International Union of Immunological Societies: 2017 … ARTICLE International Union of...
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ORIGINAL ARTICLE International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity Capucine Picard 1,2 & H. Bobby Gaspar 3 & Waleed Al-Herz 4 & Aziz Bousfiha 5 & Jean-Laurent Casanova 6,7,8,9 & Talal Chatila 10 & Yanick J. Crow 11,12 & Charlotte Cunningham-Rundles 13 & Amos Etzioni 14 & Jose Luis Franco 15 & Steven M. Holland 16 & Christoph Klein 17 & Tomohiro Morio 18 & Hans D. Ochs 19 & Eric Oksenhendler 20 & Jennifer Puck 21 & Mimi L. K. Tang 22,23,24 & Stuart G. Tangye 25,26 & Troy R. Torgerson 19 & Kathleen E. Sullivan 27 Received: 19 July 2017 /Accepted: 31 October 2017 /Published online: 11 December 2017 # The Author(s) 2017. This article is an open access publication Abstract Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing com- plexity of the field have been impressive, encompassing an * Kathleen E. Sullivan [email protected] 1 Center for the Study of Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France 2 Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris Descartes University, Paris, France 3 UCL Great Ormond Street Institute of Child Health, London, UK 4 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait 5 Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy LICIA Clinical Immunology Unit, Casablanca Children’ s Hospital, Ibn Rochd 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, USA 8 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, University Paris Descartes, Paris, France 9 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children APHP, Paris, France 10 Division of Immunology, Children’ s Hospital Boston, Boston, MA, USA 11 Laboratory of Neuroinflammation and Neurogenetics, Necker Branch, INSERM UMR1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France 12 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK 13 Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, NewYork, NY, USA 14 Ruth’ s Children’ s Hospital-Technion, Haifa, Israel 15 Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia 16 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA 17 Dr von Hauner Children’ s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany 18 Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan 19 Department of Pediatrics, University of Washington and Seattle Children’ s Research Institute, Seattle, WA, USA 20 Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Sorbonne Paris Cité, Paris, France 21 Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’ s Hospital, San Francisco, CA, USA 22 Murdoch Children’ s Research Institute, Melbourne, VIC, Australia J Clin Immunol (2018) 38:96–128 https://doi.org/10.1007/s10875-017-0464-9
Transcript of International Union of Immunological Societies: 2017 … ARTICLE International Union of...
ORIGINAL ARTICLE
International Union of Immunological Societies: 2017 PrimaryImmunodeficiency Diseases Committee Report on InbornErrors of Immunity
Capucine Picard1,2& H. Bobby Gaspar3 & Waleed Al-Herz4 & Aziz Bousfiha5 &
Jean-Laurent Casanova6,7,8,9 & Talal Chatila10 & Yanick J. Crow11,12&
Charlotte Cunningham-Rundles13 & Amos Etzioni14 & Jose Luis Franco15 &
Steven M. Holland16& Christoph Klein17
& Tomohiro Morio18 & Hans D. Ochs19 &
Eric Oksenhendler20 & Jennifer Puck21& Mimi L. K. Tang22,23,24 & Stuart G. Tangye25,26 &
Troy R. Torgerson19& Kathleen E. Sullivan27
Received: 19 July 2017 /Accepted: 31 October 2017 /Published online: 11 December 2017# The Author(s) 2017. This article is an open access publication
Abstract Beginning in 1970, a committee was constitutedunder the auspices of the World Health Organization (WHO)to catalog primary immunodeficiencies. Twenty years later,the International Union of Immunological Societies (IUIS)
took the remit of this committee. The current report detailsthe categorization and listing of 354 (as of February 2017)inborn errors of immunity. The growth and increasing com-plexity of the field have been impressive, encompassing an
* Kathleen E. [email protected]
1 Center for the Study of Immunodeficiencies, Necker Hospital forSick Children, Assistance Publique-Hôpitaux de Paris (APHP),Paris, France
2 Laboratory of Lymphocyte Activation and Susceptibility to EBV,INSERM UMR1163, Imagine Institute, Necker Hospital for SickChildren, Paris Descartes University, Paris, France
3 UCL Great Ormond Street Institute of Child Health, London, UK4 Department of Pediatrics, Faculty of Medicine, Kuwait University,
Kuwait City, Kuwait5 Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy
LICIA Clinical Immunology Unit, Casablanca Children’s Hospital,Ibn Rochd 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 Laboratory of Human Genetics of Infectious Diseases, Necker
Branch, INSERMUMR1163, Imagine Institute, Necker Hospital forSick Children, University Paris Descartes, Paris, France
9 Pediatric Hematology-Immunology Unit, Necker Hospital for SickChildren APHP, Paris, France
10 Division of Immunology, Children’s Hospital Boston, Boston, MA,USA
11 Laboratory of Neuroinflammation and Neurogenetics, NeckerBranch, INSERM UMR1163, Paris Descartes University,Sorbonne-Paris-Cité, Institut Imagine, Paris, France
12 Division of Evolution and Genomic Sciences, School of BiologicalSciences, Faculty of Biology, Medicine and Health, University ofManchester, Manchester Academic Health Science Centre,Manchester, UK
13 Departments of Medicine and Pediatrics, Mount Sinai School ofMedicine, NewYork, NY, USA
14 Ruth’s Children’s Hospital-Technion, Haifa, Israel15 Grupo de Inmunodeficiencias Primarias, Facultad de Medicina,
Universidad de Antioquia UdeA, Medellin, Colombia16 Laboratory of Clinical Infectious Diseases, National Institute of
Allergy and Infectious Diseases, Bethesda, MD, USA17 Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University
Munich, Munich, Germany18 Department of Pediatrics and Developmental Biology, Tokyo
Medical and Dental University (TMDU), Tokyo, Japan19 Department of Pediatrics, University of Washington and Seattle
Children’s Research Institute, Seattle, WA, USA20 Department of Clinical Immunology, Hôpital Saint-Louis,
Assistance Publique-Hôpitaux de Paris, University Paris Diderot,Sorbonne Paris Cité, Paris, France
21 Department of Pediatrics, University of California San Francisco andUCSF Benioff Children’s Hospital, San Francisco, CA, USA
22 Murdoch Children’s Research Institute, Melbourne, VIC, Australia
J Clin Immunol (2018) 38:96–128https://doi.org/10.1007/s10875-017-0464-9
The new disorders (since 2015 [3]) represent an impres-sive spectrum of phenotypes. There are 354 distinct disor-ders with 344 different gene defects listed. The emergingdominance of next-generation sequencing has driven therapid increase in the number of recognized disorders whichhas led to two major consequences. Often new inborn errorsof immunity are initially described in a single kindred or asmall number of kindreds. This may lead to incorrect as-sumptions about prevalence and phenotype. In fact, formost disorders, we have little idea of the prevalence withineven the recognized population with the described pheno-type. The second consequence of the rapid rise of next-generation sequencing is a striking expansion of the pheno-typic spectrum associated with many diseases. Where once
Fig. 1 Each publication of the World Health Organization and IUISPrimary Immunodeficiencies Committee was reviewed for the numberof conditions listed and displayed graphically [1–19]. The rapid increasein the twenty-first century relates to improved awareness and increasinguse of sequencing. Assuming 20,000 coding genes in the human genome,inborn errors of immunity are implicated through mutations in 1.7% ofthese genes. There are now 330 specific disorders, 320 monogenicdefects, 312 distinct genes (nine genes with both LOF and GOF and C4deficiency requiring defects in both C4A and C4B). a The categorizationof the inborn errors of immunity according the schema in the currentmanuscript. b The categorization of the inborn errors of immunityaccording to their inheritance
J Clin Immunol (2018) 38:96–128 97
increasing variety of conditions, and the classification de-scribed here will serve as a critical reference for immunolo-gists and researchers worldwide.
Keywords IUIS . primary immune deficiency . immunedysregulation . autoinflammatory disorders
Introduction
In 1970, Drs. Fudenberg, Good, Hitzig, Kunkel, Roitt,Rosen, Rowe, Seligmann, and Soothill met under the aus-pices of the World Health Organization to classify theemerging “primary immune deficiencies.” This augustgroup focused on understanding whether immunodefi-ciencies could be categorized as B cell disorders or T celldisorders [1, 2]. Their initial report identified 16 distinctimmunodeficiencies and included the prophetic commentthat “the variable immunodeficiency group probably lumpstogether a series of syndromes…. Included in this groupare cases previously classified as ‘congenital’, non-sexlinked or sporadic hypogammaglobulinemia, primary‘dysgammglobulinemia’ of both childhood and adult life,and ‘acquired’ primary hypogammaglobulinemia. It ishoped that careful analysis of such patients…. will resultin delineation of several homogeneous syndromes…”.Indeed, the emergence of monogenic causes ofhypogammaglobulinemia (Table 3) and disorders with var-iable immunoglobulin abnormalities associated with im-mune dysregulation (Table 4) have been the groups of im-munodeficiencies most transformed by the advent of newtechnologies. Another group dramatically impacted by re-setting of the clinical radar and new techniques has beenthe set of disorders associated with a limited spectrum ofinfectious susceptibility. The graphs in Fig. 1 define thetransformation of the field over the interval during whichnext-generation sequencing came to prominence. The tre-mendous progress, energy, and enthusiasm in the field cur-rently have led to a greater need than ever for a currentcataloging of the disorders.
23 Department of Paediatrics, University of Melbourne,Melbourne, VIC, Australia
24 Department of Allergy and Immunology, Royal Children’s Hospital,Melbourne, Australia
25 Immunology Division, Garvan Institute of Medical Research,Darlinghurst, NSW, Australia
26 St Vincent’s Clinical School, University of NSW, Sydney, Australia27 Division of Allergy Immunology, Department of Pediatrics, The
Children’s Hospital of Philadelphia, University of PennsylvaniaPerelman School of Medicine, ARC 1216-I 3615 Civic Center Blvd,Philadelphia, PA 19104, USA
Tab
le1
Immunodeficienciesaffectingcellu
larandhumoralim
munity
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
1.T-B+severe
combinedim
munedeficiency
(SCID
)γcdeficiency
(com
mon
gammachainSC
ID,
CD132deficiency)
IL2R
GXL
308380
Verylow
Normalto
high
Low
Low
NK
JAK3deficiency
JAK3
AR
600173
Verylow
Normalto
high
Low
Low
NK
IL7R
αdeficiency
IL7R
AR
146661
Verylow
Normalto
high
Low
NlN
KCD45
deficiency
PTP
RC
AR
151460
Verylow
Normal
Low
Nlγ
/δΤcells
CD3δ
deficiency
CD3D
AR
186790
Verylow
Normal
Low
NlN
K,noγ/δ
Tcells
CD3ε
deficiency
CD3E
AR
186830
Verylow
Normal
Low
NlN
K,noγ/δ
Tcells
CD3ζ
deficiency
CD247
AR
186780
Verylow
Normal
Low
NlN
K,noγ/δ
Tcells
Coronin-1Adeficiency
CORO1A
AR
605000
Verylow
Normal
Low
Detectablethym
us,E
BV
LATdeficiency
LAT
AR
602354
Nltolownumber
Nltolow
High
Adenopathy,splenomegaly,recurrent
infections,autoimmunity
2.T-B-SC
IDRAG1deficiency
RAG1
AR
179615
Verylow
Verylow
Decreased
NlN
KRAG2deficiency
RAG2
AR
179616
Verylow
Verylow
Decreased
NlN
KDCLRE1C
(Artem
is)
deficiency
DCLR
E1C
AR
605988
Verylow
Verylow
Decreased
NlN
K,radiationsensitive
DNAPK
csdeficiency
PRKDC
AR
176977
Verylow
Verylow
Variable
NlN
K,radiationsensitive,m
icrocephaly
Cernunnos/XLFdeficiency
NHEJ1
AR
611290
Verylow
Verylow
Decreased
NlN
K,radiationsensitive,m
icrocephaly
DNAligaseIV
deficiency
LIG4
AR
601837
Verylow
Verylow
Decreased
NlN
K,radiationsensitive,m
icrocephaly
Reticular
dysgenesis
AK2
AR
103020
Verylow
Nltolow
Decreased
Granulocytopeniaanddeafness
Adenosine
deam
inase
(ADA)deficiency
ADA
AR
608958
Verylow
Low
,decreasing
Low
,decreasing
Low
NK,bonedefects,may
have
pulm
onaryalveolar
proteinosis,
cognitive
defects
3.Com
binedim
munodeficienciesgenerally
less
profound
than
severe
combinedim
munodeficiency
DOCK2deficiency
DOCK2
AR
603122
Low
Normal
IgGNlo
rlow,poor
antib
odyresponses
NlN
Kcells,but
defectivefunction.
