humaninbornerrorsofimmunity: …digms representing the foundations of basic, clinical and...
TRANSCRIPT
ORIGINAL ARTICLE
Human Inborn Errors of Immunity: 2019 Update on the Classificationfrom the International Union of Immunological Societies ExpertCommittee
Stuart G. Tangye1,2 & Waleed Al-Herz3 & Aziz Bousfiha4 & Talal Chatila5 & Charlotte Cunningham-Rundles6 &
Amos Etzioni7 & Jose Luis Franco8& Steven M. Holland9
& Christoph Klein10& Tomohiro Morio11
& Hans D. Ochs12 &
Eric Oksenhendler13 & Capucine Picard14,15& Jennifer Puck16 & Troy R. Torgerson12
& Jean-Laurent Casanova17,18,19,20 &
Kathleen E. Sullivan21
# The Author(s) 2020, corrected publication 2020
AbstractWe report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the InternationalUnion of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update(published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies.The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare orcommon; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even knownvariants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular,cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the man-agement of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals withheritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inbornerrors of immunity and related human diseases.
Keywords IUIS . primary immune deficiency . inborn errors of immunity . immune dysregulation . autoinflammatory disorders .
next-generation sequencing
Inborn errors of immunity, also referred to as primary immu-nodeficiencies, manifest as increased susceptibility to infec-tious diseases, autoimmunity, autoinflammatory diseases, al-lergy, and/or malignancy. These conditions are caused bymonogenic germline mutations that result in loss of expres-sion, loss-of-function (LOF; amorphic/hypomorphic), or gain-of-function (GOF; hypermorphic) of the encoded protein [1,2]. Heterozygous lesions may underlie autosomal dominanttraits by GOF, haploinsufficiency, or negative dominance.Biallelic lesions typically cause autosomal recessive traits byLOF of the encoded protein (rarely GOF), while X-linkedrecessive traits arise from LOF of genes on the X chromosome,
either in the hemizygous state in males or in the homozygousstate in females. Rare X-linked dominant traits can also arisefrom LOF or GOF variants. This results in aberrant immunitydue to the critical roles of these proteins in the development,maintenance and function of cells of the immune system, orcells other than leukocytes that contribute to immunity, duringhomeostasis and in response to external (e.g., infectious agentsor environmental antigens) and internal (e.g., cytokines, self-antigens and cancer cells) stimuli [3–5]. Inborn errors of immu-nity were traditionally considered to be rare diseases, affecting~ 1 in 10,000 to 1 in 50,000 births. However, with ongoingdiscovery of novel inborn errors of immunity (Fig. 1a) andimproved definition of clinical phenotypes [6–8], the collectiveprevalence of these conditions is more likely to be at least 1/1000–1/5000 [9]. Indeed, more common inborn errors haverecently been described [10]. Regardless of their exact inci-dence and prevalence, inborn errors of immunity represent anunprecedented model to link defined monogenic defects with
* Stuart G. [email protected]
Extended author information available on the last page of the article
https://doi.org/10.1007/s10875-019-00737-xJournal of Clinical Immunology (2020) 40:24–64
Received: 4 November 2019 /Accepted: 18 December 2019 /Published online: 17 January 2020
clinical phenotypes of immune dysregulation, in a broad senseof the term. As a committee, we are aware that human immu-nity involves cells other than circulating or tissue leukocytesand that it can be scaled up from the immune system to thewhole organism. Inborn errors of immunity have unequivocallyrevealed non-redundant roles of single genes and their productsin immune function [3, 4, 6–8], formed the basis of improvedmechanism-based therapies for the immunopathology underly-ing many diseases [8, 11], established immunological para-digms representing the foundations of basic, clinical and trans-lational immunology [3–5, 9, 12–14], and provided insightsinto the molecular pathogenesis of more common diseases [9,15]. Clear examples of these include:
& The initial description by Bruton of X-linked agamma-globulinemia (XLA) and the ability to treat this conditionwith antibody replacement therapy (the mainstay treat-ment for antibody deficiency diseases such as CVID) [16]
& The discovery of mutations in BTK [12] and the subse-quent development of BTK-inhibitors such as ibrutinib forthe treatment of B cell malignancies [14]
& Progressive CD4 T cell deficiency explains opportunisticinfections secondary to HIV infection [9].
Thus, the study of inborn errors of immunity has providedprofound advances in the practice of precision molecularmedicine.
Since the early 1950s, when XLA was one of the firstprimary immune deficiencies to be described [16], clinicalimmunology has leveraged advances in the development ofnew methods to expedite the identification of defects of theimmune system and the cellular, molecular, and genetic aber-rations underlying these conditions. Indeed, the completion of
the Human Genome Project in the early 2000s, coupled withrapid developments in next generation DNA sequencing(NGS) technologies, enabled the application of cost-effectiveand time-efficient sequencing of targeted gene panels, wholeexomes, or whole genomes to cohorts of patients suspected ofhaving a monogenic explanation for their disease. These plat-forms have led to a quantum leap in the identification anddiagnosis of previously undefined genetically determined de-fects of the immune system (Fig. 1a, b; [6–8]).
The International Union of Immunological SocietiesExpert Committee of Inborn Errors of Immunity comprisespediatric and adult clinical immunologists, clinician/scientistsand researchers in basic immunology from across the globe(https://iuis.org/committees/iei/). A major objective andresponsibility of the committee is to provide the clinical andresearch communities with an update of genetic causes ofimmune deficiency and dysregulation. The committee hasexisted since 1970 and has published an updated reportapproximately every 2 years to inform the field of theseadvances (Fig. 1a). In March 2019, the committee met inNew York to discuss and debate the inclusion of geneticvariants published over the preceding 2 years (since June2017) [1, 2], as well as gene mutations that had appeared inthe literature earlier but, based on newly available evidence,were now substantiated (Fig. 1b).
Rather than simply including every gene variant reported,the committee applies very stringent criteria such that onlythose genes with convincing evidence of disease pathogenic-ity are classified as causes of novel inborn errors of immunity[17]. The Committee makes informed judgments for includingnew genetic causes of immunological conditions based onwhat we believe is most useful for practitioners caring forpatients. Our current, and continuously evolving, practice isthat criteria for inclusion can be met by several ways, for
Fig. 1 Rate of discovery of novel inborn errors of immunity: 1983–2019.a The number of genetic defects underlying monogenic immunedisorders as reported by the IUIS/WHO committee in the indicatedyear. b The number of pathogenic gene variants listed in each table bythe IUIS committee. Report published in 2017, and the number of newgenes for each table contained in this report (red bars). The numbers in
each column correspond to the number of genes reported in the 2017 IUISupdate (blue bars) [1, 2], the number of new genes for each tablecontained in this report (red bars), and the total number of genes foreach table. Note: only data for Tables 1, 2, 3, 4, 5, 6, 7, and 8 areshown, because Table 9 (bone marrow failure) is a new addition to thecurrent report.
J Clin Immunol (2020) 40:24–64 25
instance peer-reviewed publication of (1) multiple casesfrom unrelated kindreds, including detailed immunologicdata, or (2) very few cases, or even a single case (seebelow), for whom compelling mechanistic/pathogenic datais also provided, generally from parallel studies in an ani-mal or cell culture model.
Herein, we provide this latest update. The inborn errorsof immunity are listed in 10 tables: Combined immunode-ficiencies (Table 1), Combined immunodeficiencies withsyndromic features (Table 2), Predominantly antibody de-ficiencies (Table 3), Diseases of immune dysregulation(Table 4), Congenital defects of phagocytes (Table 5),Defects in intrinsic and innate immunity (Table 6),Autoinflammatory diseases (Table 7), Complement defi-ciencies (Table 8), and Phenocopies of inborn errors ofimmunity (Table 10) (Fig. 1b). Since the last update (pub-lished January 2018) [1, 2], we have added a new table toconsolidate genes that cause bone marrow failure (Table9). Our division into phenotypes does not imply that thepresentation is homogeneous. Rather, we recognize thatsubstantial phenotypic and clinical heterogeneity existswithin groups of patients with mutations in the same geneand even between individuals from the same pedigree withthe identical gene mutation. To simplify the classification,each disorder has been listed only once, although distinctdisorders due to mutations in the same gene, but with dif-ferent modes of inheritance and pathogenic mechanismsare listed individually. Thus, several genes appear morethan once in this update (some examples are listed below).Sub-divisions within each table segregate groups of disor-ders into coherent phenotypic sets. OMIM numbers arealso provided within each table. If a OMIM number hasnot yet been issued for a particular genetic condition, thenthe number provided generally refers to the OMIM for thatgene. Beneath each table, the new disorders added to thisupdate are highlighted for easy reference.
