresponse

Severeviralinfectio

ns(disseminated

vaccine-

strain

measles)

Not

yetassigned

IRF7

deficiency

Mutationin

IRF7

605047

AR

Leukocytesand

plasmacytoid

dendritic

cells,

Non-hem

atopoietic

cells

IFN-α,and

-βproductio

nIFN-λ

productio

nSevereinfluenzadisease

Not

yetassigned

CD16

deficiency

Mutationin

CD16

146740

AR

NKcells

Deficient

spontaneous

NKcellcytotoxicity

Susceptib

ility

tosevere

viral

infections,inc.H

SV,E

BV,H

PV615707

5.Herpessimplex

encephalitis(H

SE)

TLR3deficiency

(b)Mutations

ofTL

R3

603029

AD

AR

Centralnervoussystem

(CNS)

resident

cells

andfibroblasts

TLR3-dependent

IFN-α,-β,and

-λinduction

Herpessimplex

virus1encephalitis

(incom

pleteclinicalpenetrance

foralletio

logies

listedhere)

613002

UNC93B1deficiency

(a)Mutations

ofUNC93B1

608204

AR

CNSresident

cells

andfibroblasts

UNC-93B

-dependent

IFN-α,-β,and

-λinduction

Herpessimplex

virus1encephalitis

610551

TRAF3

deficiency

(c)Mutations

ofTR

AF3

601896

AD

CNSresident

cells

andfibroblasts

TRAF3

-dependent

IFN-α,-β,and

-λinduction

Herpessimplex

virus1encephalitis

614849

TRIF

deficiency

(c)Mutations

ofTR

IF,a

lsocalled

TICAM1

607601

AD

AR

CNSresident

cells

andfibroblasts

TRIF-dependent

IFN-α,-β,and

-λinduction

Herpessimplex

virus1encephalitis

614850

TBK1deficiency

(c)Mutations

ofTB

K1

604834

AD

CNSresident

cells

andfibroblasts

TBK1-dependent

IFN-α,-β,and

-λinduction

Herpessimplex

virus1encephalitis

Not

yetassigned

6.Predispositio

nto

invasive

fungaldiseases

CARD9deficiency

Mutations

ofCARD9

607212

AR

Mononuclear

phagocytes

CARD9signalingpathway

Invasive

candidiasisinfection

Deepderm

atophytoses

212050

7.Chronicmucocutaneous

candidiasis(CMC)

IL-17R

Adeficiency

(a)Mutations

inIL17RA

605461

AR

Epithelialcells,fibroblasts,

mononuclear

phagocytes

IL-17R

Asignalingpathway

CMC

Folliculitis

613953

IL-17R

Cdeficiency

Mutations

inIL17RC

610925

AR

Epithelialcells,fibroblasts,

mononuclear

phagocytes

IL-17R

Csignalingpathway

CMC

Not

yetassigned

IL-17F

deficiency

(b)Mutations

inIL17F

AD

Tcells

IL-17F-containing

dimers

CMC

Folliculitis

613956

J Clin Immunol (2015) 35:696–726 719

Tab

le6

(contin

ued)

Disease

Geneticdefect/Presumed

pathogenesis

OMIM

gene

Inheritance

AffectedCell

FunctionalD

efect

AssociatedFeatures

Phenotype

OMIM

Num

ber

606496

STAT1gain-of-functio

n(c)gain-of-functio

nmutations

inSTAT1

600555

AD

Tcells,B

cells,m

onocytes

Gain-of-functionST

AT1

mutations

thatim

pairthe

developm

ento

fIL-17-

producingTcells

CMC

Various

fungal,b

acterialand

viral(HSV

)infections

Auto-im

munity

(Thyroiditis,

diabetes,cytopenia)

Enteropathy

614162

ACT1deficiency

(c)Mutations

inACT1

,alsocalled

TRAF3IP2

(607043)