Poor
interferon
responsesin
hematopoieticandnon-hematopoietic
cells
CD40
liganddeficiency
(CD154)
CD40LG
(TNFSF
5)XL
300386
Nltolow
sIgM
+,IgD
+cells
present,
absent
sIgG
+,IgA
+,and
IgE+cells
IgM
norm
alor
high,
otherIg
isotypes
low
Neutropenia,throm
bocytopenia,
hemolyticanem
ia,opportunistic
infections,biliarytractand
liver
disease,Cryptosporidium
infections
CD40
deficiency
CD40 (TNFRSF
5)AR
109535
Normal
sIgM
+,IgD
+cells
present,
absent
sIgG
+,IgA
+and
IgE+cells
IgM
norm
alor
high,
otherIg
isotypes
low
Neutropenia,opportunisticinfections,
gastrointestinalandbiliary
tractand
liver
disease,Cryptosporidium
infections
ICOSdeficiency
ICOS
AR
604558
Normal
Normal
Low
Recurrent
infections,autoimmunity,
gastroenteritis,granulomas
CD3γ
deficiency
CD3G
AR
186740
Nln
umber,butlow
TCR
expression
Normal
Normal
CD8deficiency
CD8A
AR
186910
AbsentC
D8,nl
CD4
Normal
Normal
Recurrent
infections,m
aybe
asym
ptom
atic
ZAP-70
deficiency
(ZAP7
0LOF)
ZAP70
AR
176947
Low
CD8,NlC
D4number
butp
oorfunctio
nNormal
Normal
May
have
immunedysregulation,
autoim
munity
MHCclassIdeficiency
TAP1
AR
170260
Low
CD8,NlC
D4,absent
MHCIon
lymphocytes
Normal
Normal
Vasculitis,pyoderm
agangrenosum
MHCclassIdeficiency
TAP2
AR
170261
Low
CD8,NlC
D4,absent
MHCIon
lymphocytes
Normal
Normal
Vasculitis,pyoderm
agangrenosum
MHCclassIdeficiency
TAPBP
AR
601962
Low
CD8,NlC
D4,absent
MHCIon
lymphocytes
Normal
Normal
Vasculitis,pyoderm
agangrenosum
MHCclassIdeficiency
B2M
AR
109700
Normal
Normal
98 J Clin Immunol (2018) 38:96–128
Tab
le1
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Low
CD8,NlC
D4,absent
MHCIon
lymphocytes
Sinopulm
onaryinfections,cutaneous
granulom
as.A
bsentβ
2massociated
proteins
MHCI,CD1a,C
D1b,C
D1c
MHCclassIIdeficiency
groupA
CIITA
AR
600005
Low
CD4cells
AbsentM
HCIIexpression
onlymphocytes
Normal
Nltolow
Respiratory
andgastrointestinal
infections,liver/biliarytractd
isease
MHCclassIIdeficiency
groupB
RFXANK
AR
603200
Low
CD4cells
AbsentM
HCIIexpression
onlymphocytes
Normal
Nltolow
Respiratory
andgastrointestinal
infections,liver/biliarytractd
isease
MHCclassIIdeficiency
groupC
RFX5
AR
601863
Low
CD4cells
AbsentM
HCIIexpression
onlymphocytes
Normal
Nltolow
Respiratory
andgastrointestinal
infections,
liver/biliarytractd
isease
MHCclassIIdeficiency
groupD
RFXAP
AR
601861
Low
CD4cells
AbsentM
HCIIexpression
onlymphocytes
Normal
Nltolow
Respiratory
andgastrointestinal
infections,
liver/biliarytractd
isease
DOCK8deficiency
DOCK8
AR
243700
Low
,poorproliferation,few,
poorly
functio
ning
Treg
Low
,low
CD27+mem
ory
Bcells
Poor
peripheral
Bcelltolerance
Low
IgM,N
ltohigh
IgGandIgA,high
IgE
Low
NKcells
with
poor
function,
eosinophilia,recurrentinfections,
cutaneousviral,fungaland
staphylococcalinfections,severe
atopy,cancerdiathesis
Rhohdeficiency
RHOH
AR
602037
Nln
umber,lownaïveTcells,
restricted
repertoire,poor
proliferationto
CD3
Normal
Normal
HPV
infection,lung
granulom
as,
molluscum
contagiosum,lym
phom
aMST
1deficiency
STK4
AR
614868
Low
,low
term
inaldifferentiated
effector
mem
ory(TEMRA)
cells,low
naïveTcells,
poor
proliferation
Low
High
Interm
ittentn
eutropenia,bacterial,viral
(HPV
),candidalinfections,E
BV
lymphoproliferation,autoim
mune
cytopenias,lym
phom
a,congenital
heartd
isease
TCRαdeficiency
TRAC
AR
615387
AbsentT
CRαβ,allTcells
areγδ,poor
proliferation
Normal
Normal
Recurrent
viral,bacterial,fungal
infections,immunedysregulation
andautoim
munity,diarrhea
LCKdeficiency
LCK
AR
615758
Low
CD4+,low
Treg,
restricted
Tcellrepertoire,
poor
TCRsignaling
Normal
NlIgG
andIgA,high
IgM
Recurrent
infections,immune
dysregulation,autoim
munity
MALT
1deficiency
MALT
1AR
615468
Nln
umber,poor
proliferation
Normal
Nllevels,poor
specific
antib
odyresponse
Bacterial,fungaland
viralinfections
CARD11
deficiency
(LOF)
CARD11
AR
615206
Nln
umber,predom
inant
naïveTcells,poor
proliferation
Normal,transitionalBcell
predom
inance
Absent/low
Pneum
ocystis
jiroveciipneumonia,
bacterialand
viralinfections
BCL10
deficiency
BCL1
0AR
616098
Nln
umber,lowmem
ory
TandTregcells,poor
antigen
andanti-CD3
proliferation
Nln
umber,decreasedmem
ory
andsw
itchedBcells
Low
Recurrent
bacterialand
viralinfectio
ns,
candidiasis,gastroenteritis
BCL11Bdeficiency
BCL11B
AD
617237
Low
,poorproliferation
Normal
Normal
Congenitalabnormalities,neonatalteeth,
dysm
orphicfacies,absentcorpus
callo
sum,neurocognitive
deficits
IL-21deficiency
IL21
AR
615767
Nln
umber,nl/lo
wfunctio
nLow
Low
IgG
Severeearly-onsetcolitis,recurrent
sinopulm
onaryinfections
IL-21R
deficiency
IL21R
AR
615207
Nln
umber,lowcytokine
production,poor
antig
enproliferation
Normal
Nln
umber,poor
specificantib
ody
responses
Recurrent
infections,P
neum
ocystis
jiroveci,Cryptosporidium
infections
andliver
disease
OX40
deficiency
TNFRSF
4AR
615593
Nln
umbers,low
antigen
specificmem
oryCD4+
Nlnum
bers,low
mem
oryBcells
Normal
Impaired
immunity
toHHV8,Kaposi’s
sarcom
a
J Clin Immunol (2018) 38:96–128 99
Tab
le1
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
IKBKBdeficiency
IKBKB
AR
615592
Nln
umber,absent
Tregand
γ/δ
Tcells,impaired
TCR
activ
ation
Nln
umber,poor
function
Low
Recurrent
bacterial,viral,fungal
infections,opportunisticinfections
NIK
deficiency
MAP3K
14AR
604655
Nln
umber,poor
proliferation
toantig
enLow
,low
switchedmem
oryB
cells
Low
Ig’s
Low
NKnumberandfunction,recurrent
bacterial,viraland
Cryptosporidium
infections
RelBdeficiency
RELB
AR
604758
Nln
umber,poor
diversity,
poor
functio
nRecurrent
infections
Moesindeficiency
MSN
XL
300988
Nln
umber,defective
migratio
n,proliferation
Low
number
Low
Ig’sover
time
Recurrent
infections
with
bacteria,
varicella,neutropenia
TFR
Cdeficiency
TFRC
AR
616740
Nln
umber,poor
proliferation
Nln
umber,lowmem
oryBcells
Low
Recurrent
infections,neutropenia,
thrombocytopenia
SCID
/CID
spectrum
:Infantswith
SCID
who
have
maternalT
cellengraftm
entm
ayhave
Tcells
innorm
alnumbersthatdo
notfunctionnorm
ally;these
cells
may
causeautoim
munecytopenias
orgraft
versus
hostdisease.Hypom
orphicmutations
inseveralof
thegenesthatcauseSC
IDmay
resultin
Omennsyndrome(O
S),o
r“leaky”SC
ID,o
rstill
less
profound
combinedim
munodeficiency(CID
)phenotypes.B
othOSandleakySC
IDcanbe
associated
with
>300autologous
Tcells/μLof
peripheralbloodandreduced,rather
than
absent,proliferativeresponseswhencomparedwith
typicalS
CID
caused
bynullmutations.A
spectrum
ofclinicalfindings
includingtypicalS
CID
,OS,leakySC
ID,C
ID,granulomas
with
Tlymphopenia,autoimmunity
andCD4Tlymphopeniacanbe
foundinan
allelic
series
ofRAG1andotherSC
ID-associatedgenes.To
talnumberof
disordersin
Table1:
49(17SC
ID,32
CID
).New
disorders:5,
MOESIN,BCL11B
,TF
RC,RELB
,LA
T.Rem
oved
gene:UNC119
deficiency
hasbeen
removed.T
heUNC119variantreportedpreviously
isabenign
polymorphism
inunaffected
individuals
SCID
severecombinedim
munodeficiency,EBVEpstein-Barrvirus,MHCmajor
histocom
patib
ilitycomplex,H
PVhuman
papillo
mavirus,TregTregulatory
cell,
Nlnormal,X
LX-linkedinheritance,AR
autosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n
100 J Clin Immunol (2018) 38:96–128
Tab
le2
Com
binedim
munodeficiencieswith
associated
orsyndromicfeatures
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
1.Im
munodeficiencywith
congenitalthrom
bocytopenia
Wiskott-Aldrich
syndrome(W
ASLOF)
WAS
XL
300392
Progressivedecrease
innumbers,abnormal
lymphocyteresponsesto
anti-CD3
Normalnumbers
Low
IgM
andantib
ody
responsesto
polysaccharides,oftenhigh
IgAandIgE
Throm
bocytopeniawith
smallp
latelets,recurrent
bacterialand
viralinfectio
ns,b
loodydiarrhea,
eczema,lymphom
a,autoim
munedisease,IgA
nephropathy,vasculitis.XLthrombocytopeniais
amild
form
ofWAS,
andXLneutropeniais
caused
bymissensemutations
intheGTPase
bindingdomainof
WASp
WIP
deficiency
WIPF1
AR
602357
Reduced,defectiv
elymphocyteresponsesto
anti-CD3
Normalor
low
Normal,exceptfor
high
IgE
Throm
bocytopeniawith
orwith
outsmallp
latelets,
recurrentb
acterialandviralinfectio
ns,eczem
a,bloody
diarrhea,W
ASproteinabsent
ARPC
1Bdeficiency
ARPC1B
AR
604223
Normal
Normalnumbers
Normalexceptforh
ighIgAand
IgE
Mild
thrombocytopeniawith
norm
alsizedplatelets,
recurrentinvasiveinfections,colitis,vasculitis,
autoantibodies(A
NA,A
NCA),eosinophilia,
defectiveArp2/3,filamentb
ranching
2.DNArepairdefectsotherthan
thoselistedin
Table1
Ataxia-telangiectasia
ATM
AR
607585
Progressivedecrease,
abnorm
alproliferation
tomito
gens
Normal
Often
lowIgA,IgE
andIgG
subclasses,increased
IgM
monom
ers,antib
odies
variably
decreased
Ataxia,telangiectasia,pulmonaryinfections,
lymphoreticular
andothermalignancies,
increasedalphafetoprotein,increased
radiosensitiv
ity,chrom
osom
alinstability
and
chromosom
altranslocations
Nijm
egen
breakage
syndrome
NBS1
AR
602667
Progressivedecrease
Variablyreduced
Often
lowIgA,IgE
,and
IgG
subclasses,increased
IgM,
antib
odiesvariably
decreased
Microcephaly,dysm
orphicfacies,lym
phom
as,solid
tumors,increasedradiosensitiv
ity,chrom
osom
alinstability
Bloom
Syndrome
BLM
(RECQL3
)AR
604610
Normal
Normal
Low
Shortstature,dysmorphicfacies,sun-sensitiv
eerythema,marrowfailu
re,leukemia,lym
phom
a,chromosom
alinstability
Immunodeficiencywith
centromericinstability
andfacialanom
alies,
ICF1
DNMT3
BAR
602900
Decreased
ornorm
al,
responsesto
PHAmay
bedecreased
Decreased
ornorm
alHypogam
maglobulin
emiaor
agam
maglobulin
emia,
variableantib
odydeficiency
Immunodeficiencywith
centromericinstability
andfacialanom
alies,
ICF2
ZBTB
24AR
614064
Decreased
ornorm
al,
Decreased
ornorm
alHypogam
maglobulin
emiaor
agam
maglobulin
emia,
variableantib
odydeficiency
Immunodeficiencywith
centromericinstability
andfacialanom
alies,
ICF3
CDCA7
AR
609937
responsesto
PHAmay
bedecreased
Decreased
ornorm
alHypogam
maglobulin
emiaor
agam
maglobulin
emia,
variableantib
odydeficiency
Immunodeficiencywith
centromericinstability
andfacialanom
alies,
ICF4
HELL
SAR
603946
Decreased
ornorm
alDecreased
ornorm
alHypogam
maglobulin
emiaor
agam
maglobulin
emia,
variableantib
odydeficiency
PMS2
deficiency
PMS2
AR
600259
Normal
Low
Bcells,switched
andnon-sw
itched
Low
IgGandIgA,highIgM,
abnorm
alantib
ody
responses
Recurrent
infections,café-au-laitspots,lym
phom
a,colorectalcarcinom
a,braintumors
RNF1
68deficiency
(radiosensitivity,
immunedeficiency,
RNF168
AR
612688
Normal
Normal
Low
IgGor
IgA
Shortstature,m
ilddefectof
motor
controltoataxia,
norm
alintelligenceto
learning
difficulties,mild
J Clin Immunol (2018) 38:96–128 101
Tab
le2
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
dysm
orphicfeatures,
learning
difficulties
[RID
DLE]syndrome)
facialdysm
orphism
tomicrocephaly,increased
radiosensitiv
ity
MCM4deficiency
MCM4
AR
602638
Normal
Normal
Normal
NKcells:low
numberandfunctio
n.Viralinfections
(EBV,H
SV,V
ZV),shortstature,B
cell
lymphom
a,adrenalfailure
POLE1(polym
eraseε
subunit1
)deficiency
(FILSsyndrome)
POLE
AR
174762
Decreased
Tcell
proliferation
Low
mem
oryBcells
Low
IgG2andIgM,lackof
antibodyto
PPS
Recurrent
respiratoryinfections,m
eningitis,facial
dysm
orphism,livido,shortstature
POLE2(polym
eraseε
subunit2
)deficiency
POLE
2AR
602670
Lymphopenia,lackof
TRECS,
absent
proliferationin
response
toantig
ens
Verylow
Hypogam
maglobulin
emia
Recurrent
infections,disseminated
BCGinfections,
autoim
munity
(type1diabetes,hypothyroidism,
facialdysm
orphism
LigaseIdeficiency
LIG1
AR
126391
Lymphopenia,decreased
mito
genresponse
Normal
Low
IgAandIgG
Reduced
antib
odyresponses
Recurrentrespiratoryinfections,growthretardation,
sunsensitivity,lym
phom
a,radiationsensitivity
NSM
CE3deficiency
NSM
CE3
AR
608243
Num
berdecreased,poor
response
tomito
gens
andantigens
Normal
Normal
Decreased
AbresponsestoPP
Snorm
alIgG,IgA
,elevated
IgM
Severe
lung
disease(possiblyviral),thymic
hypoplasia,chrom
osom
albreakage,radiatio
nsensitivity
ERCC6L
2(H
ebo
deficiency)
ERCC6L
2AR
615667
Lymphopenia
Low
Normal
Facialdysm
orphism,m
icrocephaly,bone
marrow
failu
reGIN
S1deficiency
GINS1
AR
610608
Low
ornorm
alLow
ornorm
alHighIgA,low
IgM
andIgG
Neutropenia,IUGR,N
Kcells
very
low
3.Thymicdefectswith
additio
nalcongenitalanomalies
DiGeorge/velocardiofac-
ialsyndrom
eChrom
osom
e22q11.2
deletio
nsyndrome
(22q11.2DS)
Largedeletio
n(3
Mb)
typically
inchromosom
e22
AD
602054
Decreased
ornorm
al,5%
have
<1500
CD3T
cells/μLin
neonatal
period
Normal
Normalor
decreased
Hypoparathyroidism,conotruncalcardiac
malform
ation,velopalatalinsufficiency,
abnorm
alfacies,intellectuald
isability
DiGeorge/velocardiofacial
syndrome
Unknown
Sporadic
Decreased
ornorm
alNormal
Normalor
decreased
Hypoparathyroidism,conotruncalcardiac
malform
ation,velopalatalinsufficiency,
abnorm
alfacies,intellectuald
isability
TBX1deficiency
TBX1
AD
602054
Decreased
ornorm
alNormal
Normalor
decreased
Hypoparathyroidism,conotruncalcardiac
malform
ation,velopalatalinsufficiency,
abnorm
alfacies,intellectuald
isability
CHARGEsyndrome
dueto
CHD7
deficiency
CHD7
AD
608892
Decreased
ornorm
al,
response
toPH
Amay
bedecreased
Normal
Normalor
decreased
Colobom
a,heartanomaly,choanalatresia,
intellectuald
isability,genitaland
earanom
alies,
CNSmalform
ation,someareSC
ID-likeand
have
lowTRECs
CHARGEsyndrome
dueto
SEMA3E
deficiency
SEMA3E
AD
608166
Decreased
ornorm
al,
response
toPH
Amay
bedecreased
Normal
Normalor
decreased
Colobom
a,heartanomaly,choanalatresia,
intellectualretardatio
n,genitaland
earanomalies,
CNSmalform
ation,someareSC
ID-likeand
have
lowTRECs
CHARGEsyndrome
Unknown
Decreased
ornorm
al,
response
toPH
Amay
bedecreased
Normal
Normalor
decreased
Colobom
a,heartanomaly,choanalatresia,
intellectuald
isability,genitaland
earanom
alies,
CNSmalform
ation,someareSC
ID-likeand
have
lowTRECs
Wingedhelix
nude
FOXN1deficiency
FOXN1
AR
600838
Verylow
Normal
Decreased
Severe
infections,abnormalthym
icepith
elium,
immunodeficiency,congenitalalopecia,nail
dystrophy,neuraltube
defect
Del10p13-p14
AD
601362
Normal
Normal
102 J Clin Immunol (2018) 38:96–128
Tab
le2
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Chrom
osom
e10p13-p14deletio
nSy
ndrome
(10p13-p14DS)
Normal,rarely
lymphopeniaand
decreased
lymphoproliferationto
mito
gens
andantig
ens,
hypolasticthym
usmay
bepresent
Hypoparathyroidism,renaldisease,deafness,
grow
thretardation,facialdysm
orphism,cardiac
defectsmay
bepresent,recurrentinfectio
ns+/−
4.Im
muno-osseousdysplasias
Cartilagehairhypoplasia
(CHH)
RMRP
AR
157660
Variesfrom
severely
decreased(SCID
)to
norm
al,impaired
lymphocyteproliferation
Normal
Normalor
reduced,antib
odies
variably
decreased
Short-lim
beddw
arfism
with
metaphyseal
dysostosis,sparsehair,
bone
marrowfailu
re,
autoim
munity,susceptibility
tolymphom
aand
othercancers,im
paired
spermatogenesis,
neuronaldysplasiaof
theintestine
Schimke
immuno-osseous
dysplasia
SMARCAL1
AR
606622
Decreased
Normal
Normal
Shortstature,spondilo
epiphysealdysplasia,
intrauterine
grow
thretardation,nephropathy,
bacterial,viral,fungalinfections,m
aypresentas
SCID
,bonemarrowfailu
reMYSM
1deficiency
MYS
M1
AR
612176
Tcelllymphopenia,
reducednaïveTcells
ImmatureBcells
Hypogam
maglobulin
emia
Shortstature,recurrent
infections,congenitalb
one
marrowfailu
re,m
yelodysplasia,
immunodeficiencyaffectingBcells
and
granulocytes,skeletalanomalies,cataracts,
developm
entald
elay.