The advances in our understanding of clinical immunol-ogy continue to expand at a vast and remarkable rate, withthe addition in this update of many—64, distributed acrossall tables (Fig. 1b)—novel genetic defects underlying in-born errors of immunity. Perhaps not surprisingly, most ifnot all of these new variants were identified by NGS, thushighlighting that whole exome/whole genome sequencinghas become the gold standard for identifying novel patho-genic gene variants [6–8]. Indeed, since the first applica-tion of NGS to identify novel inborn errors of immunitywas published in 2010 [18], ~ 45% of all currently knowndisease-causing variants have been discovered by wholeexome/genome sequencing. Thus, a typical approach toidentifying a pathogenic variant in a new patient mightnow consist of first sequencing a phenotype-driven panelof genes and advancing to whole exome/genome sequenc-ing if the cause of disease remains elusive.
In this update, we increase the list of immunologicaldiseases to 404, with 430 known genetic defects identifiedas causing these conditions. The unbiased application ofNGS to the discovery and characterization of novel inbornerrors of immunity continues to inform clinical and basicimmunology. Thus, additional phenotypes have beenidentified for conditions resulting from variants in knownand novel genes; the penetrance of genetic variants onclinical phenotypes has been shown to be highly variable;and clinical entities sharing common phenotypes havebeen discovered. For example, this update includes thefindings that bi-allelic mutations in ZNF341 [19, 20],IL6ST (encoding gp130, a common component of the re-ceptors for IL-6, IL-11, IL-27, LIF, OSM, CNTF) [21,22], or IL6R [23, 24] all cause conditions that resembleautosomal dominant hyper-IgE syndrome due to dominantnegative mutations in STAT3 [15]. Detailed analyses ofthese patients revealed a novel mechanism of regulatingSTAT3 signaling (via the transcription factor ZNF341)and defined the exact consequences of impaired IL-6/IL-6R/gp130 and putatively IL-11/IL-11R/gp130 signaling tothe phenotype of AD-HIES.
Furthermore, key findings over the past 2 years contin-ue to reveal that distinct mechanisms of disease (GOF,LOF, dominant negative, haploinsufficient), as well asdifferent modes of inheritance (autosomal recessive, auto-somal dominant) of variants in the same gene can causedisparate clinical conditions. This is a fascinating aspectof the genetics of human disease, and a salient reminderto be cognizant of the nature of the genetic variants iden-tified from NGS. It is these genes that have several entriesin this update. A few recent examples include:
1. Heterozygous variants in CARD11 [25, 26] or STAT5B[27] can be pathogenic due to negative dominance. Thiswas potentially unexpected because autosomal recessiveLOF variants in both of these genes were previously re-ported to cause combined immunodeficiency and severeimmune dysregulation, respectively, yet heterozygous rel-atives of these affected individuals were healthy [28, 29].
2. While heterozygous dominant negative mutations inTCF3, encoding the transcription factor E47, cause B celldeficiency and agammaglobulinemia [30], nonsense mu-tations in TCF3 have now been identified that are patho-genic only in an autosomal recessive state, as heterozy-gous carriers of these particular allelic variants remainedhealthy [31, 32].
3. A heterozygous hypermorphic variant in IKBKB wasfound to cause a combined immunodeficiency [33] nottoo dissimilar to the original description of bi-allelic, re-cessive variants in IKBKB [34]. Similarly, bi-allelic LOFmutations in PIK3CD are now known to cause B celldeficiency and agammaglobulinemia [35–37], which is
J Clin Immunol (2020) 40:24–6426
quite distinct from the immune dysregulated state of indi-viduals with monoallelic activating PIK3CD mutations[1, 37]. This observation nicely parallels the earlier find-ings of either homozygous or heterozygous mutations inPIK3R1 that clinically phenocopy recessive or activatingmutations in PIK3CD respectively [1, 37].
4. Distinct diseases can result from heterozygous mutationsin IKZF1 (Ikaros): combined immunodeficiency due todominant negative alleles [38] or CVID due tohaploinsufficiency [39].
5. Similar to STAT1 [40], variants in RAC2 [41–45] orCARD11 [25, 26, 28] can be pathogenic either asmonoallelic GOF or LOF or bi-allelic recessive LOF.
Thus, these findings have revealed the fundamental im-portance of elucidating the impact of a novel variant on thefunction of the encoded protein and thus the mechanism ofpathogenicity. Furthermore, these new entries are an im-portant reminder not to overlook the potential significanceof identifying heterozygous variants in genes previouslybelieved to cause disease only in a biallelic manner or toresult in a previously defined specific clinical entity.Indeed, there are now at least 35 genes that have multipleentries in the current update, reflecting the distinct mecha-nisms by which variants result in or cause disease (e.g.,STAT1, STAT3, NLRP1, RAC2, ZAP70, CARD11, IKBKB,WAS, JAK1, IFIH1, C3, C1R, C1S–GOF or LOF; STAT5,STAT1, CARD11, ACD, CFH, CFHR1–5, FOXN1, RAC2,TCF3, AICDA, PIK3R1, IFNGR1, TREX1, TICAM1,IRF8–AD or AR; PIK3CD–AD GOF, AR LOF; IKZF1–AD, or haploinsufficient; NLRP3—distinct disease pheno-types despite all resulting from GOF alleles).
As noted above, genetic, biochemical, and functionalanalyses of putative novel pathogenic variants need tomeet stringent criteria to be considered for inclusion in thisupdate [17]. These criteria can make reporting geneticfindings from single cases challenging, as often the bestevidence that a novel variant is disease-causing is to iden-tify additional, similarly affected but unrelated individualswith the same variants, or functionally similar variants inthe same gene. While this can be challenging, particularlyin light of the rarity of individual inborn errors of immu-nity, robust mechanistic laboratory investigations continueto provide compelling data from single patients, with orwithout evidence from animal models. Specifically, homo-zygous LOF mutations in IRF9 [46] and IL18BP [47] wereidentified and rigorously characterized in single patientsand found to be the molecular cause of life-threateninginfluenza and fulminant viral hepatitis, respectively.
The study and discovery of novel inborn errors of im-munity can also enable improved patient management by
implementing gene-specific targeted therapies. Thus, JAKinhibitors are being used to treat disorders of immune dys-regulation resulting from GOF mutations in JAK1, STAT1or STAT3 [11], while mTOR inhibitors such as rapamycinor PI3K p110δ-specific inhibitors have been reported forthe treatment of individuals with PIK3CD GOF or PIK3R1LOF mutations [37]. Regarding novel gene defects, im-mune dysregulation due to DEF6 deficiency was success-fully treated with abatacept (CTLA4-Ig) [48]. This corre-lated with impaired CTLA4 expression and function inDEF6-deficient T cells [48] and parallels the therapeuticuse of abatacept and belatacept for LRBA-deficiency andCTLA4 haploinsufficiency, both of which are character-ized by reduced CTLA4 expression in affected regulatoryT cells [49, 50]. From a theoretical perspective, the findingthat MSMD can be caused by mutations in IL12RB2,IL23R or SPPL2A and that these mutations are associatedwith impaired production of IFNγ—a requisite of anti-my-cobacterial immunity—implies that IFNγ administrationcould be therapeutically beneficial in these clinical settings[51, 52]. Similarly, recombinant IL18BP could potentiallyameliorate viral-induced liver toxicity due to IL18BP defi-ciency [47].