AR

Tcells,fibroblasts

Fibroblastsfailto

respond

toIL-17A

andIL-17F,

andtheirTcells

toIL-17E

CMC

Blepharitis,Fo

lliculitisand

macroglossia

615527

8.TLRsignalingpathway

deficiency

IRAK-4

deficiency

Mutations

ofIRAK4,a

component

ofTLR-

andIL-1R-signalin

gpathway

606883

AR

Lymphocytes

+Granulocytes

+Monocytes

TIR-IRAKsignalingpathway

Bacterialinfections

(pyogens)

607676

MyD

88deficiency

Mutations

ofMYD

88,a

component

ofthe

TLRandIL-1R

signalingpathway

602170

AR

Lymphocytes

+Granulocytes

+Monocytes

TIR-M

yD88

signalingpathway

Bacterialinfections

(pyogens)

612260

9.Isolated

congenital

asplenia(ICA)

Mutations

inRPSA

150370

AD

Spleen

RPS

Aencodesribosomal

proteinSA

,acomponent

ofthesm

allsubunitof

theribosome

Bacteremia(encapsulatedbacteria)

Nospleen

271400

8.Trypanosomiasis

Mutations

inAPOL-

I603743

AD

APO

L-I

Trypanosomiasis

Not

yetassigned

Totaln

o.of

gene

defectsin

Table6:

32

New

genesadded:R

ORC,IRF7,IL17RC,A

POL-1

XLX-linkedinheritance,ARautosomal

recessiveinheritance,AD

autosomal

dominantinheritance,NF-κBnuclearfactor

Kappa

B,TIRTo

llandInterleukin1Receptor,IFNinterferon,HVPhuman

papillo

mavirus,TL

RTo

ll-lik

ereceptor,ILinterleukin

720 J Clin Immunol (2015) 35:696–726

Tab

le7

Autoinflammatorydisorders

Disease

Geneticdefect/

Presum

edpathogenesis

OMIN

gene

Inheritance

Affectedcells

Functio

nald

efects

AssociatedFeatures

Phenotype

OMIM

number

1.Defectseffectingtheinflam

masom

e

FamilialMediterraneanFever

Mutations

ofMEFV

(leadto

gain

ofpyrin

function,resulting

ininappropriateIL-1βrelease)

608107

AR

AD

Maturegranulocytes,

cytokine-activated

monocytes.

Decreased

productionof

pyrinperm

itsASC

-inducedIL-1

processing

andinflam

mationfollowing

subclinicalserosalinjury;

macrophageapoptosisdecreased.

Recurrent

fever,serositis

andinflam

mationresponsive

tocolchicine.P

redisoposes

tovasculitisandinflam

matory

boweldisease.

249100

134610

Mevalonatekinase

deficiency

(Hyper

IgDsyndrome)

Mutations

ofMVK(leadto

ablockin

themevalonate

pathway.Interleukin-1beta

mediatestheinflammatory

phenotype)

251170

AR

affectingcholesterolsynthesis;

pathogenesisof

diseaseunclear

Periodicfeverandleukocytosis

with

high

IgDlevels

260920

Muckle-Wellssyndrome

Mutations

ofNLRP3

(alsocalled

NALP

3CIAS1

orPYP

AF1)

(leadto

constitutiveactivation

oftheNLR

P3inflammasom

e)606416

AD

PMNsMonocytes

Defectincryopyrin,involved

inleukocyteapoptosisand

NFk

BsignalingandIL-1

processing

Urticaria,S

NHL,amyloidosis.

191900

Familialcold

autoinflam

matory

syndrome1

Mutations

ofNLRP3

(See

above)

606416

AD

PMNs,monocytes

sameas

above

Non-pruritic

urticaria,arthritis,

chills,feverandleukocytosis

aftercold

exposure.

120100

Familialcold

autoinflam

matorysyndrome2

Mutations

ofNLRP1

2609648

AD

PMNs,monocytes

sameas

above

Non-pruritic

urticaria,arthritis,

chills,feverandleukocytosis

aftercold

exposure.