MOPD
1deficiency
RNU4A
TAC
AR
601428
Normal
Normal
Normal,specificantib
odies
variably
decreased
Recurrent
bacterialinfectio
ns,lym
phadenopathy,
spondyloepiphysealdysplasia,extrem
eintrauterine
grow
thretardation,retin
aldystrophy,
facialdysm
orphism,m
aypresentw
ithmicrocephaly
EXTL3deficiency
EXTL
3AR
Reduced
Normal
Variablydecreased
Platyspondyly,kyphosis,variableskeletal
dysplasias,developmentald
elay
5.HyperIgEsyndromes
(HIES)
AD-H
IES
STAT3deficiency
(Job
syndrome)
STAT
3ADLOF
102582
Normaloverall,Th-17
and
T-follicularhelper
cells
decreased
Normal,reduced
switchedand
non-sw
itched
mem
oryBcells,
BAFF
expression
increased
HighIgE,specificantib
ody
productio
ndecreased
Distin
ctivefacialfeatures
(broad
nasalb
ridge),
bacterialinfectio
ns(boilsandpulm
onary
abscesses,pneumatoceles)dueto
S.aureus,
pulm
onaryaspergillus,P
neum
ocystis
jirovecii,
eczema,mucocutaneous
candidiasis,
hyperextensiblejoints,osteoporosisandbone
fractures,scoliosis,retentionof
prim
aryteeth,
coronary
andcerebralaneurysm
form
ation
Com
el-N
etherton
syndrome
SPINK5
AR
605010
Normal
Low
Switchedand
non-sw
itchedBcells
HighIgEandIgA
Antibodyvariably
decreased
Congenitalichthyosis,bamboohair,
atopic
diathesis,increasedbacterialinfectio
ns,failureto
thrive
PGM3deficiency
PGM3
AR
172100
CD8andCD4Tcells
may
bedecreased
Low
Bandmem
oryB
cells
Normalor
elevated
IgGand
IgA,m
osth
ighIgE,
eosinophilia
Severe
atopy,autoim
munity,bacterialandviral
infections,skeletalanomaliesdysplasia:short
stature,brachydactyly,dysm
orphicfacial
features,and
intellectuald
isability
cognitive
impairment,hypomyelin
ation
6.Dyskeratosiscongenita
(DKC),myelodysplasia,shorttelom
eres
XL-D
KCdueto
dyskerin
deficiency
DKC1
XL
300126
Progressivedecrease
Progressivedecrease
Variable
hypogammaglobulin
emia
Intrauterine
grow
thretardation,microcephaly,nail
dystrophy,sparse
scalphairandeyelashes,
hyperpigmentatio
nof
skin,palmar
J Clin Immunol (2018) 38:96–128 103
Tab
le2
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
hyperkeratosis,premalignant
oralleukoplakia,
pancytopenia,m
yelodysplasia,+/−
recurrent
infections.A
severe
phenotypewith
developm
entald
elay
andcerebellarhypoplasia
know
nas
Hoyeraal-Hreidarsson
syndrome
(HHS)
may
occurin
someDKCpatients
AR-D
KCdueto
nucleolarprotein
family
Amem
ber2
(NHP2
)deficiency
NHP2
AR
606470
Decreased
Variable
Variable
AR-D
KCdueto
nucleolarprotein
family
Amem
ber3
(NHP3
)or
NOP10
deficiency
NOP10
AR
606471
Decreased
Variable
Variable
AD/AR-D
KCdueto
regulatorof
telomere
elongatio
n(RTEL1)
deficiency
RTE
L1ADor
AR
608833
Decreased
Variable
Variable
AD-D
KCdueto
TERC
deficiency
TERC
AD
602322
Variable
Variable
Variable
AD/AR-D
KCdueto
TERTdeficiency
TERT
ADor
AR
187270
Variable
Variable
Variable
AD-D
KCdueto
TIN
F2deficiency
TINF2
AD
604319
Variable
Variable
Variable
AD/AR-D
KCdueto
TPP
1deficiency
TPP1
ADor
AR
609377
Variable
Variable
Variable
AR-D
KCdueto
DCLRE1B
deficiency
DCLR
E1B
/SN-
M1/APOLL
-O:
AR
609683
Variable
Variable
Variable
AR-D
KCdueto
PARN
deficiency
PARN
AR(A
D?)
604212
Variable
Variable
Variable
AR-D
KCdueto
WRAP5
3deficiency
WRAP53
AR
612661
Not
reported
Not
reported
Not
reported
Coatsplus
syndromedue
toST
N1deficiency
STN1
AR
613128
Variable
Variable
Not
know
nIntrauterine
grow
thretardation,prem
atureaging,
pancytopenia,hypocellularbone
marrow,
gastrointestinalhemorrhagedueto
vascular
ectasia,intracranialcalcification,abnorm
altelomeres
Coatsplus
syndromedue
toCTC1deficiency
CTC
1AR
613129
Normal
Normal
Normal
Intrauterine
grow
thretardation,sparse
grayinghair,
dystrophicnails,trilin
earbone
marrowfailu
re,
osteopenia,gastrointestin
alhemorrhagedueto
vascular
ectasia,retin
altelangiectasia,
intracranialcalcification,abnorm
altelomeres
SAMD9
SAMD9
AD(G
OF)
617053
Not
reported
Not
reported
Not
reported
IUGRwith
gonadalabnormalities,adrenalfailu
re,
MDSwith
chromosom
e7aberratio
ns,
predispositio
nto
infections,enteropathy,absent
spleen
SAMD9L
SAMD9L
AD(G
OF)
159550
Normal
Low
Not
reported
104 J Clin Immunol (2018) 38:96–128
Tab
le2
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Cytopenia,predisposition
toMDSwith
chromosom
e7aberratio
ns,immunodeficiency,
andprogressivecerebellardysfunction
7.Defectsof
vitamin
B12andfolatemetabolism
Transcobalamin
2deficiency
TCN2
AR
613441
Normal
Variable
Decreased
Megaloblasticanem
ia,pancytopenia,ifuntreated
forprolongedperiodsresults
inintellectual
disability
SLC46A1/PCFT
deficiency
causing
hereditary
folate
malabsorptio
n
SLC46A1
AR
229050
Variablenumbersand
activ
ationprofile
Variable
Decreased
Megaloblasticanem
ia,ifuntreatedforprolonged
periodsresults
inintellectuald
isability
Methylene-tetrahydrofo-
latedehydrogenase1
(MTHFD
1)deficiency
MTH
FD1
AR
172460
Low
thym
icoutput,normal
invitroproliferation
Low
Decreased/poorantibody
responsesto
conjugated
polysaccharide
antig
ens
Recurrent
bacterialinfectio
n,Pneum
ocystis
jirovecii,
megaloblasticanem
ia,neutropenia,
seizures,intellectuald
isability,folate-responsive
8.Anhidrotic
ectoderm
odysplasiawith
immunodeficiency(EDA-ID))
EDA-IDdueto
NEMO
/IKBKGdeficiency
(ectodermaldysplasia,
immunedeficiency)
NEMO(IKBKG)
XL
300248
Normalor
decreased,TCR
activ
ationim
paired
Normal
Low
mem
oryand
isotypesw
itchedB
cells
Decreased,som
ewith
elevated
IgA,IgM
,poorspecific
antibodyresponses,absent
antibodyto
polysaccharide
antigens
Anhidrotic
ectoderm
aldysplasia(insome),various
infections
(bacteria,mycobacteria,virusesand
fungi),colitis,conicalteeth,variabledefectsof
skin,hairandteeth,monocytedysfunction
EDA-IDdueto
IKBA
GOFmutation
IKBA(NFKBIA)
ADGOF
164008
NormaltotalT
cells,T
CR
activ
ationim
paired
NormalBcellnumbers,
impaired
BCR
activ
ation,low
mem
oryandisotype
switchedBcells
Decreased
IgGandIgA,
elevated
IgM,poorspecific
antibodyresponses,absent
antibodyto
polysaccharide
antigens
Anhidrotic
ectoderm
aldysplasia,variousinfections
(bacteria,mycobacteria,virusesandfungi),
colitis,variabledefectsof
skin,hairandteeth,T
cellandmonocytedysfunction
9.Calcium
channeld
efects
ORAI-1deficiency
ORAI1
AR
610277
Normal,d
efectiveTCR
mediatedactiv
ation
Normal
Normal
Autoimmunity,E
DA,n
on-progressive
myopathy
STIM
1deficiency
STIM
1AR
605921
Normal,d
efectiveTCR
mediatedactiv
ation
Normal
Normal
Autoimmunity,E
DA,n
on-progressive
myopathy
10.O
ther
defects
Purine
nucleoside
phosphorylase(PNP)
deficiency
PNP
AR
164050
Progressivedecrease
Normal
Normalor
low
Autoimmunehemolyticanem
ia,neurological
impairment
Immunodeficiencywith
multip
leintestinal
atresias
TTC7A
AR
609332
Variable,butsom
etim
esabsent
lowTRECs
Normalor
low
MarkedlydecreasedIgG,IgM
,IgA
Bacterial(sepsis),fungal,viralinfectio
ns,m
ultip
leintestinalatresias,often
with
intrauterine
polyhydram
nios
andearlydemise,somewith
SCID
phenotype
Hepaticveno-occlusive
diseasewith
immunodeficiency
(VODI)
SP110
AR
604457
Normal(decreased
mem
ory
Tcells)
Normal(decreased
mem
oryBcells)
Decreased
IgG,IgA
,IgM
,absent
germ
inalcentersand
tissueplasmacells
Hepaticveno-occlusive
disease,Su
sceptib
ility
toPneum
ocystis
jiroveciipneumonia,C
MV,
candida,thrombocytopenia,
hepatosplenomegaly,cerebrospinal
leukodystrophy
Vicisyndrom
edueto
EPG
5deficiency
EPG5
AR
615068
Profound
depletionof
CD4+
cells
Defectiv
eDecreased
(particularly
IgG2)
Agenesisof
thecorpus
callo
sum,cataracts,
cardiomyopathy,skin
hypopigm
entatio
n,intellectuald
isability,m
icrocephaly,recurrent
infections,chronicmucocutaneous
candidiasis
HOIL1deficiency
HOIL1(RBCK1)
AR
610924
Normalnumbers
Normal,decreased
mem
oryBcells
Poorantib
odyresponsesto
polysaccharides
Bacterialinfections,autoinflammation,
amylopectin
osis
HOIP
deficiency
RNF31
AR
612487
Normalnumbers
decreased
J Clin Immunol (2018) 38:96–128 105
Tab
le2
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Normal,decreased
mem
oryBcells
Bacterialinfections,autoinflammation,
amylopectin
osis,lym
phangiectasia
Hennekam-lym
phangie-
ctasia-lym
phedem
asyndromedueto
CCBE1deficiency
CCBE1
AR
612753
Low
/variable
Low
/variable
decreased
Lymphangiectasiaandlymphedem
awith
facial
abnorm
alities
andotherdysm
orphicfeatures
Hennekam-lym
phangie-
ctasia-lym
phedem
asyndromeduetoFA
T4
deficiency
FAT4
AR
612411
Low
/variable
Low
/variable
decreased
Lymphangiectasiaandlymphedem
awith
facial
abnorm
alities
andotherdysm
orphicfeatures
STAT5b
deficiency
STAT
5BAR
604260
Modestly
decreased
Normal
Normal
Growth-hormoneinsensitive
dwarfism
,dysmorphic
features,eczem
a,lymphocyticinterstitial
pneumonitis,autoim
munity
Kabukisyndrom
e1due
toKMT2D
deficiency
KMT2
D(M
LL2)
AD
602113
Normal
Normal
Low
IgAandoccasionally
low
IgG
Typicalfacialabnormalities,cleftor
high
arched
palate,skeletalabnormalities,shortstature,
intellectuald
isability,congenitalh
eartdefects,
recurrentinfectio
ns(otitismedia,pneum
onia)in
50%
ofpatients.Autoimmunity
may
bepresent
Kabukisyndrom
e2due
toKDM6A
deficiency
KDM6A
XL(fem
ales
may
beaffected)
300128
Normal
Normal
Low
IgAandoccasionally
IgG
Purebone
marrowfailu
resyndromes
have
notbeenincluded.Totalnumbero
fdisordersinTable2:67.N
ewdisorders:23,A
RPC1B
,CDCA7,HELL
S,POLE
2,LIG1,GINS1,N
SMCE3,ERCC6L
2,TB
X1,
MYS
M1,MOPD1,ST
N1,CTC
1,KMT2
D,K
DM6A
,SAMD9,SA
MD9L
,EXTL
3,WRAP53,FAT
4.Unknowncauseof
DiGeorgesyndrome,unknow
ncauseCHARGE,10p13-14deletio
n
IUGRintrauterine
grow
thretardation,HSV
herpes
simplex
virus,VZV
varicella
zostervirus,BCGBacillus
Calmette-G
uerin,XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomal
dominantinheritance,LO
Floss-of-functio
n,GOFgain-of-functio
n
106 J Clin Immunol (2018) 38:96–128