The goals of the IUIS Expert Committee on InbornErrors of Immunity are to increase awareness, facilitaterecognition, promote optimal treatment, and support re-search in the field of disorders of immunity. Thus, this2019 Update and the accompanying “Phenotypical IUISClassification” publications are intended as resources forclinicians and researchers. Importantly, these tables un-derpin the design of panels used for targeted gene se-quencing to facilitate genetic diagnoses or inborn errors.In the past 5 years, the number of gene defects underly-ing inborn errors of immunity has nearly doubled from ~250 to 430 (Fig. 1a). The human genome contains 1800–2000 genes that are known to be involved in immuneresponses [13]. Thus, the discovery and study of inbornerrors of immunity has elegantly illustrated that > 20% ofthese immune genes play non-redundant roles in hostdefense and immune regulation. With the improved iden-tification and phenotyping of patients with rare diseases,combined with high throughput genome sequencing, thenumber of genes fundamentally required for immunitywill no doubt continue to increase, further revealing crit-ical and novel roles for specific genes, molecules, path-ways and cell types in immune responses, as well asmechanisms of disease pathogenesis and targets for im-munotherapies. The field of inborn errors of immunity,and the global clinical and research communities, willtherefore continue to provide key insights into basic andclinical immunology.
J Clin Immunol (2020) 40:24–64 27
Table1
Immunodeficienciesaffectingcellu
larandhumoralim
munity
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
1.T-B+severe
combinedim
mun
edeficiency
(SCID
)γcdeficiency
(com
mon
gammachainSC
ID,C
D132
deficiency)
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
NormalNK
CD45
deficiency
PTP
RC
AR
151460
Verylow
Normal
Low
Normalγ/δ
Τcells
CD3δ
deficiency
CD3D
AR
186790
Verylow
Normal
Low
NormalNK,noγ/δ
Tcells
CD3ε
deficiency
CD3E
AR
186830
Verylow
Normal
Low
NormalNK,noγ/δ
Tcells
CD3ζ
deficiency
CD3Z
AR
186780
Verylow
Normal
Low
NormalNK,noγ/δ
Tcells
Coronin-1Adeficiency
CORO1A
AR
605000
Verylow
Normal
Low
Detectablethym
us
LATdeficiency
LAT
AR
602354
Normalto
low
Normalto
low
High
TypicalS
CID
orcombined
immunodeficiency,thelatter
with
adenopathy,splenom
egaly,
recurrentinfections,
autoim
munity
2.T-B-SC
IDRAGdeficiency
RAG1
RAG2
AR
179615
179616
Verylow
Verylow
Decreased
NormalNKcellnumber,but
increasedrisk
ofgraftrejection,
possibly
dueto
activated
NKcells
DCLRE1C
(Artem
is)deficiency
DCLR
E1C
AR
605988
Verylow
Verylow
Decreased
NormalNKcellnumber,but
increasedrisk
ofgraftrejection,
possibly
dueto
activated
NKcells,
radiationsensitivity
DNAPK
csdeficiency
PRKDC
AR
615966
Verylow
Verylow
Variable
NormalNK,radiationsensitivity,
microcephaly
Cernunnos/XLFdeficiency
NHEJ1
AR
611290
Verylow
Verylow
Decreased
NormalNK,radiationsensitivity,
microcephaly
DNAlig
aseIV
deficiency
LIG4
AR
601837
Verylow
Verylow
Decreased
NormalNK,radiationsensitivity,
microcephaly
Adenosine
deam
inase(A
DA)deficiency
ADA
AR
608958
Verylow
Low
,decreasing
Low
,decreasing
Low
NK,bonedefects,may
have
pulm
onaryalveolar
proteinosis,
cognitive
defects
AK2defect
AK2
AR
103020
Verylow
VeryLow
Decreased
Reticular
dysgenesiswith
neutropenia;deafness
Activated
RAC2defect
RAC2
ADGOF
602049
Verylow
VeryLow
Low
,poorspecific
antibodyresponses
Recurrent
bacterialand
viralinfections,
lymphoproliferation;
neutropenia
3.Com
bined
immun
odeficiency(C
ID),generally
less
profoun
dthan
SCID
CD40
ligand(CD154)
deficiency
CD40LG
XL
308230
Normalto
low
sIgM
+IgD+naïve
Bcells
present;
IgG+,IgA
+,IgE
+
mem
oryBcells
absent
IgM
norm
alor
high,
otherIg
isotypes
low
Severeandopportunistic
infections,
idiopathicneutropenia;hepatitis
andcholangitis,C
ryptosporidium
infections,cholangiocarcinom
a;
autoim
munebloodcytopenias;
peripheralneuroectodermaltumors
CD40
deficiency
CD40
AR
606843
Normal
Neutropenia,opportunisticinfections,
gastrointestinalandbiliary
tract
andliver
disease,Cryptosporidium
infections
J Clin Immunol (2020) 40:24–6428
Tab
le1
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
ICOSdeficiency
ICOS
AR
604558
Normal
Normal
Low
Recurrent
infections,autoimmunity,
gastroenteritis,granulomas
ICOSLdeficiency
ICOSL
GAR
605717
Low
Low
Low
Recurrent
bacterialand
viral
infections,neutropenia
CD3γ
deficiency
CD3G
AR
186740
Normalnumber,
butlow
TCR
expression
Normal
Normal
Immunedeficiency
andautoim
munity
ofvariableseverity
CD8deficiency
CD8A
AR
186910
AbsentC
D8,
NormalCD4
Normal
Normal
Recurrent
infections,m
aybe
asym
ptom
atic
ZAP-70
deficiency
(ZAP7
0LOF)
ZAP70
AR
269840
Low
CD8number,
norm
alCD4number
butw
ithpoor
function
Normal
Normal
May
have
immunedysregulation,
autoim
munity
ZAP-70
combinedhypomorphic
andactivatingmutations
ZAP70
AR(LOF/GOF)
617006
Decreased
CD8,norm
al
ordecreasedCD4
cells
Normalor
decreased
NormalIgA,low
IgM,
low/normalIgG;p
rotective
Abresponsesto
vaccines
Severeautoim
munity
(bullous
pemphigoid,inflam
matorycolitis
MHCclassIdeficiency
TAP1
AR
170260
Low
CD8,norm
alCD4,
absent
MHCIon
lymphocytes
Normal
Normal
Vasculitis,pyoderm
agangrenosum
TAP2
AR
170261
TAPBP
AR
601962
B2M
AR
109700
Sinopulm
onaryinfections,
cutaneousgranulom
as.
Absentβ
2massociated
proteins
MHC-I,C
D1a,
CD1b,and
CD1c
MHCclassIIdeficiency
groupA,B
,C,D
CIITA
AR
600005
Low
CD4+
Tcells,
reducedMHCII
expression
on
lymphocytes
Normal
Normalto
low
Failure
tothrive,respiratory
and
gastrointestinalinfections,
liver/biliarytractd
isease
RFXANK
AR
603200
RFX5
AR
601863
RFXAP
AR
601861
IKAROSdeficiency
IKZF
1ADDN
603023
nomem
oryTcells
nomem
oryBcells
Low
Ig,
recurrentsinopulmonaryinfections,
pneumocystis
earlyCID
onset
DOCK8deficiency
DOCK8
AR
243700
Tcelllymphopenia,
reducednaïveCD8
Tcells,increased
exhaustedCD8+
TEM
cells,reduced
MAIT,
NKTcells,increased
γδTcells;p
oor
proliferation;
fewTreg
with
poor
function
increasedtotalB
cells,
reducedmem
ory
Bcells
Poor
peripheralBcell
tolerance.
Low
IgM,normal/highIgG
andIgA,veryhigh
IgE,
poor
antibodyresponses
Low
NKcells
with
poor
functio
n.