611762

Neonatalo

nsetmultisystem

inflam

matorydisease

(NOMID

)or

chronicinfantile

neurologiccutaneousand

articular

syndrome(CIN

CA)

Mutations

ofNLRP3

CIA

S1(See

above)

606416

AD

PMNs,chondrocytes

sameas

above

Neonatalo

nsetrash,chronic

meningitis,and

arthropathy

with

feverandinflam

mation.

607115

NLRC4-MAS(m

acrophage

activatingsyndrome)

Familialcold

autoinflam

matorysyndrome4

Mutationin

NLRC4

(see

functio

nald

efect)

606831

AD

PMNsmonocytes

macrophages

Gainof

functionmutation

inNLRC4results

inelevated

secretionof

IL-1βandIL-18as

wellasmacrophage

activation

Severeenterocolitisand

macrophage

activationsyndrome

616050

616115

PLAID

(PLCγ2associated

antibodydeficiency

and

immunedysregulation)

Familialcold

autoinflam

matorysyndrome3

Mutationin

PLCG2

((seefunctio

nald

efect)

600220

AD

Bcells,N

K,M

astcells

Mutations

causeactiv

ation

ofIL-1

pathways

Coldurticaria

hypogammaglobulinem

ia614468

APL

AID

(autoinflammation

andPL

Cγ2associated

antibody

deficiency

andim

munedysregulation)

Mutation(c2120C>A)

inPL

CG2(see

functiondefect)

600220

AD

Bcells,N

K,m

astcells

The

mutationleadsto

activ

ation

oftheNLRP3

inflam

masom

e(not

provoked

bycold

temperature)

Blistering

skin

lesion,

pulm

onaryand

boweldisease

614878

2.Non

inflam

masom

e-relatedconditions

(TNFreceptor-associated

periodicsyndrome(TRAPS

)Mutations

ofTN

FRSF

1A(resultin

gin

increased

TNFinflam

matorysignaling)

191190

AD

PMNs,monocytes

Mutations

of55-kDTNFreceptor

leadingto

intracellularreceptor

retentionor

diminishedsoluble

cytokine

receptor

availableto

bind

TNF

Recurrent

fever,serositis,

rash,and

ocular

orjoint

inflam

mation

142680

Pyogenicsterile

arthritis,

pyodermagangrenosum,

acne

(PAPA

)syndrome

Mutations

ofPST

PIP1

(alsocalledC2B

P1)

(affectsboth

pyrinand

AD

Hem

atopoietictissues,

upregulatedin

activated

T-cells

Disorderedactin

reorganization

leadingto

comprom

ised

Destructivearthritis,inflammatory

skin

rash,m

yositis

604416

J Clin Immunol (2015) 35:696–726 721

Tab

le7

(contin

ued)

Disease

Geneticdefect/

Presum

edpathogenesis

OMIN

gene

Inheritance

Affectedcells

Functio

nald

efects

AssociatedFeatures

Phenotype

OMIM

number

proteintyrosine

phosphatase

toregulateinnateand

adaptiveim

muneresponses)

606347

physiologicsignalingduring

inflam

matoryresponse

Blausyndrome

Mutations

ofNOD2(also

calledCARD15)(involved

invariousinflam

matoryprocesses)

605956

AD

Monocytes

Mutations

innucleotidebinding

siteof

CARD15,possibly

disruptinginteractions

with

lipopolysaccharides

andNF-κB

signaling

Uveitis,granulom

atoussynovitis,

camptodactyly,rashandcranial

neuropathies,30%

develop

Crohn’sdisease

186580

ADAM17

deletion

Mutationin

ADAM17

(leads

totumor

necrosisfactor

αconvertingenzymedeficiency)

603639

AR

Leukocytesand

epithelialcells

DefectiveTNFα

production

Early

onsetd

iarrheaand

skin

lesions

614328

Chronicrecurrentm

ultifocal

osteom

yelitisandcongenital

dyserythropoietic

anem

ia(M

ajeedsyndrome)