Tab
le3
Predom
inantly
antib
odydeficiencies
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
1.Severe
reductionin
allserum
immunoglobulin
isotypes
with
profoundly
decreasedor
absent
Bcells,agammaglobulin
emia
BTKdeficiency,X
-linked
agam
maglobulin
emia
(XLA)
BTK
XL
300300
Allisotypes
decreasedin
majority
ofpatients,somepatientshave
detectableim
munoglobulin
s
Severe
bacterialinfectio
ns,normal
numbersof
pro-Bcells
μheavychaindeficiency
IGHM
AR
147020
Allisotypes
decreased
Severebacterialinfectio
ns,normal
numbersof
pro-Bcells
λ5deficiency
IGLL
1AR
146770
Allisotypes
decreased
Severebacterialinfectio
ns,normal
numbersof
pro-Bcells
Igαdeficiency
CD79A
AR
112205
Allisotypes
decreased
Severebacterialinfectio
ns,normal
numbersof
pro-Bcells
Igβdeficiency
CD79B
AR
147245
Allisotypes
decreased
Severebacterialinfectio
ns,normal
numbersof
pro-Bcells
BLNKdeficiency
BLN
KAR
604515
Allisotypes
decreased
Severebacterialinfectio
ns,normal
numbersof
pro-Bcells
PIK3R
1deficiency
PIK3R
1AR
171833
Allisotypes
decreased
Severebacterialinfectio
ns,
decreasedor
absent
pro-Bcells
E47
transcriptionfactor
deficiency
TCF3
AD
147141
Allisotypes
decreased
Recurrent
bacterialinfectio
ns
2.Severe
reductionin
atleast2
serum
immunoglobulin
isotypes
with
norm
alor
lownumberof
Bcells,C
VID
phenotype
Com
mon
variableim
mune
deficiency
with
nogene
defectspecified(CVID
)
Unknown
Variable
Low
IgGandIgAand/or
IgM
Clin
icalphenotypes
vary:m
osthave
recurrentinfectio
ns,som
ehave
polyclonallymphoproliferation,
autoim
munecytopenias
and/or
granulom
atousdisease
PIK3C
Dmutation(G
OF)
PIK3C
DGOF
AD
602839
Allisotypes
decreased
Severebacterialinfectio
ns;
decreasedor
absent
pro-Bcells,
EBV
PIK3R
1deficiency
(LOF)
PIK3R
1AD
616005
Allisotypes
decreased
Severebacterialinfectio
ns,pro-B
cells
presentand
lownumbersof
mem
oryBcells,E
BV
PTENDeficiency(LOF)
PTE
NAD
601728
Decreased
Lym
phoproliferation,autoim
munity
CD19
deficiency
CD19
AR
107265
Low
IgGandIgAand/or
IgM
Recurrent
infections,m
ayhave
glom
erulonephritis
CD81
deficiency
CD81
AR
186845
Low
IgG,low
ornorm
alIgAandIgM
Recurrent
infections,m
ayhave
glom
erulonephritis
CD20
deficiency
MS4A1
AR
112210
Low
IgG,normalor
elevated
IgM
and
IgA
Recurrent
infections
CD21
deficiency
CR2
AR
120650
Low
IgG,impaired
anti-pneumococcal
response
Recurrent
infections
TACIdeficiency
TNFRSF
13B(TACI)
ADor
AR
604907
Low
IgGandIgAand/or
IgM
Variableclinicalexpression
BAFFreceptor
deficiency
TNFRSF
13C(BAFF-R)
AR
606269
Low
IgGandIgM,
Variableclinicalexpression
J Clin Immunol (2018) 38:96–128 107
Tab
le3
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
TWEAKdeficiency
TNFSF
12AD
602695
Low
IgM
andA,lackof
anti-pneumococcalantibody
Pneumonia,bacterialinfections,
warts,throm
bocytopenia.
Neutropenia
Mannosyl-oligosaccharide
glucosidasedeficiency
(MOGS)
MOGS(G
CS1)
AR
601336
Severe
hypogammaglobulin
emia,
Bacterialandviralinfectio
ns,severe
neurologicdisease,also
know
nas
congenitald
isorderof
glycosylationtype
IIb(CDG-IIb)
TRNT1deficiency
TRNT1
AR
612907
Bcelldeficiency
and
hypogammaglobulin
emia
Congenitalsideroblasticanem
ia,
deafness,developmentald
elay
TTC37
deficiency
TTC37
AR
614649
Poor
antibodyresponse
topneumococcalv
accine
Recurrent
bacterialand
viral
infections,abnormalhair
findings:trichorrhexisnodosa
NFKB1deficiency
NFKB1
AD
164011
Normalor
lowIgG,IgA
,IgM
,low
ornorm
alBcells,low
mem
oryBcells
Recurrentsinopulm
onaryinfections,
COPD
,EBVproliferation,
autoim
munecytopenias,alopecia
andautoim
munethyroiditis
NFKB2deficiency
NFKB2
AD
615577
Low
serum
IgG,A
andM;low
Bcell
numbers
Recurrentsinopulm
onaryinfections,
alopecia,and
endorinopathies
IKAROSdeficiency
IKZF
1AD
603023
Low
IgG,IgA
,IgM
,low
ornorm
alB
cells,potentially
reducing
levelswith
age
Recurrent
sinopulm
onaryinfections
IRF2
BP2
deficiency
IRF2B
P2
AD
615332
Hypogam
maglobulenia,absent
IgA
Recurrent
infections,possible
autoim
munity
andinflam
matory
disease
ATP6A
P1deficiency
ATP6A
P1
XL
300197
Variableim
munoglobulin
findings
Hepatopathy,leukopenia,low
copper
3.Severe
reductionin
serum
IgGandIgAwith
norm
al/elevatedIgM
andnorm
alnumbersof
Bcells,hyper
IgM
AID
deficiency
AICDA
AR
605257
IgGandIgAdecreased,IgM
increased
Bacterialinfections,enlargedlymph
nodesandgerm
inalcenters
UNGdeficiency
UNG
AR
191525
IgGandIgAdecreased,IgM
increased
Enlargedlymph
nodesandgerm
inal
centers
INO80
INO80
AR
610169
IgGandIgAdecreased,IgM
increased
Severebacterialinfectio
ns
MSH
6MSH
6AR
600678
VariableIgG,defects,increased
IgM
insome,norm
alBcells,low
switched
mem
oryBcells,Ig-classsw
itch
recombinatio
nandsomatic
hyperm
utationdefects
Family
orpersonalhistoryof
cancer
4.Isotype,lig
htchain,or
functio
nald
eficiencieswith
generally
norm
alnumbersof
Bcells
Igheavychainmutations
anddeletio
nsMutationor
chromosom
aldeletio
nat
14q32
AR
One
ormoreIgGand/or
IgAsubclasses
aswellasIgEmay
beabsent
May
beasym
ptom
atic
108 J Clin Immunol (2018) 38:96–128
Tab
le3
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
Kappa
chaindeficiency
IGKC
AR
147200
Allim
munoglobulin
shave
lambdalig
htchain
Asymptom
atic
Isolated
IgGsubclass
deficiency
Unknown
?Reductio
nin
oneor
moreIgGsubclass
Usually
asym
ptom
atic,a
minority
may
have
poor
antib
odyresponse
tospecificantig
ensandrecurrent
viral/b
acterialinfections
IgGsubclass
deficiency
with
IgAdeficiency
Unknown
?Reduced
IgAwith
decrease
inoneor
moreIgGsubclass
Recurrent
bacterialinfectio
ns
SelectiveIgAdeficiency
Unknown
?Verylowto
absent
IgAwith
other
isotypes
norm
al,normalsubclasses
andspecificantib
odies
Bacterialinfections,autoimmunity
mild
lyincreased
Specificantib
ody
deficiency
with
norm
alIg
levelsandnorm
alBcells
Unknown
?Normal
Reduced
ability
toproduce
antib
odiesto
specificantig
ens
Transient
hypogammaglobulin
emia
ofinfancy
Unknown
?IgGandIgAdecreased
Normalabilitytoproduceantib
odies
tovaccineantig
ens,usually
not
associated
with
significant
infections
CARD11
GOF
CARD11
ADGOF
607210
HighBcellnumbersduetoconstitutive
NF-κBactiv
ation
Splenomegaly,lymphadenopathy,
poor
vaccineresponse
SelectiveIgM
deficiency
Unknown
?Absentserum
IgM
Pneum
ococcal/
bacterialinfectio
ns
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.Identificationof
causalvariantscanassistin
defining
treatm
ent.In
additio
nto
monogenic
causeson
thistable,asm
allm
inority
ofpatientswith
XLP(Table4),W
HIM
syndrome(Table6),ICF(Table2),V
OD1(Table2),thymom
awith
immunodeficiency(G
oodsyndrome)ormyelodysplasiaare
firstseen
byan
immunologistbecauseof
recurrentinfections,h
ypogam
maglobulin
emiaandnorm
alor
reducednumbersof
Bcells.T
otalnumberof
disordersin
Table3:
40.N
ewdisorders:7,
PTE
N,
NFKB1,IKZF
1,IRF2B
P2,AT
P6A
P1.Selectiv
eigAdeficiency,selectiv
eIgM
deficiency
EBVEpstein-Barrvirus,C
OPDchronicobstructivepulm
onarydisease,XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n,GOFgain-
of-function
J Clin Immunol (2018) 38:96–128 109
Tab
le4
Diseasesof
immunedysregulation
Disease
Geneticdefect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gBcells
Functio
nald
efect
Associatedfeatures
1.Familialhemophagocytic
lymphohistio
cytosis(FHLsyndromes)
Perforin
deficiency
(FHL2)
PRF1
AR
170280
Increasedactiv
ated
Tcells
Normal
Decreased
toabsentNKandCTL
activ
ities
cytotoxicity
Fever,(H
)SM,hem
ophagocytic
lymphohistio
cytosis(H
LH),
cytopenias
UNC13D/M
unc13-4
deficiency
(FHL3)
UNC13D
AR
608897
Increasedactiv
ated
Tcells
Normal
Decreased
toabsentNKandCTL
activ
ities
(cytotoxicity
and/or
degranulation)
Fever,(H
)SM,H
LH,cytopenias,
Syntaxin11
deficiency
(FHL4)
STX11
AR
605014
Increasedactiv
ated
Tcells
Normal
Decreased
NKactiv
ity(cytotoxicity
and/or
degranulation)
Fever,(H
)SM,cHLH,cytopenias,
STXBP2
/Munc18-2
deficiency
(FHL5)
STXBP2
ARor
AD
601717
Increasedactiv
ated
Tcells
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Fever,(H
)SM,cHLH,cytopenias,
enteropathy
FAAP2
4deficiency
FAAP24
AR
610884
Increasedactiv
ated
Tcells
Normal
Failu
reto
killautologous
EBV
transformed
Bcells.N
ormal
NKcellfunctio
n
EBVinfection-driven
lymphoproliferativedisease
2.FH
Lsyndromes
with
hypopigm
entatio
n
Chediak-H
igashi
syndrome
LYST
AR
606897
Increasedactiv
ated
Tcells
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Partialalbinism,recurrent
infections,
fever,HSM
,HLH,giant
lysosomes,
neutropenia,cytopenias,bleeding
tendency,progressive
neurological
dysfunction
Griscellisyndrome,type
2RAB27A
AR
603868
Normal
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Partialalbinism,fever,H
SM,H
LH,
cytopenias
Hermansky-Pudlak
syndrome,type
2AP3B
1AR
603401
Normal
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Partialalbinism,recurrent
infections,
pulm
onaryfibrosis,increased
bleeding,neutropenia,H
LH
Hermansky-Pudlak
syndrome,type
10AP3D
1AR
617050
Normal
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Oculocutaneousalbinism
,severe
neutropenia,recurrentinfectio
ns,
seizures,hearing
loss,and
neurodevelopmentald
elay
3.RegulatoryTcelldefects
IPEX,immune
dysregulation,
polyendocrinopathy,
enteropathyX-linked
FOXP3
XL
300292
Normal
Normal
Lackof(and/orimpaired
functio
nof)CD4+
CD25
+FOXP3+
regulatory
Tcells
(Tregs)
Autoimmuneenteropathy,early-onset
diabetes,thyroiditishemolytic
anem
ia,throm
bocytopenia,eczema,
elevated
IgE,IgA
CD25
deficiency
IL2R
AAR
147730
Normalto
decreased
Normal
NoCD4+C25+cells
with
impaired
functio
nof
Tregs
cells
Lymphoproliferation,autoim
munity,
impaired
Tcellproliferation
CTLA4deficiency
(ALPS
V)
CTL
A4
AD
123890
Decreased
Decreased
Impaired
functio
nof
Tregs.
