The Clinical Presentation of Primary Immunodeficiency Diseases
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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 [email protected]
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