Mutations

ofLP

IN2(increased

expression

ofthe

proinflammatorygenes)

605519

AR

Neutrophils,bone

marrowcells

undefined

Chronicrecurrentm

ultifocal

osteom

yelitis,transfusion-

dependentanemia,cutaneous

inflam

matorydisorders

609628

DIRA(D

eficiencyof

the

Interleukin1Receptor

Antagonist)

Mutations

ofIL1R

N(see

functio

nald

efect)

147679

AR

PMNs,Monocytes

Mutations

intheIL1receptor

antagonistallowunopposed

actionof

Interleukin1

Neonatalo

nsetof

sterile

multifocalosteom

yelitis,

periostitisandpustulosis.

612852

DITRA–Deficiency

ofIL-36receptor

antagonist

Mutationin

IL36RN

(see

functio

nald

efect)

605507

AR

KeratinocyteLeukocytes

Mutations

inIL-36R

Nleads

toincrease

IL-8

production

Pustular

Psoriasis

614204

SLC29A3mutation

Mutationin

SLC29A3

612373

AR

Leukocyte,bonecells

Hyperpigm

entationhypertrichosis

Histiocytosis-lymphadenopathy

plus

syndrome

602782

CAMPS

(CARD14

mediatedpsoriasis)

Mutationin

CARD14

(see

functio

nald

efect)

607211

AD

Mainlyin

Keratinocyte

Mutations

inCARD14

activate

theNF-kB

pathway

and

productionof

IL-8

Psoriasis

602723

Cherubism

Mutationin

SH3B

P2

(see

functio

nald

efect)

602104

AD

Stromacells,bonecells

Hyperactived

macrophage

andincrease

NF-kB

Bonedegenerationin

jaws

118400

CANDLE(chronicatypical

neutrophilicderm

atitis

with

lipodystrophy)

Mutationin

PSM

B8,

(see

functio

nald

efect)

177046

AR

Keratinocyte,Bcell

adiposecells

Mutations

causeincrease

IL-6

production

Dystrophy,panniculitis

256040

COPA

defect

Mutationin

COPA

(Coatamer

protein

complex,subunitalpha)

AD

PMNsandtissues

specificcells

MutantC

OPA

leadsto

defectiveintracellular

transportv

iathecoatprotein

complex

I(COPI)

Autoimmuneinflam

matory

arthritis

andinterstitiallung

diseasewith

Th17dysregulation

andautoantibodyproduction

601924

Totaln

o.of

gene

defectsin

Table7:

17

New

genesadded:

NLRC4,ADAM17,C

OPA

Notes:A

utoinflammatorydiseases

areclinicaldisordersmarkedby

abnorm

allyincreasedinflam

mation,mediatedpredom

inantly

bythecells

andmolecules

oftheinnateim

munesystem

,with

asignificant

hostpredispositio

n.Whilethegenetic

defectof

oneof

themostcom

mon

autoinflam

matoryconditions,PFA

PA,isnotknown,recentstudiessuggestthatitisassociated

with

activ

ationof

IL-1

pathway

and

response

toIL-1betaantagonists

Muckle-Wellssyndrome,familialcoldautoinflam

matorysyndromeandneonatalonsetm

ultisysteminflam

matorydisease(N

OMID

)which

isalso

calledchronicinfantile

neurologiccutaneousandarticular

syndrome(CIN

CA)arecaused

bysimilarm

utations

inCIAS1/NLR

P3mutations.T

hediseasephenotypeinanyindividualappearstodepend

onmodifying

effectsof

otherg

enes

andenvironm

entalfactors

ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,PMNpolymorphonuclearcells,A