Autoimmunecytopenias,enteropathy,
interstitiallungdisease,
110 J Clin Immunol (2018) 38:96–128
Tab
le4
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gBcells
Functio
nald
efect
Associatedfeatures
extra-lymphoidlymphocytic
infiltrationrecurrentinfectio
ns
LRBAdeficiency
LRBA
AR
606453
Normalor
decreased
CD4numbers,T
cell
dysregulation
Low
ornorm
alnumbersof
Bcells
Reduced
IIgGandIgAin
most
Recurrent
infections,inflammatory
boweldisease,autoim
munity,E
BV
infections
STA
T3GOFmutation
STAT
3AD(G
OF)
102582
Decreased
Decreased
EnhancedST
AT3signaling,
leadingto
increasedTh17cell
differentiatio
n,lymphoproliferationand
autoim
munity.D
ecreased
Tregs
andim
paired
functio
n
Lymphoproliferation,solid
organ
autoim
munity,recurrent
infections
BACH2deficiency
BACH2
AD
605394
ProgressiveTcell
lymphopenia
Impaired
mem
oryB
celldevelopm
ent
Haplosufficiencyforacritical
lineage
specification
transcriptionfactor
Lymphocyticcolitis,sinopulmonary
infections
4.Autoimmunity
with
orwith
outL
ymphoproliferation
APE
CED(A
PS-1),
autoim
mune
polyendocrinopathy
with
candidiasisand
ectoderm
aldystrophy
AIRE
ARor
AD
607358
Normal
Normal
AIREserves
ascheck-pointinthe
thym
usfornegativeselection
ofautoreactiv
eTcells
andfor
generatio
nof
Tregs
Autoimmunity
:hypoparathyroidism
hypothyroidism
,adrenal
insufficiency,diabetes,gonadal
dysfunctionandotherendocrine
abnorm
alities,chronic
mucocutaneous
candidiasis,dental
enam
elhypoplasia,alopeciaareata
enteropathy,pernicious
anem
ia
ITCHdeficiency
ITCH
AR
606409
Not
assessed
Not
assessed
Itch
deficiency
may
cause
immunedysregulationby
affectingboth
anergy
inductionin
autoreactiv
eeffector
Tcells
andgeneratio
nof
Tregs
Early-onsetchroniclung
disease
(interstitialpneumonitis),
autoim
munity
(thyroiditis,type
Idiabetes,chronic
diarrhea/enteropathy,and
hepatitis),
failu
reto
thrive,developmental
delay,dysm
orphicfacialfeatures
ZAP-70combined
hypomorphicand
activ
ationmutations
ZAP70
AR (L
OF/GOF)
176947
Decreased
CD8,norm
alor
decreasedCD4
cells
Normalor
decreased
Hyperactiv
eZap70
kinase
Severe
autoim
munity
Tripeptidyl-peptid
aseII
deficiency
TPP2
AR
190470
Decreased
Decreased
TPP
2deficiency
results
inprem
atureim
munosenescence
andim
munedysregulation
Variablelymphoproliferation,severe
autoim
munecytopenias,
hypergam
maglobulin
emia,recurrent
infections
JAK1GOF
JAK1
ADGOF
147795
Not
assessed
Not
assessed
Hyperactiv
eJA
K1
HSM
,eosinophilia,eosinophilic
enteritis,thyroid
disease,poor
grow
th,viralinfections
Prolid
asedeficiency
PEPD
AR
613230
Normal
Normal
PeptidaseD
Autoantibodiescommon,chronicskin
ulcers,eczem
a,infections
5.Autoimmunelymphoproliferativesyndrome(A
LPS
,Canale-Sm
ithsyndrome)
J Clin Immunol (2018) 38:96–128 111
Tab
le4
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gBcells
Functio
nald
efect
Associatedfeatures
ALPS-FAS
TNFRSF
6ADor
AR
134637
Increased
CD4−CD8−TCR
α/β-doublenegativ
e(D
N)Tcells
Normal,low
mem
oryBcells
ApoptosisdefectFA
Smediated
Splenomegaly,adenopathies,
autoim
munecytopenias,increased
lymphom
arisk,IgG
andAnorm
alor
increased,elevated
serum
FasLand
IL-10,vitamin
B12
ALPS-FASL
GFA
SLG
AR
134638
IncreasedDNTcells
Normal
ApoptosisdefectFA
Smediated
Splenomegaly,adenopathies,
autoim
munecytopenias,S
LE,
solubleFasL
isnotelevated
ALPS-caspase
10CASP
10AD
601762
IncreasedDNTcells
Normal
Defectiv
elymphocyteapoptosis
Adenopathies,splenomegaly,
autoim
munity
ALPS-caspase
8CASP
8AR
601763
SlightlyincreasedDNT
cells
Normal
Defectiv
elymphocyteapoptosis
andactiv
ation
Adenopathies,splenomegaly,bacterial
andviralinfectio
ns,
hypogammaglobulin
emia
FADDdeficiency
FADD
AR
602457
IncreasedDNTcells
Normal
Defectiv
elymphocyteapoptosis
Functio
nalh
yposplenism,bacterialand
viralinfectio
ns,recurrentepisodes
ofencephalopathy
andliv
erdysfunction
6.Im
munedysregulationwith
colitis
IL-10deficiency
IL10
AR
124092
Normal
Normal
Nofunctio
nalIL-10secretion
Inflam
matoryboweldisease(IBD),
Folliculitis,recurrent
respiratory
diseases,arthritis,
IL-10R
adeficiency
IL10RA
AR
146933
Normal
Normal
Leukocytesunresponsive
toIL-10
IBD,F
olliculitis,recurrentrespiratory
diseases,arthritis,lymphom
a
IL-10R
bdeficiency
IL10RB
AR
123889
Normal
Normal
Leukocytesunresponsive
toIL-10,IL-22,IL-26,IL-28A
,IL-28B
,and
IL-29
IBD,folliculitis,recurrentrespiratory
diseases,arthritis,lymphom
a
NFA
T5
haploinsufficiency
NFA
T5AD
604708
Normal
Normal
Decreased
mem
oryBcells
and
plasmablasts
IBD,recurrent
sinopulm
onary
infections
7.Su
sceptib
ility
toEBVandlymphoproliferativeconditions
SH2D
1Adeficiency
(XLP1
)SH
2D1A
XL
300490
Normalor
increased
activ
ated
Tcells
Reduced
mem
oryB
cells
norm
alNKcellandCTL
cytotoxicactiv
ityClin
icalandim
munologicfeatures
triggeredby
EBVinfection:
HLH,
lymphoproliferation,aplastic
anem
ia,lym
phom
a.hypogammaglobulin
emia,absent
iNKTcells
XIA
Pdeficiency
(XLP2
)XIAP
XL
300079
Normalor
Increased
activ
ated
Tcells;
low/normaliNKT
cells
Normalor
reduced
mem
oryBcells
IncreasedTcells
susceptib
ility
toapoptosisto
CD95
and
enhanced
activ
ation-induced
celldeath(A
ICD)
EBVinfection,splenomegaly,
lymphoproliferationHLH,colitis,
IBD,hepatitislowiNKTcells,
hypogammaglobulin
emia
CD27
deficiency
CD27
AR
615122
Normal
Nomem
oryBcells
Low
immunoglobulin
afterEBV
infection
Features
triggeredby
EBVinfection,
HLH,aplastic
anem
ia,low
iNKT
cells,lym
phom
a
112 J Clin Immunol (2018) 38:96–128
Tab
le4
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gBcells
Functio
nald
efect
Associatedfeatures
CTPS1deficiency
CTP
S1AR
615897
Nltolow,poor
proliferationto
antig
en
Nl/low
Nl/h
ighIgG
Recurrent/chronicbacterialand
viral
infections
(EBV,V
ZV),
lymphoproliferation,Bcell
non-Hodgkin
lymphom
a
RASGRP1
deficiency
RASG
RP1
AR
603962
Poor
activ
ation,
proliferation,motility
Poor
activ
ation,
proliferation,
motility
NormalIgM,IgG
,increased
IgA
Recurrent
pneumonia,herpesvirus
infections,E
BVassociated
lymphom
a
CD70
deficiency
CD70 (TNFSF
7)AR
602840
Nln
umber,lowTreg,
poor
activ
ationand
functio
n
Nln
umber,poor
antib
odyand
mem
oryresponses
Reduced
IgM,IgG
,IgA
(75%
)andreducedAg-specificAb
responses(50%
)
EBVsusceptib
ility,H
odgkin
lymphom
a
RLT
PR(CARMIL2)
deficiency
RLT
PR
AR
610859
Nln
umber,lowTreg,
high
CD4,poor
functio
n
Nln
umber
Nltolow,poorTdependent
antib
odyresponse
Recurrent
bacterial,fungaland
mycobacterialinfections,viralwarts,
molluscum
andEBV
lymphoproliferativeandother
malignancy,atopy
ITKdeficiency
ITK
AR
186973
Progressivedecrease
Normal
Nltolow
EBVassociated
Bcell
lymphoproliferation,lymphom
a,Nl
orlowIgG
MAGT1deficiency
(XMEN)
MAGT1
XL
300853
Low
CD4
Low
recent
thym
icem
igrant
cells,poor
proliferationto
CD3
Normal
Normal
EBVinfection,lymphom
a,viral
infections,respiratory
andGI
infections
PRKCDdeficiency
PRKCD
AR
176977
Normal
Low
mem
oryB
cells,highCD5B
cells
Apoptoticdefectin
Bcells
Recurrent
infections,E
BVchronic
infection,lymphoproliferation,
SLE-likeautoim
munity
(nephrotic
andantip
hospholip
idsyndromes),
lowIgG
Totalnum
bero
fdisordersinTable4:40.N
ewdisorders:9,FA
AP24,R
ASG
RP1,CD70,R
LTPR,ZAP70
(GOF+LOF),AP3D
1,BACH2,JA
K1GOF,PEPD.R
emoved
gene:H
ermansky-Pu
dlak
syndrome
type
9was
removed
dueto
retractio
nof
thedefining
publication
FHLfamilialhemophagocytic
lymphohistio
cytosis,HLH
hemophagocytic
lymphohistio
cytosis,HSM
hepatosplenomegaly((H)SM
indicatin
gvariablehepatomegaly),D
Ndoublenegativ
e,SL
Esystem
iclupuserythematous,IBDinflam
matoryboweldisease,XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n,GOFgain-of-functio
n
J Clin Immunol (2018) 38:96–128 113
Tab
le5
Congenitald
efectsof
phagocytenumberor
functio
n
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
1.Congenitaln
eutropenias
Elastasedeficiency
(SCN1)
ELA
NE
AD
130130
NMyeloid
differentiatio
nSu
sceptib
ility
toMDS/leukem
iaSeverecongenitaln
eutropeniaor
cyclic
neutropenia
GFI
1deficiency
(SCN2)
GFI1
AD
600871
NMyeloid
differentiation
B/T
lymphopenia
HAX1deficiency
(Kostm
anndisease)
(SCN3)
HAX1
AR
605998
NMyeloid
differentiatio
nCognitiv
eandneurologicaldefectsin
patients
with
defectsin
both
HAX1isoforms,
susceptib
ility
toMDS/leukem
iaG6P
C3deficiency
(SCN4)
G6P
C3
AR
611045
NMyeloid
differentiation,
chem
otaxis,O
2−productio
nStructuralheartd
efects,urogenitalabnormalities,
innereardeafness,and
venous
angiectasias
oftrunks
andlim
bsVPS
45deficiency
(SCN5)
VPS45
AR
610035
NMyeloid
differentiation,
migratio
nExtramedullary
hematopoiesis,bonemarrow
fibrosis,nephrom
egaly
Glycogenstorage
diseasetype
1bG6P
T1AR
602671
N+M
Myeloid
differentiation,
chem
otaxis,O
2−productio
nFastinghypoglycem
ia,lactic
acidosis,
hyperlipidem
ia,hepatom
egaly
X-linkedneutropenia/
myelodysplasiaWASGOF
WAS
XL
300392
NDifferentiatio
n,mito
sis
Neutropenia,m
yeloid
maturationarrest,
monocytopenia,variablelymphoidanom
alies
P14/LAMTOR2deficiency
LAMTO
R2
AR
610389
N+M
Endosom
albiogenesis
Neutropenia
Hypogam
maglobulinem
ia↓C
D8cytotoxicity,
partialalbinism,g
rowth
failu
reBarth
syndrome
(3-m
ethylglutaconic
aciduriatype
II)
TAZ
XL
300394
N+LMel
Mito
chondrialfunction
Cardiom
yopathy,myopathy,grow
thretardation,
neutropenia
Cohen
syndrome
VPS13B
AR
607817
NMyeloid
differentiatio
nDysmorphism,m
entalretardatio
n,obesity,
deafness,neutropenia
Clericuziosyndrome
(poikiloderm
awith
neutropenia)
USB
1AR
613276
NMyeloid
differentiatio
nRetinopathy,d
evelopmentald
elay,facial
dysm
orphisms,poikilo
derm
a
JAGN1deficiency
JAGN1
AR
616012
NMyeloid
differentiatio
nMyeloid
maturationarrest,osteopenia
3-Methylglutaconicaciduria
CLP
BAR
616254
NMyeloid
differentiation
Mito
chondrialp
rotein
Neurocognitive
developm
entalaberrations,
microcephaly,hypoglycem
ia,hypotonia,
ataxia,seizures,cataracts,IU
GR
G-CSF
receptor
deficiency
CSF
3RAR
138971
NStress
granulopoiesisdisturbed
SMARCD2deficiency
SMARCD2
AR
601736
NChrom
atin
remodeling,myeloid
differentiatio
nandneutrophil
functio
nald
efect
Neutropenia,developmentalaberrations,
skeletalabnorm
alities,h
ematopoieticstem
cells,m
yelodysplasia
HYOU1deficiency
HYO
U1
AR
601746
NUnfoldedproteinresponse
Hypoglycemia,inflammatorycomplications
2.Defectsof
motility
Leukocyteadhesion
deficiency
type
1(LAD1)
ITGB2
AR
600065
N+M
+L+NK
Adherence,chemotaxis,
endocytosis,T/NKcytotoxicity
Delayed
cord
separatio
n,skin
ulcers,
periodontitis,leukocytosis
Leukocyteadhesion
deficiency
type
2(LAD2)
SLC35C1
AR
605881
N+M
Rollin
g,chem
otaxis
Mild
LADtype
1features
with
hh-blood
group,grow
thretardation,developm
ental
delay
Leukocyteadhesion
deficiency
type
3(LAD3)
FERMT3
AR
607901
N+M
+L+NK
Adherence,chemotaxis
LADtype
1plus
bleeding
tendency
Rac
2deficiency
RAC2
AD
602049
NAdherence,chemotaxisO2−
production
Poor
wound
healing,leukocytosis
βactin
deficiency
ACTB
AD
102630
N+M
Motility
Mentalretardatio
n,shortstature
FPR1
AR
136537
NFo
rmylpeptideinducedchem
otaxis
Periodontitisonly
114 J Clin Immunol (2018) 38:96–128
Tab
le5
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
Localized
juvenile
periodontitis
Papillo
n-Lefèvresyndrome
CTS
CAR
602365
N+M
Chemotaxis
Periodontitis,palmoplantar
hyperkeratosis
insomepatients
Specificgranuledeficiency
CEBPE
AR
189965
NChemotaxis
Neutrophilswith
bilobednuclei
Shwachm
an-D
iamond
syndrome
SBDS
AR
607444
NChemotaxis
Pancytopenia,exocrinepancreaticinsufficiency,
chondrodysplasia
WDR1deficiency
WDR1
AR
604734
NSp
reading,survival,chemotaxis
Mild
neutropenia,poor
wound
healing,
severestom
atitis,neutrophilnucleiherniate
Cystic
fibrosis
CFTR
AR
602421
Monly
Chemotaxis
Respiratory
infections,pancreatic
insufficiency,
elevated
sweatchloride
Schw
achm
anDiamond
syndromedueto
DNAJC
21deficiency
DNAJC
21AR
617048
NMotility,ribosom
ebiogenesis
Metaphysealchanges,shortstature,
developm
entald
elay,pancreatic
dysfunction,
bone
marrowfailu
reNeutropeniawith
combined
immunedeficiency
due
toMKL1deficiency
MKL1
AR
606078
N+M
+L+NK
Impaired