Eosinophilia,recurrent
infections,
cutaneousviral,fungaland
staphylococcalinfections,severe
atopy/allergicdisease,cancer
diathesis
DOCK2deficiency
DOCK2
AR
603122
Low
Normal
IgGnorm
alor
low,poor
antibodyresponses
Early
invasive
herpes
viral,bacterial
infections,N
ormalNKcellnumber,
butd
efectivefunction.Po
orinterferon
responsesin
hematopoietic
andnon-hematopoieticcells
Polymeraseanddeficiency
POLD
1POLD
2AR
174761
600815
Low
CD4Tcells
Low
igG
J Clin Immunol (2020) 40:24–64 29
Tab
le1
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Low
Bcells
but
norm
al
maturation
Recurrent
respiratorytractinfectio
ns,
skin
infections,w
artsandmolluscum
,
shortstature,intellectuald
isability
RHOHdeficiency
RHOH
AR
602037
Normal,few
naïve
Tcells,restricted
repertoire,poor
proliferationto
CD3
Normal
Normal
HPV
infection,lung
granulom
as,
molluscum
contagiosum,lym
phom
a
STK4deficiency
STK4
AR
614868
CD4lymphopenia,
reducednaïveTcells,
increasedTEM
and
TEMRAcells,poor
proliferation
Reduced
mem
ory
Bcells
Reduced
IgM,increased
IgG,IgA
,IgE
;impaired
Abresponses
Interm
ittentn
eutropenia,bacterial,
viral(HPV
,EBV,m
olluscum
),
candidalinfections,
lymphoproliferation,autoim
mune
cytopenias,lym
phom
a,congenital
heartd
isease
TCRαdeficiency
TRAC
AR
615387
AbsentT
CRαβexcept
foraminor
CD3-dim
TCRαβpopulation;
mostT
cells
γδ;
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
NormalIgGandIgA,
high
IgM
Recurrent
infections,immune
dysregulation,autoim
munity
ITKdeficiency
ITK
AR
186973
Progressive
CD4Tcell
lymphopenia;reduced
Tcellactivation
Normal
Normalto
lowserum
IgEBVassociated
Bcell
lymphoproliferation,lymphom
a,
immunedysregulation
MALT
1deficiency
MALT
1AR
615468
Normalnumber,poor
proliferation
Normal
Normallevels,poor
specificantibodyresponse
Bacterial,fungaland
viralinfections
CARD11
deficiency
CARD11
ARLOF
615206
Normalnumber,
predom
inantly
naïve
Tcells,poorproliferation
Normal,transitional
Bcellpredom
inance
Absent/low
Pneum
ocystis
jiroveciipneumonia,
bacterialand
viralinfections
BCL10
deficiency
BCL1
0AR
616098
Normalnumber,few
mem
oryTandTreg
cells,poorantigen
and
anti-CD3proliferation
Normalnumber,
decreased
mem
oryand
switchedBcells
Low
Recurrent
bacterialand
viralinfections,
candidiasis,gastroenteritis
IL-21deficiency
IL21
AR
615767
Normalnumber,
norm
al/lowfunction
Low
,decreased
mem
ory
andsw
itchedBcells
Hypogam
maglobulinem
ia,
poor
specificantibody
responses;increasedIgE
Severeearlyonsetcolitis,recurrent
sinopulm
onaryinfections
IL-21R
deficiency
IL21R
AR
615207
Normalnumber,low
cytokine
production,
poor
antigen
proliferation
Normal,decreased
mem
oryand
switchedBcells
Recurrent
infections,P
neum
ocystis
jiroveci,
Cryptosporidium
infections,liver
disease
OX40
deficiency
TNFRSF
4AR
615593
Normalnumbers,low
antigen
specificmem
ory
CD4+
Normalnumbers,low
mem
oryBcells
Normal
Impaired
immunity
toHHV8,
Kaposi’s
sarcom
a
IKBKBdeficiency
IKBKB
AR
615592
Normalnumber,absent
Tregandγ/δ
Tcells,
impaired
TCRactiv
ation
Normalnumber,
poor
function
Low
Recurrent
bacterial,viral,fungal
infections,opportunisticinfections
J Clin Immunol (2020) 40:24–6430
Tab
le1
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
NIK
deficiency
MAP3K
14AR
604655
Normalnumber,poor
proliferationto
antig
en
Low
,low
switched
mem
oryBcells
Low
Ig’s
Low
NKnumberandfunction,
recurrentb
acterial,viraland
Cryptosporidium
infections
RelBdeficiency
RELB
AR
604758
Normalnumber,poor
diversity,reduced
proliferationto
mitogens;
noresponse
toAg
Markedincrease
inBcellnumber
NormalIg
levelsbut
Impaired
specific
antibodyresponses
Recurrent
infections
RelAhaploinsufficiency
RELA
AD
618287
Normal/increased
Normal
Normal
Chronicmucocutaneous
ulceratio
n,
Impaired
NFk
Bactiv
ation;
reducedproductionof
inflam
matorycytokines
Moesindeficiency
MSN
XL
300988
Normalnumber,defective
migration,proliferation
Low
number
Low
Ig’sover
time
Recurrent
infections
with
bacteria,
varicella,neutropenia
TFR
Cdeficiency
TFRC
AR
616740
Normalnumber,poor
proliferation
Normalnumber,low
mem
oryBcells
Low
Recurrent
infections,neutropenia,
thrombocytopenia
c-Reldeficiency
REL
AR
164910
Normal,decreased
mem
ory
CD4,poor
proliferation
Low
,mostly
naïve;fewsw
itched
mem
oryBcells,
impaired
proliferation
Low
,poorspecific
antibodyresponses
Recurrent
infections
with
bacteria,
mycobacteria,salm
onellaand
opportunistic
organism
s.
Defectiveinnateim
munity
FCHO1deficiency
FCHO1
AR
613437
Low
,poorproliferation
Normalnumber
Normal
Recurrent
infections
(viral,m
ycobacteria,
bacterial,fungal),lymphoproliferation,
failu
reto
thrive,increased
activation-inducedTcelldeath,
defectiveclathrin-m
ediatedendocytosis
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
ofRAG1/2andotherSC
ID-associatedgenes.There
canbe
clinicaloverlapbetweensomegeneslistedhere
andthoselistedin
Table7
Totaln
umberof
disordersin
Table1:
50
Totaln
umberof
mutantg
enes:5
8
New
inborn
errorsof
immunity
:8;N
ewinborn
errorsof
immunity
:8;R
AC2GOF[42–45];ICOSL
G[53];A
DDNIKZF
1[38];P
OLD
1[54,55];POLD
2[54];R
ELA
[56,57];REL[58];F
CHO1[59]
SCID
severecombinedim
munodeficiency,CID
combinedim
munodeficiency,EBVEpstein-Barrv
irus,M
HCmajor
histocom
patib
ilitycomplex,H
PVhuman
papillo
mavirus,TregTregulatory
cell,XLX-
linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n,GOFgain-of-functio
n
J Clin Immunol (2020) 40:24–64 31
Table2
Com
binedim
munodeficiencieswith
associated
orsyndromicfeatures
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
1.Im
mun
odeficiencywithcong
enital
thrombo
cytopenia
Wiskott-Aldrich
syndrome(W
ASLOF)
WAS
XL
300392
Progressivedecrease
innumbers,abnormal
lymphocyteresponsesto
anti-CD3
Normalnumbers
Low
IgM
andantib
ody
responsesto
polysaccharides,often
high
IgAandIgE
Throm
bocytopeniawith
smallplatelets,
eczema,recurrentbacterial/viral
infections,bloodydiarrhea,lym
phom
a,autoimmunedisease,IgA-nephropathy.