SCapoptosis-associated

speck-lik

eproteinwith

acaspaserecruitm

entdom

ain,CARDcaspase

recruitm

entdomain,

CD2B

P1CD2bindingprotein-1,

PST

PIP1Proline/serine/th

reoninephosphatase-interactingprotein1,

SNHLsensorineuralhearingloss,CIAS1

cold-induced

autoinflam

matory

syndrome1

722 J Clin Immunol (2015) 35:696–726

Tab

le8

Com

plem

entd

eficiencies

Disease

Geneticdefect;p

resumed

pathogenesis

OMIM

gene

Inheritance

Laboratoryfeatures

AssociatedFeatures

Phenotype

OMIM

number

1)Integralcomplem

entcascade

component

deficiencies

C1q

deficiency

C1Q

A,:Classicalcomplem

ent

pathway

component

120550

AR

AbsentC

H50

hemolyticactiv

ity,

Defectiv

eactivationof

the

classicalp

athw

ayDim

inishedclearanceof

apoptotic

cells

SLE,infectio

nswith

encapsulated

organism

s613652

C1q

deficiency

C1Q

B:Classicalcomplem

ent

pathway

component

120570

AR

AbsentC

H50

hemolyticactiv

ity,

Defectiv

eactivationof

the

classicalp

athw

ayDim

inishedclearanceof

apoptotic

cells

SLE,infectio

nswith

encapsulated

organism

s613652

C1q

deficiency

C1Q

C:Classicalcomplem

ent

pathway

component

120575

AR

AbsentC

H50

hemolyticactiv

ity,

Defectiv

eactivationof

theclassicalp

athw

ayDim

inishedclearanceof

apoptotic

cells

SLE,infectio

nswith

encapsulated

organism

s613652

C1r

deficiency

C1R

:Classicalcomplem

ent

pathway

component

613785

AR

AbsentC

H50

hemolyticactiv

ity,D

efectiv

eactiv

ationof

theclassicalp

athw

aySL

E,infectio

nswith

encapsulated

organism

s216950

C1s

deficiency

C1S:C

lassicalcomplem

ent

pathway

component

120580

AR

AbsentC

H50

hemolyticactiv

ityDefectiv

eactivationof

theclassicalp

athw

aySL

E,infectio

nswith

encapsulated

organism

s613783

C4deficiency

C4A

,Classicalcomplem

ent

pathway

components

120810

AR

AbsentC

H50

hemolyticactiv

ity,

Defectiv

eactivationof

theclassicalp

athw

ayCom

pletedeficiency

requires

biallelic

mutations/deletions/conversions

ofboth

C4A

andC4B

SLE,infectio

nswith

encapsulated

organism

s614380

C4deficiency

C4B

:Classicalcomplem

ent

pathway

components

120820

AR

AbsentC

H50

hemolyticactiv

ity,D

efectiv

eactiv

ationof

theclassicalp

athw

ayCom

pletedeficiency

requires

biallelic

mutations/deletions/conversions

ofboth

C4A

andC4B

SLE,infectio

nswith

encapsulated

organism

s614379

C2deficiency

C2:

Classicalcomplem

ent

pathway

component

217000

AR

AbsentC

H50

hemolyticactiv

ity,

Defectiv

eactivationof

theclassicalp

athw

aySL

E,infectio

nswith

encapsulated

organism

s,atherosclerosis

613927

C3deficiency

LOF

C3:

Centralcomplem

entcom

ponent

120700

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

eopsonizatio

nDefectiv

ehumoralim

muneresponse

Infections;g

lomerulonephritis;

AtypicalH

emolytic-uremic

syndromewith

gain-of-functio

nmutations.