expression
ofcytoskeletalgenes
Mild
thrombocytopenia
3.Defectsof
respiratoryburst
X-linkedchronic
granulom
atousdisease
(CGD),gp91phox
CYB
BXL
300481
N+M
Killing(faulty
O2−
productio
n)Infections,autoinflammatoryphenotype,IBD
McL
eodphenotypein
patientswith
deletio
nsextendinginto
thecontiguous
Kelllocus
Autosom
alrecessive
CGDp22phox
CYB
AAR
608508
N+M
Killing(faulty
O2−
productio
n)Infections,autoinflammatoryphenotype
Autosom
alrecessive
CGDp47phox
NCF1
AR
608,512
N+M
Killing(faulty
O2−
productio
n)Infections,autoinflammatoryphenotype
Autosom
alrecessive
CGDp67phox
NCF2
AR
608515
N+M
Killing(faulty
O2−
productio
n)Infections,autoinflammatoryphenotype
Autosom
alrecessive
CGDp40phox
NCF4
AR
601488
N+M
Killing(faulty
O2−
productio
n)Infections,autoinflammatoryphenotype
G6P
Ddeficiency
classI
G6P
DXL
305900
NReduced
O2−productio
nInfections
4.Other
non-lymphoid
defects
GATA
2deficiency
(MonoM
acsyndrome)
GAT
A2:
loss
ofstem
cells
AD
137295
Monocytes
+peripheralDC
Multilin
eage
cytopenias
Susceptib
ility
tomycobacteria,HPV
,histoplasm
osis,alveolarproteinosis,
MDS/AML/CMMoL
,lym
phedem
aCongenitalp
ulmonary
alveolar
proteinosisdue
toCSF
2RBmutations
CSF
2RB
AR
138981
Alveolar
macrophages
GM-CSF
signaling
Alveolarproteinosis
Congenitalp
ulmonary
alveolar
proteinosisdue
toCSF
2RAmutations
CSF
2RA
XL (p
seudoautosom
al)
306250
Alveolar
macrophages
GM-CSF
signaling
Alveolarproteinosis
Totalnumberof
disordersin
Table5:
39.N
ewdisorders:9,
WDR1,
CFTR
,SMARCD2,
JAGN1,
HYO
U1,
MKL1
,DNAJC
21,G
6PD,C
SF2R
B.R
emoved:cyclicneutropeniawas
mergedwith
elastase
deficiency
MDSmyelodysplasticsyndrome,IU
GRintrauterine
grow
thretardation,LA
Dleukocyteadhesion
deficiency,A
MLacutemyelogenous
leukem
ia,C
MMLchronicmyelomonocyticleukem
ia,N
neutrophil,M
monocyte,MELmelanocyte,Llymphocyte,NKnaturalk
iller,X
LX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,GOFgain-of-functio
n
J Clin Immunol (2018) 38:96–128 115
Tab
le6
Defectsin
intrinsicandinnateim
munity
Disease
Genetic
defect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
1.Mendeliansusceptib
ility
tomycobacterialdisease(M
SMD)
IL-12andIL-23receptor
β1
chaindeficiency
IL12RB1
AR
601604
L+NK
IFN-γ
secretion
Susceptib
ility
tomycobacteriaand
Salmonella
IL-12p40
(IL-12andIL-23)
deficiency
IL12B
AR
161561
MIFN-γ
secretion
Susceptib
ility
tomycobacteriaand
Salmonella
IFN-γ
receptor
1deficiency
IFNGR1
AR/AD
107470
M+L
IFN-γ
bindingandsignaling
Susceptib
ility
tomycobacteriaand
Salmonella
IFN-γ
receptor
2deficiency
IFNGR2
AR
147569
M+L
IFN-γ
signaling
Susceptib
ility
tomycobacteriaand
Salmonella
STAT1deficiency
(ADLOF)
STAT
1AD
600555
M+L
IFN-γsignaling
Susceptib
ility
tomycobacteria,
Salmonella
Macrophagegp91
phox
deficiency
CYB
BXL
300481
Macrophageonly
Killing(faulty
O2−
productio
n)Isolated
susceptib
ility
tomycobacteria
IRF8deficiency
(AD)
IRF8
AD
601565
CD1c+MDC
Differentiatio
nof
CD1c+
MDCsubgroup
Susceptib
ility
tomycobacteria
IRF8deficiency
(AR)
IRF8
AR
601565
CD1c+MDC
Differentiatio
nof
CD1c+
MDCsubgroup
Susceptib
ility
tomycobacteriaand
multip
leotherinfectious
agents
Tyk2
deficiency
TYK2
AR
176941
Normal,but
multip
lecytokine
signalingdefect
Normal
Susceptib
ility
tointracellularbacteria
(mycobacteria,Salmonella),viruses,
+/−
elevated
IgE
ISG15
deficiency
ISG15
AR
147571
IFNγproductio
ndefect
Susceptib
ility
tomycobacteria(BCG),
braincalcification
RORcdeficiency
RORC
AR
602943
L+NK
Lackof
functio
nalR
ORγT
protein,IFNγproductio
ndefect,com
pleteabsenceof
IL-17A
/F-producing
Tcells
Susceptib
ility
tomycobacteriaand
candida
JAK1(LOF)
JAK1
AR
147795
N+L
IFNγproductio
nSu
sceptib
ility
tomycobacteriaand
viruses,urothelialcarcinoma
2.Epiderm
odysplasiaverruciformis(H
PV)
EVER1deficiency
TMC6
AR
605828
Keratinocytes
and
leukocytes
EVERproteins
may
beinvolved
intheregulatio
nof
cellu
larzinc
homeostasis
inlymphocytes
Hum
anpapillo
mavirus
(HPV
)(group
B1)
infections
andcancer
oftheskin
(typicalEV)
EVER2deficiency
TMC8
AR
605829
Keratinocytes
and
leukocytes
EVERproteins
may
beinvolved
intheregulatio
nof
cellu
larzinc
homeostasis
inLy
HPV
(group
B1)
infections
andcancer
oftheskin
(typicalEV)
WHIM
(warts,
hypogammaglobulin
emia,
infections,m
yelokathexis)
syndrome
CXCR4
ADGOF
162643
Granulocytes+
lymphocytes
Increasedresponse
ofthe
CXCR4chem
okine
receptor
toits
ligand
CXCL12
(SDF-1)
Warts,neutropenia,low
Bcellnumber,
hypogammaglobulin
emia
116 J Clin Immunol (2018) 38:96–128
Tab
le6
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
3.Predisposition
tosevere
viralinfectio
n
STAT1deficiency
(ARLOF)
STAT
1AR
600555
TandNKcells
and
monocytes
STAT1-dependentIFN
-α,β
,andγresponse
Severe
viralinfections,m
ycobacterial
infection
STAT2deficiency
STAT
2AR
600556
TandNKcells
STAT2-dependentIFN
-α,β
,andγresponse
Severe
viralinfectio
ns(disseminated
vaccine-strain
measles)
IRF7deficiency
IRF7
AR
605047
Leukocytes,plasmacytoid
dendritic
cells,
non-hematopoieticcells
IFN-α,β
,and
γproductio
nandIFN-λ
productio
nSevere
influenzadisease
IFNAR2deficiency
IFNAR2
AR
602376
Broadly
expressed
Noresponse
toIFN-α
Severe
viralinfectio
ns(disseminated
vaccine-strain
measles,H
HV6)
CD16
deficiency
FCGR3A
AR
146740
NKcells
AlteredNKcells
functio
nSevere
herpes
viralinfectio
ns,
particularly
VZV,E
pstein-Barrvirus
(EBV),and(H
PV)
MDA5deficiency
(LOF)
IFIH
1AR
606951
Somaticandhematopoietic
Viralrecognition
RhinovirusandotherRNAviruses
4.Herpessimplex
encephalitis(H
SE)
TLR3deficiency
TLR3
ADor
AR
603029
Centralnervoussystem
(CNS)resident
cells
and
fibroblasts
TLR3-dependentIFN
-α,β
,andγresponse
Herpessimplex
virus1encephalitis
(incom
pleteclinicalpenetrance
for
alletio
logies
listedhere)
UNC93B1deficiency
UNC93B1
AR
608204
CNSresident
cells
and
fibroblasts
UNC-93B
-dependent
IFN-α,
β,and
γresponse
Herpessimplex
virus1encephalitis
TRAF3
deficiency
TRAF3
AD
601896
CNSresident
cells
and
fibroblasts
TRAF3
-dependent
IFN-α,β
,andγresponse
Herpessimplex
virus1encephalitis
TRIF
deficiency
TICAM1
ADor
AR
607601
CNSresident
cells
and
fibroblasts
TRIF-dependent
IFN-α,β
,andγresponse
Herpessimplex
virus1encephalitis
TBK1deficiency
TBK1
AD
604834
CNSresident
cells
and
fibroblasts
TBK1-dependentIFN
-α,β
,andγresponse
Herpessimplex
virus1encephalitis
IRF3deficiency
IRF3
AD
616532
CNSresident
cells
and
fibroblasts
Low
IFN-α/β
productio
nin
response
toHSV
1and
decreasedIRF3
phosphorylation
Herpessimplex
virus1encephalitis
5.Predispositio
nto
invasive
fungaldiseases
CARD9deficiency
CARD9
AR
607212
Mononuclear
phagocytes
CARD9signalingpathway
Invasive
candidiasisinfection,deep
derm
atophytoses,otherinvasive
fungalinfections
6.Predispositio
nto
mucocutaneous
candidiasis
IL-17R
Adeficiency
IL17RA
AR
605461
Epithelialcells,fibroblasts,
mononuclear
phagocytes
IL-17R
Asignalingpathway
CMC,folliculitis
IL-17R
Cdeficiency
IL17RC
AR
610925
Epithelialcells,fibroblasts,
mononuclear
phagocytes
IL-17R
Csignalingpathway
CMC
J Clin Immunol (2018) 38:96–128 117
Tab
le6
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
IL-17F
deficiency
IL17F
AD
606496
Tcells
IL-17F
-containingdimers
CMC,folliculitis
STAT1GOF
STAT
1ADGOF
600555
Tcells,B
cells,m
onocytes
Gain-of-functionST
AT1
mutations
thatim
pairthe
developm
ento
fIL-17-producingTcells
CMC,various
fungal,bacterialand
viral(HSV
)infections,
autoim
munity
(thyroiditis,diabetes,
cytopenias),enteropathy
ACT1deficiency
TRAF3IP2
AR
607043
Tcells,fibroblasts
Fibroblastsfailto
respondto
IL-17A
andIL-17F,and
theirTcells
toIL-17E
CMC,blepharitis,folliculitisand
macroglossia
7.TLRsignalingpathway
deficiency
with
bacterialsusceptibility
IRAK-4
deficiency
IRAK4
AR
606883
Lym
phocytes
+granulocytes
+monocytes
TIR-IRAK4signaling
pathway
Bacterialinfections
(pyogens)
MyD
88deficiency
MYD
88AR
602170
Lym
phocytes
+granulocytes
+monocytes
TIR-M
yD88
signaling
pathway
Bacterialinfections
(pyogens)
IRAK1deficiency
IRAK1
XL
Not
yet
attributed
Lym
phocytes
+granulocytes
+monocytes
TIR-IRAK1signaling
pathway
Bacterialinfections,X
-linkedMECP2
deficiency-related
syndromeduetoa
largede
novo
Xq28chromosom
aldeletio
nencompassingboth
MECP2
andIRAK1
TIRAPdeficiency
TIRAP
AR
614382
Lym
phocytes
+granulocytes+
monocytes
TIRAP-signalingpathway,
TLR1/2,TLR2/6,and
TLR4agonistswere
impaired
inthefibroblasts
andleukocytes
Staphylococcaldiseaseduring
child
hood
8.Other
inborn
errorsof
immunity
relatedto
non-hematopoietictissues
Isolated
congenitalasplenia
(ICA)dueto
RPSA
deficiency
RPSA
AD
271400
Nospleen
RPS
Aencodesribosomal
proteinSA,a
componentof
thesm
allsubunitof
the
ribosome
Bacteremia(encapsulatedbacteria)
Isolated
congenitalasplenia
(ICA)dueto
HMOX
deficiency
HMOX
AR
141250
Macrophages
HO-1
regulatesiron
recycling
andheme-dependent
damageoccurs
Hem
olysis,nephritis,inflam
mation
Trypanosomiasis
APOL1
AD
603743
Somatic
Lipid
Trypanosomiasis
Acuteliv
erfailu
redueto
NBASdeficiency
NBAS
AR
608025
Somaticandhematopoietic
ERstress
Feverinducesliv
erfailu
re
Acutenecrotizing
encephalopathy
RANBP2
AD
601181
Ubiquito
usexpression
Nuclear
pore
Feverinducesacuteencephalopathy
CLCN7deficiency
associated
osteopetrosis
CLC
N7
AR
602727
Osteoclasts
Secretorylysosomes
Osteopetrosiswith
hypocalcem
ia,
neurologicfeatures
SNX10
deficiency
associated
osteopetrosis
SNX10
AR
614780
Osteoclasts
Secretorylysosomes
Osteopetrosiswith
visualim
pairment
118 J Clin Immunol (2018) 38:96–128
Tab
le6
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
OSTM1deficiency
associated
osteopetrosis
OST
M1
AR
607649
Osteoclasts
Secretorylysosomes
Osteopetrosiswith
hypocalcem
ia,
neurologicfeatures
PLEKHM1deficiency
associated
osteopetrosis
PLE
KHM1
AR
611466
Osteoclasts
Secretorylysosomes
Osteopetrosis
TCIRG1deficiency
associated
osteopetrosis
TCIRG1
AR
604592
Osteoclasts
Secretorylysosomes
Osteopetrosiswith
hypocalcem
ia
TNFR
SF11Adeficiency
associated
osteopetrosis
TNFRSF
11A
AR
603499
Osteoclasts
Osteoclastogenesis
Osteopetrosis
TNFS
F11
deficiency
associated
osteopetrosis
TNFSF
11AR
602642
Stromal
Osteoclastogenesis
Osteopetrosiswith
severe
grow
thretardation
NCSTNdeficiency
hidradenitis
suppurativa
NCST
NAD
605254
Epiderm
isGam
ma-secretasein
hair
follicleregulates
keratin
ization
Hidradenitis
suppurativawith
acne
PSENdeficiency
hidradenitis
suppurativa
PSE
NAD
104311
Epiderm
isGam
ma-secretasein
hair
follicleregulates
keratin
ization
Hidradenitis
suppurativewith
cutaneoushyperpigmentatio
n
PSENENdeficiency
hidradenitissuppurativa
PSE
NEN
AD
607632
Epiderm
isGam
ma-secretasein
hair
follicleregulates
keratin
ization
Hidradenitis
suppurativa
Totalnum
bero
fdisordersinTable6:52.N
ewgenes:19,IFNAR2,IRF3,JA
K1,IRAK1,TIRAP,IFIH
1,HMOX,N
BAS,RANBP2,CLC
N7,SN
X10,O
STM1,PLE
KHM1,TC
IRG1,TN
FRSF
11A,TNFSF
11,
NCST
N,P
SEN,P
SENEN
NF-κBnuclearfactor
kappaB,TIRTo
llandinterleukin-1receptor,IFN
interferon,TL
RTo
ll-lik
ereceptor,MDC
myeloid
dendritic
cell,
CNScentralnervoussystem
,CMCchronicmucocutaneous
candidiasis,HPVhuman
papillo
mavirus,V
ZVvaricella
zoster
virus,EBVEpstein-Barrvirus,HHV6human
herpesvirus6,
XLX-linkedinheritance,ARautosomalrecessiveinheritance,AD
autosomal
dominantinheritance,LO
Floss-of-functio
n,GOFgain-of-functio
n
J Clin Immunol (2018) 38:96–128 119
Tab
le7
Autoinflammatorydisorders
1.Ty
pe1interferonopathies
Disease
Geneticdefect
Inheritance
OMIM
Tcells
Bcells
Functio
nald
efect
Associatedfeatures
TREX1deficiency,
Aicardi-G
outieres
syndrome1(A
GS1
)
TREX1
ARor
AD
606609
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alss
DNAspecies
leadingto
increasedtype
IIFNproduction
ClassicalAGS,
SLE,F
CL
RNASE
H2B
deficiency,
AGS2
RNASE
H2B
AR
610326
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alRNA-D
NAhybrid
speciesleadingto
increased
type
IIFNproduction
ClassicalAGS,
SP
RNASE
H2C
deficiency,
AGS3
RNASE
H2C
AR
610330
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alRNA-D
NAhybrid
speciesleadingto