Patientswith
XL-thrombocytopenia
have
lateronsetofcomplications
and
morefavourablelifeexpectancy
but
eventuallydevelopsimilarcom
plications
asobserved
inWAS
WIP
deficiency
WIPF1
AR
602357
Reduced,defective
lymphocyteresponsesto
anti-CD3
Normalor
low
Normal,exceptfor
high
IgE
Throm
bocytopeniawith
orwith
outsmall
platelets,recurrentb
acterialandviral
infections,eczem
a,bloody
diarrhea;
WASproteinabsent
Arp2/3-mediatedfilamentb
ranching
defect
ARPC1B
AR
604223
Normal
Normalnumbers
Normalexceptforh
ighIgA
andIgE
Mild
thrombocytopeniawith
norm
alsizedplatelets,recurrentinvasive
infections;colitis,vasculitis,
autoantibodies(A
NA,A
NCA),
eosinophilia;defectiveArp2/3
filamentb
ranching
2.DNArepa
irdefectsotherthan
thoselistedin
Tab
le1
Ataxia-telangiectasia
ATM
AR
607585
Progressivedecrease,poor
proliferationto
mitogens;
may
have
lowTRECs
andTcells
bynewborn
screening(N
BS)
Normal
Often
lowIgA,IgE
andIgG
subclasses,increased
IgM
monom
ers;
antib
odiesvariably
decreased
Ataxia,telangiectasiaespecially
ofsclerae;pulm
onaryinfections;
lymphoreticular
andother
malignancies;increasedalpha
fetoprotein;
increasedradiosensitiv
ity,
chromosom
alinstability
and
chromosom
altranslocations
Nijm
egen
breakage
syndrome
NBS1
AR
602667
Progressivedecrease;m
ayhave
lowTRECsandT
cells
byNBS
Variablyreduced
Often
lowIgA,IgE
,and
IgGsubclasses,
increasedIgM;
antib
odiesvariably
decreased
Microcephaly,dysm
orphicfacies;
lymphom
asandsolid
tumors;
increasedradiosensitiv
ity;,
chromosom
alinstability
Bloom
syndrome
BLM
AR
604610
Normal
Normal
Low
Shortstature,dysmorphicfacies
sun-sensitive
erythema;marrow
failure;leukemia,lym
phom
a;chromosom
alinstability
Immunodeficiencywith
centromeric
instabilityandfacialanom
alies(ICFtypes
1,2,3,4)
DNMT3
BAR
602900
Decreased
ornorm
al,
responsestoPH
Amay
bedecreased
Decreased
ornorm
alHypogam
maglobulinem
iaor agam
maglobulin
emia,
variableantib
ody
deficiency
Facialdysm
orphicfeatures,developmental
delay,macroglossia;
bacterial/opportunisticinfections;
malabsorption;cytopenias;
malignancies;multiradialconfigurations
ofchromosom
es1,9,16
ZBTB
24AR
614064
Decreased
ornorm
al
J Clin Immunol (2020) 40:24–6432
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Facialdysm
orphicfeatures,m
acroglossia;
bacterial/opportunisticinfections;
malabsorption;cytopenias;
malignancies;multiradialconfigurations
ofchromosom
es1,9,16
CDCA7
AR
609937
Decreased
ornorm
al;
responsestoPH
Amay
bedecreased
HELL
SAR
603946
Decreased
ornorm
al
PMS2
deficiency
PMS2
AR
600259
Normal
Low
Bcells,switched
andnon-sw
itched
Low
IgGandIgA,high
IgM,abnormalantibody
responses
Recurrent
infections;café-au-laitspots;
lymphom
a,colorectalcarcinom
a,braintumors
RNF1
68deficiency
(Radiosensitivity,
ImmuneDeficiency,Dysmorphic
features,L
earningdifficulties[RID
DLE]
syndrome)
RNF168
AR
612688
Normal
Normal
Low
IgGor
IgA
Shortstature,m
ilddefectofmotorcontrol
toataxia;n
ormalintelligenceto
learning
difficulties;mild
facial
dysm
orphism
tomicrocephaly;
increasedradiosensitiv
ityMCM4deficiency
MCM4
AR
602638
Normal
Normal
Normal
NKcells:low
numberandfunction;viral
infections
(EBV,H
SV,V
ZV);short
stature;Bcelllymphom
a;adrenal
failu
rePO
LE1(Polym
eraseεsubunit1)deficiency
(FILSsyndrome)
POLE
1AR
174762
Normal;d
ecreased
Tcell
proliferation
Low
mem
oryBcells
Low
IgG2andIgM,lackof
antib
odyto
PPS
Recurrent
respiratoryinfections,
meningitis;faciald
ysmorphism,
livido,shortstature
POLE2(Polym
eraseεsubunit2)deficiency
POLE
2AR
602670
Lymphopenia,lackof
TRECSatNBS,
absent
proliferationin
response
toantig
ens
Verylow
Hypogam
maglobulinem
iaRecurrent
infections,disseminated
BCG
infections;autoimmunity
(type1
diabetes),hypothyroidism
,facial
dysm
orphism
LigaseIdeficiency
LIG1
AR
126391
Lymphopenia,increased
γδ
Tcells,decreased
mitogenresponse
Normal
Hypogam
maglobulinem
ia,
Reduced
antib
ody
responses
Recurrent
bacterialand
viralinfections;
grow
thretardation;
sunsensitivity,
radiationsensitivity;m
acrocytic
red
bloodcells
NSM
CE3deficiency
NSM
CE3
AR
608243
Decreased
number,poor
responsesto
mito
gens
andantigens
Normal
NormalIgG,IgA
,normal
toelevated
IgM;
decreasedantib
ody
responsesto
PPS
Severe
lung
disease(possiblyviral);
thym
ichypoplasia;chrom
osom
albreakage,radiatio
nsensitivity
ERCC6L
2(H
ebodeficiency)
ERCC6L
2AR
615667
Lymphopenia
Low
Normal
Facialdysm
orphism,m
icrocephaly;bone
marrowfailure
GIN
S1deficiency
GINS1
AR
610608
Low
ornorm
alLow
ornorm
alHighIgA,low
IgM
and
IgG
Neutropenia;IUGR;N
Kcells
very
low
3.Thy
micdefectswithad
dition
alcong
enital
anom
alies
DiGeorge/velocardio-facialsyndrom
eChrom
osom
e22q11.2deletionsyndrome
(22q11.2DS)
Large
deletio
n(3
Mb)
typically
in
AD
602054
Decreased
ornorm
al,5%
have
lowTRECsatNBS
and<1500
CD3T
cells/μLin
neonatal
period
Normal
Normalor
decreased
Hypoparathyroidism;conotruncalcardiac
malform
ation,velopalatal
insufficiency;
abnorm
alfacies;
intellectuald
isability
J Clin Immunol (2020) 40:24–64 33
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
chromo-
some22
(TBX1)
DiGeorge/velocardio-facialsyndrom
eUnknown
Sporadic
Decreased
ornorm
alTBX1deficiency
TBX1
AD
602054
Decreased
ornorm
al,m
ayhave
lowTRECsatNBS
CHARGEsyndrome
CHD7
AD
608892
Decreased
ornorm
al,m
ayhave
lowTRECsatNBS;
response
toPH
Amay
bedecreased
Normal
Normalor
decreased
Colobom
aof
eye;heartanomaly;choanal
atresia;intellectuald
isability;g
enital
andearanomalies,CNSmalform
ation;
someareSC
ID-like
SEMA3E
AD
608166
Unknown
Wingedhelix
nude
FOXN1deficiency
FOXN1
AR
601705
Verylow
Normal
Decreased
Severe
infections;abnormalthym
icepith
elium,immunodeficiency;
congenitalalopecia,naildystrophy;
neuraltube
defect
FOXN1haploinsufficiency
FOXN1
AD
600838
Severe
Tcelllymphopenia
atbirth,norm
alised
byadulthood
Normal/lo
wNot
assessed
Recurrent,viralandbacterialrespiratory
tractinfections;skininvolvem
ent
(eczem
a,derm
atitis),naild
ystrophy
Chrom
osom
e10p13-p14deletio
nsyndrome(10p13-p14DS)
Del10p13-p14
AD
601362
Normal,rarelylymphopenia
anddecreased
lymphoproliferationto
mito
gens
andantig
ens;
hypoplastic
thym
usmay
bepresent
Normal
Normal
Hypoparathyroidism;renaldisease;
deafness;g
rowth
retardation;
facial
dysm
orphism;cardiac
defectsmay
bepresent;recurrentinfections
±
Chrom
osom
e11qdeletio
nsyndrome
(Jacobsensyndrome)