613779

C3GOF

C3:

Centralcomplem

entcom

ponent

120700

Gain-of-functionAD

Increasedactiv

ationof

complem

ent

AtypicalH

emolytic-uremic

syndrome

612925

C5deficiency

C5:

Term

inalcomplem

entcom

ponent

120900

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns609536

C6deficiency

C6:

Term

inalcomplem

entcom

ponent

217050

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns612446

C7deficiency

C7:

Term

inalcomplem

entcom

ponent

217070

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns610102

C8αdeficiency

C8A

:Terminalcomplem

entcom

ponent

120950

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns613790

C8γ

deficiency

C8G

:Term

inalcomplem

entcom

ponent

120930

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns613790

C8β

deficiency

C8B

:Terminalcomplem

entcom

ponent

120960

AR

AbsentC

H50

andAH50

hemolyticactiv

ityDefectiv

ebactericidalactivity

Neisserialinfectio

ns613789

C9deficiency

C9:

Term

inalcomplem

entcom

ponent

120940

AR

Reduced

CH50

andAP5

0hemolyticactiv

ityDeficient

bactericidalactivity

Mild

susceptib

ility

toNeisserialinfectio

ns613825

J Clin Immunol (2015) 35:696–726 723

Tab

le8

(contin

ued)

Disease

Geneticdefect;p

resumed

pathogenesis

OMIM

gene

Inheritance

Laboratoryfeatures

AssociatedFeatures

Phenotype

OMIM

number

MASP

2deficiency

MASP

2:Cleavageof

C4

605102

AR

Deficient

activ

ationof

thelectin

activ

ationpathway

Pyogenicinfections;

Inflam

matorylung

disease,

autoim

munity

613791

Ficolin

3deficiency

FCN3:

Activates

theclassical

complem

entp

athw

ay604973

AR

Absence

ofcomplem

entactivation

bytheFicolin

3pathway.

Respiratory

infections,

abscesses

613860

2)Com

plem

entR

egulatorydefects

C1inhibitordeficiency

SERPING1:

regulatio

nof

kinins

andcomplem

entactivation

606860

AD

Spontaneousactiv

ationof

thecomplem

ent

pathway

with

consum

ptionof

C4/C2

Spontaneousactiv

ationof

thecontactsystem

with

generationof

bradykinin

from

high

molecular

weightk

ininogen

Hereditary

angioedema

106100

Factor

BCFB:Activationof

thealternative

pathway

138470

AD

Gain-of-functionmutationwith

increased

spontaneousAH50

aHUS

612924

FactorDdeficiency

CFD:R

egulationof

thealternative

complem

entp

athw

ay134350

AR

AbsentA

H50

hemolyticactiv

ityNeisserialinfectio

ns613912

Properdin

deficiency

CFP:R

egulationof

thealternative

complem

entp

athw

ay300383

XL

AbsentA

H50

hemolyticactiv

ityNeisserialinfectio

ns312060

Factor

Ideficiency

CFI:Regulationof

thealternative

complem

entp

athw

ay217030

AR

Spontaneousactiv

ationof

thealternative

complem

entp

athw

aywith

consum

ptionof

C3

Infections,N

eisserial

infections,aHUS,

preeclam

psia

610984

612923

FactorHdeficiency

CFH:R

egulationof

thealternative

complem

entp

athw

ay134370

AR/AD

Spontaneousactiv

ationof

thealternative

complem

entp

athw

aywith

consum

ptionof

C3

Infections,N

eisserialinfectio

ns,

aHUS,

preeclam

psia

609814

235400

Factor

H–related

proteindeficiencies

CFHR1-5:

BindC3b

134371

600889

605336

605337

608593

AR/AD

NormalCH50,A

H50,autoantibodiesto

Factor

H.L

inkeddeletio

nsof

oneor

moreCFH

Rgenesleadsto

susceptibility

autoantib

ody-mediatedaH

US

aHUS,

Neisserialinfectio

ns235400

Throm

bomodulin

THBD:R

egulates

complem

ent

andcoagulantactivation

188040

AD

NormalCH50,A

H50

aHUS

612926

Com

plem

entR

eceptor3

(CR3)

deficiency

ITGAM

120980

AR

CR3expression

islostin

LAD1.