increased
type
IIFNproduction
ClassicalAGS
RNASE
H2A
deficiency,
AGS4
RNASE
H2A
AR
606034
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alRNA-D
NAhybrid
speciesleadingto
increased
type
IIFNproduction
ClassicalAGS
SAMHD1deficiency,
AGS5
SAMHD1
AR
606754
Not
assessed
Not
assessed
ControlsdN
TPs
inthecytosol,
failu
reof
which
leadsto
increasedtype
IIFN
productio
n
ClassicalAGS,
FCL
ADAR1deficiency,
AGS6
ADAR1
AR
146920
Not
assessed
Not
assessed
Catalyzes
thedeam
inationof
adenosineto
inosinein
dsRNAsubstrates,failureof
which
leadsto
increasedtype
IIFNproductio
n
ClassicalAGS,
BSN
,SP
Aicardi-G
outieres
syndrome7(A
GS7
)IFIH
1(G
OF)
AD
606951
Not
assessed
Not
assessed
IFIH
1gene
encodesa
cytoplasmicviralR
NA
receptor
thatactiv
ates
type
Iinterferon
signalingthrough
theMAVSadaptormolecule
ClassicalAGS,
SLE,S
P,SM
S
Spondyloenchondro-dys-
plasiawith
immune
dysregulation
(SPE
NCD)
ACP5
AR
171640
Not
assessed
Not
assessed
Upregulationof
IFNthrough
mechanism
possibly
relatin
gto
pDCS
Shortstature,S
P,ICC,S
LE,
thrombocytopeniaand
autoim
munehemolytic
anem
ia,possiblyrecurrent
bacterialand
viral
infections
STIN
G-associated
vasculopathy,
infantile-onset
TMEM173
AR
612374
Not
assessed
Not
assessed
STIN
Gactivates
both
the
NF-kappa-BandIRF3
transcriptionpathwaysto
induce
expression
ofIFN
Skin
vasculopathy,
inflam
matorylung
disease,system
icautoinflam
mationand
ICC,F
CL
X-linkedreticulate
pigm
entary
disorder
POLA
1XL
301220
Not
assessed
Not
assessed
POLA1isrequired
forsynthesis
ofcytosolic
RNA:DNAand
itsdeficiency
leadsto
increase
productio
nof
type
Iinterferon
Hyperpigm
entatio
n,characteristicfacies,lung
andGIinvolvem
ent
USP
18deficiency
USP
18AR
607057
Not
assessed
Not
assessed
TORCHlik
esyndrome
120 J Clin Immunol (2018) 38:96–128
Tab
le7
(contin
ued)
Defectivenegativeregulatio
nof
ISG15
leadingto
increased
IFN
CANDLE(chronic
atypicalneutrophilic
derm
atitiswith
lipodystrophy)
PSM
B8a
ARandAD
256040
Not
assessed
Not
assessed
Mutations
causeincreasedIFN
signalingthroughan
undefinedmechanism
Contractures,panniculitis,
ICC,fevers
Singleton-Merten
syndrome
DDX58
AD
609631
Not
assessed
Not
assessed
Recognizesdoublestranded
RNA
Dentald
ysplasia),
calcifications
intheaorta,
osteoporosis,especially
inthehandsandfeet
2.Defectsaffectingtheinflam
masom
eDisease
Geneticdefect
Inheritance
OMIM
Affectedcells
Functio
nald
efects
Associatedfeatures
FamilialMediterranean
fever
MEFV
ARor
AD
249100
134610
Maturegranulocytes,
cytokine-activated
monocytes
Decreased
productionof
pyrin
perm
itsASC
-induced
IL-1
processing
andinflam
mation
follo
wingsubclin
icalserosal
injury,m
acrophageapoptosis
decreased
Recurrent
fever,serositis
and
inflam
mationresponsive
tocolchicine.P
redisposes
tovasculitisandinflam
matory
boweldisease
Mevalonatekinase
deficiency
(Hyper
IgD
syndrome)
MVK
AR
260920
Somaticand
hemaotpoietic
Affectin
gcholesterolsynthesis,
pathogenesisof
disease
unclear
Periodicfeverandleukocytosis
with
high
IgDlevels
Muckle-Wellssyndrome
NLRP3
(alsocalled
NALP3
CIA
S1or
PYPA
F1)
ADGOF
191900
PMNsMonocytes
Defectincryopyrin,involved
inleukocyteapoptosisand
NFk
BsignalingandIL-1
processing
Urticaria,S
NHL,amyloidosis
Familialcold
autoinflam
matory
syndrome1
NLRP3
ADGOF
120100
PMNs,monocytes
Asabove
Non-pruritic
urticaria,arthritis,
chills,feverandleukocytosis
aftercold
exposure
Familialcold
autoinflam
matory
syndrome2
NLRP1
2ADGOF
611762
PMNs,monocytes
Asabove
Non-pruritic
urticaria,arthritis,
chills,feverandleukocytosis
aftercold
exposure
Neonatalo
nset
multisystem
inflam
matorydisease
(NOMID
)or
chronic
infantile
neurologic
cutaneousandarticular
syndrome(CIN
CA)
NLRP3
ADGOF
607115
PMNs,chondrocytes
Asabove
Neonatalo
nsetrash,chronic
meningitis,and
arthropathy
with
feverandinflam
mation
NLRC4-MAS
(macrophage
activatingsyndrome)
orfamilialcold
autoinflam
matory
syndrome4
NLRC4
ADGOF
616050
616115
PMNsmonocytes
macrophages
Gain-of-functionmutationin
NLRC4results
inelevated
secretionof
IL-1βandIL-18
aswellasmacrophage
activ
ation
Severeenterocolitisand
macrophageactivation
syndrome
PLAID
(PLCγ2
associated
antibody
deficiency
andim
mune
dysregulation)
orfamilialcold
PLC
G2
ADGOF
614468
Bcells,N
K,m
astcells
Mutations
causeactiv
ationof
IL-1
pathways
Coldurticaria
hypogammaglobulin
emia,
autoinflam
mation
J Clin Immunol (2018) 38:96–128 121
Tab
le7
(contin
ued)
autoinflam
matory
syndrome3or
APL
AID
(c2120A>C)
NLRP1
deficiency
NLRP1
AR
606579
Leukocytes
System
icelevationof
IL-18and
caspase1,suggestin
ginvolvem
ento
fNLRP1
inflam
masom
e
Dyskeratosis,autoim
munity
and
arthritis
3.Non-inflammasom
e-relatedconditions
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Functio
nald
efects
AssociatedFeatures
TNFreceptor-associated
periodicsyndrome
(TRAPS
)
TNFRSF
1AAD
142680
PMNs,monocytes
Mutations
of55-kDTNF
receptor
leadingto
intracellularreceptor
retentionor
diminished
solublecytokine
receptor
availableto
bind
TNF
Recurrent
fever,serositis,rash,
andocular
orjoint
inflam
mation
Pyogenicsterile
arthritis,
pyoderma
gangrenosum,acne
(PAPA
)syndrome,
hyperzincemia,and
hypercalprotectinem
ia
PST
PIP1(alsocalled
C2B
P1)
AD
604416
Hem
atopoietictissues,
upregulatedin
activated
Tcells
Disorderedactin
reorganization
leadingto
comprom
ised
physiologicsignalingduring
inflam
matoryresponse
Destructiv
earthritis,
inflam
matoryskin
rash,
myositis
Blausyndrome
NOD2(alsocalled
CARD15)
AD
186580
Monocytes
Mutations
innucleotid
ebinding
siteof
CARD15,possibly
disruptin
ginteractions
with
lipopolysaccharides
and
NF-kB
signaling
Uveitis,granulom
atous
synovitis,cam
ptodactyly,
rash
andcranialneuropathies,
30%
developCrohn
colitis
ADAM17
deficiency
ADAM17
AR
614328
Leukocytesandepith
elial
cells
Defectiv
eTNFα
production
Early-onsetdiarrhea
andskin
lesions
Chronicrecurrent
multifocal
osteom
yelitisand
congenital
dyserythropoietic
anem
ia(M
ajeed
syndrome)
LPIN2
AR
609628
Neutrophils,bone
marrowcells
Undefined
Chronicrecurrentm
ultifocal
osteom
yelitis,
transfusion-dependent
anem
ia,cutaneous
inflam
matorydisorders
DIRA(deficiencyof
the
interleukin-1receptor
antagonist)
IL1R
NAR
612852
PMNs,Monocytes
Mutations
intheIL-1
receptor
antagonistallowunopposed
actio
nof
interleukin-1
Neonatalo
nsetof
sterile
multifocalosteom
yelitis,
periostitisandpustulosis
DITRA(deficiencyof
IL-36receptor
antagonist)
IL36RN
AR
614204
Keratinocytes,leukocytes
Mutations
inIL-36R
Nleadsto
increase
IL-8
productio
nPu
stular
psoriasis
SLC29A3mutation
SLC29A3
AR
602782
Leukocytes,bone
cells
Hyperpigm
entation
hypertrichosis,
histiocytosis--
lymphadenopathy
plus
syndrome
CAMPS
(CARD14
mediatedpsoriasis)
CARD14
AD
602723
Mainlyin
keratin
ocytes
Mutations
inCARD14
activate
theNF-kBpathway
and
productionof
IL-8
Psoriasis
Cherubism
SH3B
P2
AD
118400
Stromacells,bonecells
Bonedegeneratio
nin
jaws
122 J Clin Immunol (2018) 38:96–128
Tab
le7
(contin
ued)
Hyperactiv
edmacrophageand
increase
NF-kB
COPA
defect
COPA
AD
6011924
PMNandtissuespecific
cells
Defectiv
eintracellulartransport
viathecoatproteincomplex
I(COPI)
Autoimmuneinflam
matory
arthritis
andinterstitiallung
diseasewith
Th17
dysregulationand
autoantib
odyproductio
nOtulip
enia/ORAS
OTU
LIN
AR
615712
Leukocytes
Increase
LUBACinductionof
NF-KBactiv
ationleadingto
high
proinflammatory
cytokineslevels
Fever,diarrhea,dermatitis
A20
deficiency
TNFA
IP3
ADLOF
616744
Lymphocytes
Defectiv
einhibitio
nof
NF-KB
signalingpathway
Arthralgia,mucosalulcers,
ocular
inflam
mation
ADA2deficiency
CECR1
AR
607575
Lymphocytes
ADAsdeactiv
ateextracellular
adenosineandterm
inate
signalingthroughadenosine
receptors
Polyarteritisnodosa,
child
hood-onset,early-onset
recurrentischemicstroke
and
fever
AP1
S3deficiency
AP1S3
AR
615781
Keratinocytes
Disrupted
TLR3translocation
Pustular
psoriasis
Totaln
umberof
disordersin
Table7:
37.N
ewdisorders:7,DDX58,P
OLA
1,USP
18,N
LRP1,OTU
LIN,T
NFA
IP3,AP1S3
IFNinterferon;H
SMhepatosplenomegaly;CSF
cerebrospinalfluid;SLE
system
iclupuserythematosus;TORCHtoxoplasmosis,other,rubella,cytom
egalovirus,and
herpes
infections;SNHLsensorineural
hearingloss;AGSAicardi-G
outièressyndrome;BSN
bilateralstriatalnecrosis;F
CLfamilialchilb
lain
lupus;ICCintracranialcalcification;
IFNinterferon
type
I;pD
Csplasmacytoiddendritic
cells;SP
spastic
paraparesis;SM
SSingleton-Mertensyndrome;ss
single-strandedDNA;X
LX-linkedinheritance;ARautosomalrecessiveinheritance;ADautosomaldominantinheritance;LO
Floss-of-functio
n;GOFgain-of-functio
naVariantsin
PSM
B4,PSM
B9,PSM
A3,andPOMPhave
been
proposed
tocauseasimilarCANDLEphenotypein
monogenicanddigenicmodels
J Clin Immunol (2018) 38:96–128 123
Tab
le8
Com
plem
entd
eficiencies
1.Com
plem
entd
eficiencies
Disease
Geneticdefect
Inheritance
GeneOMIM
Laboratoryfeatures
Associatedfeatures
C1q
deficiency
dueto
defectsin
C1Q
AC1Q
AAR
120550
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ation
oftheclassicalp
athw
ay,dim
inishedclearance
ofapoptotic
cells
SLE,infectio
nswith
encapsulated
organism
s
C1q
deficiency
dueto
defectsin
C1Q
BC1Q
BAR
120570
AbsentC
H50
hemolyticactiv
ity,D
efectiv
eactiv
ation
oftheclassicalp
athw
ay,dim
inishedclearance
ofapoptotic
cells
SLE,infectio
nswith
encapsulated
organism
s
C1q
deficiency
dueto
defectsin
C1Q
CC1Q
CAR
120575
AbsentC
H50
hemolyticactiv
ity,D
efectiv
eactiv
ation
oftheclassicalp
athw
ay,dim
inishedclearance
ofapoptotic
cells
SLE,infectio
nswith
encapsulated
organism
s
C1r
deficiency
C1R
AR
613785
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ation
oftheclassicalp
athw
aySL
E,infectio
nswith
encapsulated
organism
s,Ehlers-Danlosphenotype
C1s
deficiency
C1S
AR
120580
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ation
oftheclassicalp
athw
aySL
E,infectio
nswith
encapsulated
organism
s,Ehlers-Danlosphenotype
Com
pleteC4deficiency
C4A
+C4B
AR
120810
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ation
oftheclassicalp
athw
ay,com
pletedeficiency
requires
biallelic
mutations/deletions/conversions
ofboth
C4A
andC4B
SLE,infectio
nswith
encapsulated
organism
s,partiald
eficiencyiscommon
(eith
erC4A
orC4B
)andappearsto
have
amodest
effecton
hostdefense
C2deficiency
C2
AR
217000
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ation
oftheclassicalp
athw
aySL
E,infectio
nswith
encapsulated
organism
s,atherosclerosis
C3deficiency
(LOF)
C3
AR
120700
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectiveopsonizatio
n,defectivehumoral
immuneresponse
Infections,glomerulonephritis,atypical
hemolytic-uremicsyndromewith
GOFmutations
C3GOF
C3
AD
120700
Increasedactiv
ationof
complem
ent
Atypicalh
emolytic-uremicsyndrome
C5deficiency
C5
AR
120900
AbsentC
H50
andAH50
hemolyticactiv
ityDefectiv
ebactericidalactiv
ityDisseminated
neisserialinfections
C6deficiency
C6
AR
217050
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectivebactericidalactiv
ityDisseminated
neisserialinfections
C7deficiency
C7
AR
217070
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectivebactericidalactiv
ityDisseminated
neisserialinfections
C8α
deficiency
C8A
AR
120950
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectivebactericidalactiv
ityDisseminated
neisserialinfections
C8γ
deficiency
C8G
AR
120930
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectivebactericidalactiv
ityDisseminated
neisserialinfections
C8β
-deficiency
C8B
:AR
120960
AbsentC
H50
andAH50
hemolyticactiv
ity,
defectivebactericidalactiv
ityDisseminated
neisserialinfections
C9deficiency
C9
AR
120940
Reduced
CH50
andAP5
0hemolyticactiv
ity,
deficientb
actericidalactivity
Mild
susceptib
ility
todissem
inated
neisserialinfections
MASP2deficiency
MASP
2AR
605102
Deficient
activ
ationof
thelectin
activ
ationpathway
Pyogenicinfections,inflammatory
lung
disease,autoim
munity
Ficolin
3deficiency
FCN3
AR
604973
Absence
ofcomplem
entactivationby
the
Ficolin
3pathway.