11q23del
AD
147791
Lymphopenia;low
NKcells
Decreased
Bcells
and
switchedmem
ory
Bcells
Hypogam
maglobulinem
ia,
decreasedantib
ody
responses
Recurrent
respiratoryinfections;m
ultip
lewarts;faciald
ysmorphism,growth
retardation
4.Im
mun
o-osseou
sdy
splasias
Cartilagehairhypoplasia(CHH)
RMRP
AR
157660
Variesfrom
severely
decreased(SCID
)to
norm
al;impaired
lymphocyteproliferation
Normal
Normalor
reduced,
antib
odiesvariably
decreased
Short-lim
beddw
arfism
with
metaphyseal
dysostosis;sparsehair;b
onemarrow
failure;autoimmunity
;susceptibilityto
lymphom
aandothercancers;impaired
spermatogenesis;n
euronald
ysplasia
oftheintestine
Schimke
immuno-osseousdysplasia
SMARCAL1
AR
606622
Decreased
Normal
Normal
Shortstature,spondiloepiphyseal
dysplasia,intrauterine
grow
thretardation;
nephropathy;
bacterial,
viral,fungalinfections;m
aypresentas
SCID
;bonemarrowfailu
reMYSM
1deficiency
MYS
M1
AR
612176
Tcelllymphopenia,reduced
naïveTcells,low
NK
cells
Bcelldeficiency
Hypogam
maglobulin
emia
Shortstature;recurrent
infections;
congenitalb
onemarrowfailure,
myelodysplasia;im
munodeficiency
affectingBcells
andgranulocytes;
skeletalanom
alies;cataracts;
developm
entald
elay
J Clin Immunol (2020) 40:24–6434
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
MOPD
1deficiency
(Roifm
ansyndrome)
RNU4A
TAC
AR
601428
Decreased
NKcellfunctio
nDecreased
totaland
mem
oryBcells
Hypogam
maglobulinem
ia,
variably
decreased
specificantib
odies
Recurrent
bacterialinfections;
lymphadenopathy;
spondyloepiphysealdysplasia,
extrem
eintrauterine
grow
thretardation;
retin
aldystrophy;
facial
dysm
orphism;m
aypresentw
ithmicrocephaly;
shortstature
Immunoskeletald
ysplasiawith
neurodevelopmentalabnormalities
(EXTL3deficiency)
EXTL
3AR
617425
Decreased
Normal
Decreased
tonorm
alSh
ortstature;cervicalspinalstenosis,
neurodevelopmentalimpairment;
eosinophilia;may
have
earlyinfant
mortality
5.Hyp
erIgEsynd
romes
(HIE
S)AD-H
IESST
AT3deficiency
(Job
syndrome)
STAT
3ADLOF
(dom
i-nant
nega-
tive)
147060
Normaloverall;Th17,T
follicularhelper,M
AIT,
NKTcells
decreased,
Tregs
may
beincreased;
impaired
responsesto
STAT3-activ
atng
cytokines
Normal,reduced
mem
oryBcells,
BAFF
expression
increased,
impaired
responses
to STAT3-activ
ating
cytokines
Veryhigh
IgE,specific
antib
odyproductio
ndecreased
Distinctivefacialfeatures
(broad
nasal
bridge);bacterialinfectio
ns(boils,
pulm
onaryabscesses,pneumatoceles)
dueto
S.aureus,pulmonary
aspergillus,P
neum
ocystis
jirovecii;
eczema,mucocutaneous
candidiasis;
hyperextensiblejoints,osteoporosis
andbone
fractures,scoliosis,retained
prim
aryteeth;
coronary
andcerebral
aneurysm
s
IL6receptor
deficiency
IL6R
AR
147880
Normal/increased;
norm
alresponsesto
mito
gens
Normaltotaland
mem
oryB;
reducedsw
itched
mem
oryB
Normal/lo
wserum
IgM,G
,A.V
eryhigh
IgE;
specificantibody
productio
nlow
Recurrent
pyogenicinfections,cold
abscesses;high
circulatingIL-6
levels
IL6signaltransducer
(IL6S
T)deficiency
IL6ST
AR
618523
Decreased
Th17cells
Reduced
switched
andnon-sw
itched
mem
oryBcells
HighIgE,specificantibody
productio
nvariably
affected
Bacterialinfections,boils,eczem
a,pulm
onaryabscesses,pneumatoceles;
bone
fractures;scoliosis;retentionof
prim
aryteeth;
craniosynostosis
ZNF3
41deficiency
AR-H
IES
ZNF341
AR
618282
Decreased
Th17andNK
cells
Normal,reduced
mem
oryBcells,
impaired
responses
to STAT3-activ
aitng
cytokines
HighIgEandIgG,specific
antib
odyproductio
ndecreased
Phenocopyof
AD-H
IES;
mild
facial
dysm
orphism;early
onseteczem
a,MCC,bacterialskin
infections,
abscesses,recurrentb
acterial
respiratoryinfections
(S.aureus),lung
abscessesandpneumatoceles;
hyperextensiblejoints;b
onefractures
andretentionof
prim
aryteeth
ERBIN
deficiency
ERBB2IP
AD
606944
IncreasedcirculatingTreg
Normal
ModeratelyincreasedIgE
Recurrent
respiratoryinfections,
susceptibility
toS.
aureus,eczem
a;hyperextensiblejoints,scolio
sis;
arterialdilatatio
nin
somepatients
J Clin Immunol (2020) 40:24–64 35
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Loeys-D
ietzsyndrome(TGFB
Rdeficiency)
TGFBR1
AD
609192
Normal
Normal
ElevatedIgE
Recurrent
respiratoryinfectons;eczema,
food
allergies;hyper-extensiblejoints,
scoliosis,retentionof
prim
aryteeths;
aorticaneurism
s.
TGFBR2
610168
Com
el-N
etherton
syndrome
SPINK5
AR
605010
Normal
Low
switchedand
non-sw
itchedB
cells
HighIgEandIgA,
Antibodyvariably
decreased
Congenitalichthyosis,bamboohair,
atopicdiathesis;increasedbacterial
infections;failureto
thrive
PGM3deficiency
PGM3
AR
172100
CD8andCD4Tcells
may
bedecreased
Low
Bandmem
ory
Bcells
Normalorelevated
IgGand
IgA,m
ostw
ithhigh
IgE,
eosinophilia
Severe
atopy;
autoim
munity;b
acterial
andviralinfections;skeletal
anom
alies/dysplasia:shortstature,
brachydactyly,dysm
orphicfacial
features;intellectuald
isability
and
cognitive
impairment,delayedCNS
myelin
ationin
someaffected
individuals
CARD11
deficiency
(heterozygous)
CARD11
AD
LOF
(dom
i-nant
nega-
tive)
617638
Normaloverall,but
defectiveTcellactiv
ation
andproliferation;
skew
ingtowardTh2
Normalto
low
HighIgE,poorspecific
antib
odyproductio
n;im
paired
activ
ationof
both
NF-κB
and
mTORC1pathways
Variableatopy,eczema,food
allergies,
eosinophilia;cutaneousviral
infections,recurrent
respiratory
infections;lym
phom
a;CID
6.Defectsof
vitamin
B12
andfolate
metab
olism
Transcobalamin
2deficiency
TCN2
AR
613441
Normal
Variable
Decreased
Megaloblasticanem
ia,pancytopenia;if
untreated(B12)forprolongedperiods
results
inintellectuald
isability
SLC46A1/PC
FTdeficiency
causing
hereditary
folatemalabsorptio
nSL
C46A1
AR
229050
Variablenumbersand
activationprofile
Variable
Decreased
Megaloblasticanem
ia,failuretothrive;if
untreatedforprolongedperiodsresults
inintellectuald
isability
Methylene-tetrahydrofolatedehydrogenase
1(M
THFD
1)deficiency
MTH
FD1
AR
172460
Low
thym
icoutput,normal
invitroproliferation
Low
Decreased/poorantib
ody
responsesto
conjugated
polysaccharide
antig
ens
Recurrent
bacterialinfection,
Pneum
ocystis
jirovecii;
megaloblastic
anem
ia;failureto
thrive;n
eutropenia;
seizures,intellectuald
isability;
folate-responsive
7.Anh
idroticectoderm
odysplasia
withim
mun
odeficiency(EDA-ID)
EDA-IDdueto
NEMO/IKBKGdeficiency
(ectodermaldysplasia,im
mune
deficiency)
IKBKG
XL
300248
Normalor
decreased,TCR