SeeLAD1in

Table5

Infections

609939

Mem

braneCofactorProtein

(CD46)deficiency

CD46:D

issociates

C3b

andC4b

120920

AD

Inhibitorof

complem

entalternate

pathway,decreased

C3b

binding

aHUS,

infections,

preeclam

psia

612922

Mem

braneAttack

Com

plex

Inhibitor(CD59)deficiency

CD59:Regulates

the

mem

braneattack

complex

form

ation

107271

AR

Erythrocyteshighly

susceptib

leto

complem

ent-mediatedlysis

Hem

olyticanem

ia,

polyneuropathy

612300

Totaln

o.of

genesTables

8and9:

30

Nonewgenesaddedto

the2015

classificatio

n

XLX-linkedinheritance,ARautosomalrecessiveinheritance,AD

autosomaldominantinheritance,MACmem

braneattack

complex,S

LEsystem

iclupuserythematosus,M

ASP

MBPassociated

serine

protease

2

724 J Clin Immunol (2015) 35:696–726

Tab

le9

Phenocopiesof

PID

Disease

Geneticdefect/presumed

pathogenesis

Circulatin

gTcells

Circulatin

gBcells

Serum

IgAssociatedfeatures/sim

ilarPID

Associatedwith

somaticmutations

Autoimmunelymphoproliferative

syndrome(A

LPS

–SFA

S)So

maticmutationin

TNFRSF

6IncreasedCD4−

CD8−

double

negativ

e(D

N)Talpha/beta

cells

Normal,but

increased

numberof

CD5+

Bcells

Normalor

increased

Splenomegaly,lymphadenopathy,

autoim

munecytopenias

Defectiv

elymphocyteapoptosis/

ALP

S–FA

S(=ALPStype

Im)

RAS-associatedautoim

mune

leukoproliferative

disease(RALD)

Somaticmutationin

KRAS

(gain-of-function)

Normal

Bcelllymphocytosis

Normalor

increased

Splenomegaly,lymphadenopathy,

autoim

munecytopenias,

granulocytosis,m

onocytosis/

ALP

S-like

RAS-associatedautoim

mune

leukoproliferativedisease

(RALD)

Somaticmutationin

NRAS(gain-of-

functio

n)IncreasedCD4−

CD8−

double

negativ

e(D

N)Talpha/beta

cells

Lym

phocytosis

Splenomegaly,lymphadenopathy,

autoantib

odies/ALP

S-like

Cryopyrinopathy,(Muckle-

Wells/CIN

CA/NOMID

-lik

esyndrome)

Somaticmutationin

NLR

P3

Normal

Normal

Normal

Urticaria-likerash,arthropathy,

neurologicalsymptom

s

Associatedwith

autoantib

odies

Chronicmucocutaneous

candidiasis

(isolatedor

with

APE

CED

syndrome)

Germlin

emutationin

AIREAutoA

bto

IL-17

and/or

IL-22

Normal

Normal

Normal

Endocrinopathy,chronic

mucocutaneous

candidiasis/CMC

Adult-onsetimmunodeficiency

AutoA

bto

IFNgamma

Decreased

naiveTcells

Normal

Normal

Mycobacterial,fungal,Salmonella

VZVinfections/M

SMD,orCID

Recurrent

skin

infection

AutoA

bto

IL-6

Normal

Normal

Normal

Staphylococcalinfections/STA

T3

deficiency

Pulm

onaryalveolar

proteinosis

AutoA

bto

GM-CSF

Normal

Normal

Normal

Pulm

onaryalveolar

proteinosis,

cryptococcalmeningitis/CSF

2RA

deficiency

Acquiredangioedema

AutoA

bto

CIinhibitor

Normal

Normal

Normal

Angioedem

a/C1INHdeficiency

(hereditary

angioedema)

AtypicalH

emolytic

UremicSy

ndrome

AutoA

bto

Com

plem

entF

actorH

Normal

Normal

Normal

aHUS

Spontaneousactiv

ationof

the

alternativecomplem

entp

athw

ay

J Clin Immunol (2015) 35:696–726 725

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726 J Clin Immunol (2015) 35:696–726