Respiratory
infections,abscesses
124 J Clin Immunol (2018) 38:96–128
Tab
le8
(contin
ued)
1.Com
plem
entd
eficiencies
Disease
Geneticdefect
Inheritance
GeneOMIM
Laboratoryfeatures
Associatedfeatures
C1inhibitordeficiency
SERPING1
AD
606860
Spontaneousactiv
ationof
thecomplem
ent
pathway
with
consum
ptionof
C4/C2,
spontaneousactiv
ationof
thecontactsystem
with
generatio
nof
bradykinin
from
high
molecular
weightk
ininogen
Hereditary
angioedema
FactorBGOF
CFB
AD
138470
Gain-of-functionmutationwith
increased
spontaneousAH50
Atypicalh
emolytic-uremicsyndrome
FactorBLOF
CFB
AR
138470
Deficient
activ
ationof
thealternativepathway
Infections
with
encapsulated
organism
s
FactorDdeficiency
CFD
AR
134350
AbsentA
H50
hemolyticactivity
Neisserialinfectio
ns
Properdindeficiency
CFP
XL
300383
AbsentA
H50
hemolyticactivity
Neisserialinfectio
ns
FactorIdeficiency
CFI
AR
217030
Spontaneousactiv
ationof
thealternative
complem
entp
athw
aywith
consum
ptionof
C3
Infections,disseminated
neisserialinfections,
atypicalhemolytic-uremicsyndrome,
preeclam
psia
FactorHdeficiency
CFH
ARor
AD
134370
Spontaneousactiv
ationof
thealternative
complem
entp
athw
aywith
consum
ptionof
C3
Infections,disseminated
neisserialinfections,
atypicalhemolytic-uremicsyndrome,
preeclam
psia
FactorH-related
protein
deficiencies
CFHR1-5
ARor
AD
134371,600889,
605336,605337,
608593
NormalCH50,A
H50,autoantibodiesto
factor
H,
linkeddeletio
nsof
oneor
moreCFHRgenes
leadsto
susceptib
ility
autoantib
ody-mediated
aHUS
Older
onsetatypicalh
emolytic-uremic
syndrome,dissem
inated
neisserial
infections
Throm
bomodulin
deficiency
THBD
AD
188040
NormalCH50,A
H50
Atypicalh
emolytic-uremicsyndrome
Mem
branecofactor
protein
(CD46)deficiency
CD46
AD
120920
Inhibitorof
complem
entalternatepathway,
decreasedC3b
binding
Atypicalh
emolytic-uremicsyndrome,
infections,preeclampsia
Mem
braneattack
Com
plex
inhibitor(CD59)deficiency
CD59
AR
107271
Erythrocyteshighly
susceptib
leto
complem
ent-mediatedlysis
Hem
olyticanem
ia,polyneuropathy
CD55
deficiency
(CHAPE
Ldisease)
CD55
AR
125240
Hyperactiv
ationof
complem
ento
nendothelium
Proteinlosing
enteropathy,thrombosis
Totaln
umberof
disordersin
Table8:
30.N
ewdisorders:1,CD55
MACmem
braneattack
complex,SLE
system
iclupuserythematosus,X
LX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n,GOFgain-
of-function
J Clin Immunol (2018) 38:96–128 125
Tab
le9
Phenocopiesof
inborn
errorsof
immunity
1.Ph
enocopiesof
inborn
errorsof
immunity
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−
doublenegativ
e(D
N)
Talpha/betacells
Normal,but
increased
numberof
CD5+
Bcells
Normalor
increased
Splenomegaly,lymphadenopathy,
autoim
munecytopenias,defectiv
elymphocyteapoptosis/ALPS
–FAS
(=ALPS
type
Im)
RAS-associated
autoim
mune
leukoproliferativedisease
(RALD)
Somaticmutationin
KRAS
(GOF)
Normal
Bcelllymphocytosis
Normalor
increased
Splenomegaly,lymphadenopathy,
autoim
munecytopenias,
granulocytosis,m
onocytosis/
ALPS
-like
RAS-associated
autoim
mune
leukoproliferativedisease
(RALD)
Somaticmutationin
NRAS
(GOF)
IncreasedCD4−
CD8−
doublenegativ
e(D
N)
Talpha/betacells
Lymphocytosis
Normalor
increased
Splenomegaly,lymphadenopathy,
autoantibodies/ALPS
-like
Cryopyrinopathy,(Muckle-Wells/CIN
CA/
NOMID
-likesyndrome)
Somaticmutationin
NLR
P3
Normal
Normal
Normal
Urticaria-likerash,arthropathy,
neurologicalsigns
Hypereosinophilicsyndrome
dueto
somaticmutations
inST
AT5b
Somaticmutationin
STAT5b
(GOF)
Normal
Normal
Normal
Eosinophilia,atopicderm
atitis,
urticarialrash,diarrhea
Large
granular
lymphocytosis
Somaticmutations
inST
AT3(G
OF)
Clonalexpansion
oflargeTcells
Normal
Normal
Anemia,neutropenia,splenom
egaly
Associatedwith
autoantib
odies
Chronicmucocutaneous
candidiasis(isolatedor
with
APE
CEDsyndrome)
Germlin
emutationin
AIRE
AutoA
bto
IL-17and/or
IL-22
Normal
Normal
Normal
Endocrinopathy,chronic
mucocutaneous
candidiasis/CMC
Adult-onsetimmunodeficiency
with
susceptib
ility
tomycobacteria
AutoA
bto
IFNγ
Decreased
naive
Tcells
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,
dissem
inated
nocardiosis/CSF
2RA
deficiency
Acquiredangioedema
AutoA
bto
CIinhibitor
Normal
Normal
Normal
Angioedem
a/C1INHdeficiency
(hereditary
angioedema)
Atypicalh
emolytic-uremic
syndrome
AutoA
bto
complem
ent
factor
HNormal
Normal
Normal
aHUS=spontaneousactivationof
thealternativecomplem
entp
athw
ayThymom
awith
hypogammaglobulin
emia
(Goodsyndrome)
AutoA
bto
various
cytokines
IncreasedCD8+
Tcells
NoBcells
Decreased
Invasive
bacterial,viralo
ropportunistic
infections,
autoim
munity,P
RCA,lichenplanus,
cytopenia,colitis,chronicdiarrhea
Totaln
umberof
conditionsforTable9:
12
aHUSatypicalhemolytic-uremicsyndrome,GOFgain-of-functio
n,PRCApure
redcellaplasia
126 J Clin Immunol (2018) 38:96–128
the phenotype of a given disorder was clear, the spectrum ofmanifestations often extends impressively once the ascer-tainment is not linked to a preconceived idea [20]. As acommunity, we recognize the importance of publishingcases and small series and to report specific mutations withclinical findings because publications are used to definelikelihood of causality during bioinformatic analysis ofnext-generation sequencing results.
In 1999, the Committee on Primary Immunodeficienciescame under the auspices of the International Union ofImmunological Societies (IUIS). The current committee meton February 23–24, 2017, in London to update the classifica-tion of human primary immunodeficiencies. Inclusion in this“master list” requires a body of literature supporting causalityof a gene defect and a penetrance indicating clinical relevance[21]. Committee members vote on inclusion of each new dis-order and this publications lists those included as of theFebruary 2017 meeting. The landscape is changing so rapidly,and the number of primary immunodeficiencies growing sofast, that two major changes have been implemented. Thepublished list will continue to serve as a reference; however,this list will now be available as a csv file on the IUIS websiteto enable sorting according to gene, disease name, or clinical/laboratory feature. This file will also include the associatedICD10 codes in order to promote harmonization of utilization.The second major change is to the nomenclature. The termprimary immunodeficiency has an important legacy—the ab-breviations PID or PIDD are often used by patient organiza-tions and are recognized around the world. However, thisterminology does limit the conceptualization of disorders tothose in which susceptibility to infection is the main manifes-tation. The improving recognition of immune dysregulationdiseases, including the growing field of autoinflammatory dis-orders and interferonopathies, has mandated that a moreencompassing terminology be used. This manuscript, there-fore, utilizes “inborn errors of immunity” as the descriptor forthe work and the categorization. In addition to embracingtechnology to remain updated, the companion publication“Update of the Phenotypical IUIS Classification for PrimaryImmunodeficiencies” will provide a phenotype-oriented ap-proach to the IUIS categorization of disorders. Moreover, anew free application can be found as “PID phenotypical diag-nosis” or “PID classification” from iTunes and Android appstores [22, 23]. Information that is readily accessible is thenew standard, and the IUIS Expert Committee on PrimaryImmunodeficiencies believes that improved access to infor-mation will positively impact patient care around the world.
The tables divide disease categories according to com-mon phenotypes for ease of review and searching. Table 1lists combined immunodeficiencies, Table 2 lists com-bined immunodeficiencies with syndromic features,Table 3 lists predominantly antibody deficiencies,Table 4 lists diseases of immune dysregulation, Table 5
lists defects of phagocyte number or function, Table 6lists defects in intrinsic and innate immunity, Table 7 listsautoinflammatory diseases, Table 8 lists complement de-ficiencies, and Table 9 lists phenocopies of inborn errorsof immunity. The division into phenotypes for the purposeof this list does not imply that the presentation is homo-geneous. Each disorder is listed only once for the sake ofsimplicity although distinct modes of inheritance can belisted separately. There are nine genes for which bothloss-of-function and gain-of-function variants have beenidentified: CFB, C3, CARD11, STAT1, STAT3, WAS,JAK1, IFIH1, and ZAP70. For these, the loss-of-functionand gain-of-function aspects are listed. Within each table,there are additional sub-tables that segregate into coherentphenotypic sets. At the end of each table, the new disor-ders, added for this publication, are listed for easy refer-ence. Other features important for navigation of the listinclude the use of OMIM links [24]. For additional infor-mation on a gene, the links can be accessed from withinthe online publication. For the second time, we also in-clude non-inborn errors of immunity in Table 9,representing phenocopies of inborn errors which mightbe important to consider diagnostically.
The goal of the IUIS Expert Committee on PrimaryImmunodeficiencies is to increase awareness, facilitate recog-nition, promote optimal treatment, and support research in thefield of immune deficiency disorders. Thus, the “IUIS PIDCommittee Report on Inborn Errors of Immunity” and“Update of the Phenotypical IUIS Classification for PrimaryImmunodeficiencies” publications are important resources forclinicians and researchers. In addition, these tables form thebasis of lists used for sequencing panels and are used to mon-itor health utilization which will influence health servicesfunding by federal or state governments and/or insurancecompanies in various global settings. The addition of ICD10codes for the online version will promote a harmonizationbetween the diagnostic tables and coding items that will facil-itate bioinformatics research going forward.
Acknowledgements The authors wish to thank DawnWesterfer for theexpert secretarial support and Ulrika Smrekova for the administrativesupport.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts ofinterest.
Open Access This article is distributed under the terms of the CreativeCommons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you give appro-priate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made.
J Clin Immunol (2018) 38:96–128 127
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128 J Clin Immunol (2018) 38:96–128