activationim
paired
Normal;L
owmem
oryand
isotypesw
itchedB
cells
Decreased,som
ewith
elevated
IgA,IgM
,poor
specificantibody
responses,absent
antib
odiesto
polysaccharide
antig
ens
Anhidrotic
ectoderm
aldysplasia(in
some);v
arious
infections
(bacteria,
mycobacteria,viruses,fungi);colitis;
conicalteeth,variabledefectsof
skin,
hairandteeth;
monocytedysfunction
EDA-IDdueto
IKBAGOFmutation
NFKBIA
ADGOF
164008
NormaltotalT
cells,T
CR
activationim
paired
NormalBcell
numbers,impaired
BCRactiv
ation,
lowmem
oryand
Decreased
IgGandIgA,
elevated
IgM,poor
specificantibody
responses,absent
Anhidrotic
ectoderm
aldysplasia;various
infections
(bacteria,mycobacteria,
viruses,fungi);colitis;variabledefects
J Clin Immunol (2020) 40:24–6436
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
isotypesw
itchedB
cells
antib
odyto
polysaccharide
antig
ens
ofskin,hairandteeth;
Tcelland
monocytedysfunction
EDA-IDdueto
IKBKBGOFmutation
IKBKB
ADGOF
618204
Decreased
Tcells,impaired
TCRactiv
ation
Normalnumber,poor
functio
nReduced
Recurrent
bacterial,viral,fungal
infections;v
ariableectoderm
aldefects
8.Calcium
chan
neld
efects
ORAI-1deficiency
ORAI1
AR
610277
Normal,defectiv
eTCR
mediatedactivation
Normal
Normal
Autoimmunity;E
DA;n
on-progressive
myopathy
STIM
1deficiency
STIM
1AR
605921
9.Other
defects
Purine
nucleoside
phosphorylase(PNP)
deficiency
PNP
AR
164050
Progressivedecrease
Normal
Normalor
low
Autoimmunehemolyticanem
ia;
neurologicalim
pairment
Immunodeficiencywith
multip
leintestinal
atresias
TTC7A
AR
609332
Variable,butsom
etim
esabsent
orlowTRECsat
NBS;
may
have
SCID
phenotypeatbirth
Normalor
low
MarkedlydecreasedIgG,
IgM,IgA
Bacterial(sepsis),fungal,viralinfectio
ns;
multip
leintestinalatresias,often
with
intrauterine
polyhydram
nios
andearly
demise
Tricho-Hepato-EntericSy
ndrome(THES)
TTC37
AR
222470
Impaired
IFNγproductio
nVariablylownumbers
ofsw
itched
mem
oryBcells
Hypogam
maglobulinem
ia,
may
have
lowantibody
responses
Respiratory
infections;IUGR;facial
dysm
orphicfeatures,w
oolyhair;early
onsetintractablediarrhea,liver
cirrhosis;plateletabnorm
alities
SKIV2L
614602
Hepaticveno-occlusive
diseasewith
immunodeficiency(V
ODI)
SP110
AR
604457
Normal(decreased
mem
ory
Tcells)
Normal(decreased
mem
oryBcells)
Decreased
IgG,IgA
,IgM
,absent
germ
inalcenter
andtissueplasmacells
Hepaticveno-occlusive
disease;
susceptibilitytoPneum
ocystis
jirovecii
pneumonia,C
MV,candida;
thrombocytopenia;
hepatosplenomegaly;
cerebrospinal
leukodystrophy
BCL11Bdeficiency
BCL11B
AD
617237
Low
,poorproliferation
Normal
Normal
Congenitalabnormalities,neonatalteeth,
dysm
orphicfacies;absentcorpus
callosum,neurocognitive
deficits
EPG
5deficiency
(Vicisyndrom
e)EPG5
AR
615068
Profound
depletionof
CD4+
cells
Defectiv
eDecreased
(particularly
IgG2)
Agenesisof
thecorpus
callo
sum;
cataracts;cardiomyopathy;
skin
hypopigm
entation;
intellectual
disability;
microcephaly;
recurrent
infections,chronicmucocutaneous
candidiasis
HOIL1deficiency
RBCK1
AR
610924
Normalnumbers
Normal,decreased
mem
oryBcells
Poor
antib
odyresponsesto
polysaccharides
Bacterialinfections;autoinflammation;
amylopectinosis
HOIP
deficiency
RNF31
AR
612487
Normalnumbers
Normal,decreased
mem
oryBcells
decreased
Bacterialinfections;autoinflammation;
amylopectinosis;lym
phangiectasia
Hennekam-lym
phangiectasia-lymphedem
asyndrome
CCBE1
AR
612753
Low
/variable
Low
/variable
decreased
Lymphangiectasiaandlymphedem
awith
facialabnorm
alities
andother
dysm
orphicfeatures
FAT4
AR
612411
Low
/variable
Low
/variable
decreased
J Clin Immunol (2020) 40:24–64 37
Tab
le2
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
IgAssociatedfeatures
Lymphangiectasiaandlymphedem
awith
facialabnorm
alities
andother
dysm
orphicfeatures
Activatingde
novo
mutations
innuclear
factor,erythroid
2-lik
e(N
FE2L
2)NFE2L
2AD
617744
Not
reported
Decreased
switched
mem
oryBcells
Hypogam
maglobulin
emia,
decreasedantibody
responses
Recurrentrespiratoryandskininfections;
grow
thretardation,developm
ental
delay;
whitemattercerebrallesions;
increasedlevelo
fhomocysteine;
increasedexpression
ofstressresponse
genes
STAT5b
deficiency
STAT
5BAR
245590
Modestly
decreased,
reducedTregnumberand
functio
n
Normal
hypergam
maglobulinem
ia,
increasedIgE
Growth-hormoneinsensitive
dwarfism
;dysm
orphicfeatures;eczem
a;lymphocyticinterstitialp
neum
onitis;
prom
inentautoimmunity
STAT5b
deficiency
STAT
5BAD (d
omi-
nant
nega-
tive)
604260
Normal
Normal
IncreasedIgE
Growth-failure;eczem
a(noim
mune
defectscomparedto
ARST
AT5
deficiency)
Kabukisyndrom
e(type1and2)
KMT2
DAD
602113
Normal
Normal
Low
IgAandoccasionally
lowIgG
Typicalfacialabnormalities,cleftor
high
arched
palate,skeletalabnormalities,
shortstature;intellectuald
isability;
congenitalh
eartdefects;recurrent
infections
(otitismedia,pneum
onia)in
50%
ofpatients;autoim
munity
may
bepresent
KDM6A
XL (fem
ales
may
beaffected)
300128
KMT2A
deficiency
(Wiedemann-Steiner
syndrome)
KMT2
AAD
605130
Normal
Decreased
switched
andnon-sw
itched
mem
oryBcells
Hypogam
maglobulin
emia,
decreasedantibody
responses
Respiratory
infections;shortstature;
hypertelorism;h
airy
elbows;
developm
entald
elay,intellectual
disability
Totaln
umberof
disordersin
Table2:
58
Totaln
umberof
mutantg
enes
inTable2:
62
New
inborn
errorsof
immunity
:13;LIG1[60];F
OXN1haploinsufficiency
[61];IL6
R[23,24];IL6ST[21,22];ZN
F341[19,20];ERBB2IP[62];T
GFBR1[63];T
GFBR2[63];A
DLOFCARD11
[25,26];
ADGOFIKBKB[33];S
KIV2L
[64];N
FE2L
2[65];S
TAT5B
ADDN[27]
Unknowncauseof
DiGeorgesyndrome,unknow
ncauseof
CHARGEsyndrome,unknow
ngene(s)with
in10p13–14
deletio
nresponsibleforphenotype
EDAectoderm
aldysplasiaanhydrotic,H
SVherpes
simplex
virus,VZV
varicella
zostervirus,BCGBacillus
Calmette-G
uerin,NBSnewborn
screen,TRECTcellreceptor
excision
circle(biomarkerfor
low
Tcells
used
inNBS),IUGRinteruterine
grow
thretardation
J Clin Immunol (2020) 40:24–6438
Table3
Predom
inantly
antib
odydeficiencies
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
1.Severe
redu
ctionin
allserum
immun
oglobu
linisotyp
eswithprofou
ndly
decreasedor
absent
Bcells,agammaglobu
linem
iaBTKdeficiency,X
-linked
agam
maglobulin
emia(X
LA)
BTK
XL
300300
Allisotypes
decreasedin
majority
ofpatients,somepatientshave
detectable
immunoglobulins
Severe
bacterialinfections,normal
numbersof
pro-Bcells
μheavychaindeficiency
IGHM
AR
147020
Allisotypes
decreased
Severe
bacterialinfections,normal
numbersof
pro-Bcells
λ5deficiency
IGLL
1AR
146770
Igαdeficiency
CD79A
AR
112205
Igβdeficiency
CD79B
AR
147245
BLNKdeficiency
BLN
KAR
604515
p110δdeficiency
PIK3C
DAR
602839
Severe
bacterialinfections;autoimmune
complications
(IBD)
p85deficiency
PIK3R
1AR
615214
Severe
bacterialinfections,cytopenias,
decreasedor
absent
pro-Bcells
E47
transcriptionfactor
deficiency
TCF3
AD
616941
Recurrent
bacterialinfectio
nsTC
F3
AR
147141
Severe,recurrent
bacterialinfections,
failu
reto
thrive
SLC39A7(ZIP7)
deficiency
SLC39A7
AR
601416
Early
onsetinfectio
ns,blistering
derm
atosis,failureto
thrive,
thrombocytopenia
Hoffm
ansyndrome/TOP2
Bdeficiency
TOP2B
AD
126431
Recurrent
infections,faciald
ysmorphism,
limbanom
alies
2.Severe
redu
ctionin
atleast2serum
immun
oglobu
linisotyp
eswithno
rmal
orlownu
mberof
Bcells,C
VID
phenotyp
eCom
mon
variableim
munedeficiency
with
nogene
defectspecified(CVID
)Unknown
Variable
Low
IgGandIgAand/or
IgM
Clin
icalphenotypes
vary:m
osth
ave
recurrentinfections,som
ehave
polyclonal
lymphoproliferation,autoim
mune
cytopenias
and/or
granulom
atousdisease
Activated
p110δsyndrome(A
PDS)
PIK3C
DGOF
AD
615513
(APD
S1)
Normal/in
creasedIgM,
reducedIgGandIgA
Severe
bacterialinfections;reduced
mem
ory
Bcells
andincreasedtransitio
nalB
cells,
EBV±CMVviremia,lym
phadenopathy/
splenomegaly,autoim
munity,
lymphoproliferation,lymphom
aPIK3R
1AD
616005
(APD
S2)
Severe
bacterialinfections,reduced
mem
ory
Bcells
andincreasedtransitio
nalB
cells,
lymphadenopathy/splenom
egaly,
lymphoproliferation,lymphom
a;developm
ental
delay
PTENdeficiency
(LOF)
PTE
NAD
158350
Normal/Decreased
Recurrent
infections,L
ymphoproliferation,
Autoimmunity
;developmentald
elay
CD19
deficiency
CD19
AR
107265
Low
IgGandIgAand/or
IgM
Recurrent
infections,m
ayhave
glom
erulonephritis(CD81
mutation
abolishesexpression
ofCD19,
therebyphenocopying
CD19
mutations)
CD81
deficiency
CD81
AR
186845
Low
IgG,low
ornorm
alIgAandIgM
CD20
deficiency
CD20
AR
112210
Low
IgG,normalor
elevated
IgM
andIgA
Recurrent
infections
CD21
deficiency
CD21
AR
120650
Low
IgG,impaired
anti-pneumococcal
response
Recurrent
infections
TACIdeficiency
#TN
FRSF
13B
ARor
AD
604907
Low
IgGandIgAand/or
IgM
Variableclinicalexpression
andpenetrance
formonoallelic
variants
J Clin Immunol (2020) 40:24–64 39
Tab
le3
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
BAFF
receptor
deficiency
TNFRSF
13C
AR
606269
Low
IgGandIgM,
Variableclinicalexpression
TWEAKdeficiency
TNFSF
12AD
602695
Low
IgM
andA,lackof
anti-pneumococcalantibody
Pneumonia,bacterialinfections,w
arts,
thrombocytopenia.Neutropenia
TRNT1deficiency
TRNT1
AR
612907
Bcelldeficiency
and
hypogammaglobulin
emia
Congenitalsideroblasticanem
ia,deafness,
developm
entald
elay
NFK
B1deficiency
NFKB1
AD
164011
Normalor
lowIgG,IgA
,IgM
,low
ornorm
alBcells,low
mem
oryBcells
Recurrent
sinopulm
onaryinfections,
COPD
,EBVproliferation,autoim
mune
cytopenias,alopeciaandautoim
munethyroiditis
NFK
B2deficiency
NFKB2
AD
615577
Low
serum
IgG,A
andM;low
Bcell
numbers
Recurrent
sinopulm
onaryinfections,
alopeciaandendocrinopathies
IKAROSdeficiency
IKZF
1AD (h
aploinsufficienc-
y)
603023
Low
IgG,IgA
,IgM
,low
ornorm
alBcells;B
cells
andIg
levelsreduce
with
age
Decreased
pro-Bcells,recurrent
sinopulm
onary
infections;increased
risk
ofALL,
autoim
munity,C
VID
phenotype
IRF2
BP2
deficiency
IRF2B
P2
AD
615332
Hypogam
maglobulinem
ia,absentIgA
Recurrent
infections,possibleautoim
munity
andinflam
matorydisease
ATP6
AP1
deficiency
ATP6A
P1
XL
300972
Variableim
munoglobulin
findings
Hepatopathy,leukopenia,lowcopper
ARHGEF1
deficiency
ARHGEF1
AR
618459
Hypogam
maglobulinem
ia;lackof
antibody
Recurrent
infections,bronchiectasis
SH3K
BP1
(CIN
85)deficiency
SH3K
BP1
XL
300310
IgM,IgG
deficiency;lossof
antibody
Severe
bacterialinfections
SEC61A1deficiency
SEC61A1
AD
609213
Hypogam
maglobulinem
iaSevere
recurrentrespiratory
tractinfections
RAC2deficiency
RAC2
AR
602049
Low
IgG,IgA
,IgM
,low
ornorm
alBcells;reduced
Abresponses
follo
wingvaccination
Recurrent
sinopulm
onaryinfections,
selectiveIgAdeficiency;p
oststreptococcal
glom
erulonephritis;urticaria
Mannosyl-oligosaccharideglucosidase
deficiency
MOGS
AR
601336
Low
IgG,IgA
,IgM
,increased
Bcells;
poor
Abresponsesfollo
wingvaccination
Bacterialandviralinfections;severe
neurologicdisease;also
know
nas
congenitald
isorderof
glycosylation
type
IIb(CDG-IIb)
3.Severe
redu
ctionin
serum
IgG
andIgAwithno
rmal/elevatedIgM
andno
rmal
numbers
ofBcells,h
yper
IgM
AID
deficiency
AICDA
AR
6055258
IgGandIgAdecreased,IgM
increased;
norm
almem
oryBcells
butlacking
somatichyperm
utation
Bacterialinfections,enlargedlymph
nodes
andgerm
inalcenters;autoim
munity
AD
605257
IgGabsent
ordecreased,IgAundetected,
IgM
increased;
norm
almem
ory
Bcells
with
intactsomatichyperm
utation
Bacterialinfections,enlargedlymph
nodes
andgerm
inalcenters.Mutations
uniquely
localizeto
thenuclearexportsignal.
UNGdeficiency
UNG
AR
191525
IgGandIgAdecreased,IgM
increased
Enlargedlymph
nodesandgerm
inalcenters
INO80
deficiency
INO80
AR
610169
IgGandIgAdecreased,IgM
increased
Severe
bacterialinfections
MSH
6deficiency
MSH
6AR
600678
VariableIgG,defects,increased
IgM
insome,norm
alBcells,low
switched
mem
oryBcells,Igclasssw
itch
recombinatio
nandsomatic
hyperm
utationdefects
Family
orpersonalhistoryof
cancer
4.Isotyp
e,light
chain,
orfunction
aldeficiencies
withgenerally
norm
alnu
mbers
ofBcells
Igheavychainmutations
anddeletions
Mutationor
chromosom
aldeletio
nat14q32
AR
One
ormoreIgGand/or
IgAsubclasses
aswellasIgEmay
beabsent
May
beasym
ptom
atic
Kappa
chaindeficiency
IGKC
AR
147200
Allim
munoglobulin
shave
lambdalig
htchain
Asymptom
atic
Isolated
IgGsubclass
deficiency
Unknown
?Reductionin
oneor
moreIgGsubclass
J Clin Immunol (2020) 40:24–6440
Tab
le3
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
IgAssociatedfeatures
Usually
asym
ptom
atic,a
minority
may
have
poor
antib
odyresponse
tospecificantigens
andrecurrentv
iral/bacterialinfections
IgGsubclass
deficiency
with
IgAdeficiency
Unknown
?Reduced
IgAwith
decrease
inoneor
moreIgGsubclass
Recurrent
bacterialinfectio
ns
May
beasym
ptom
atic
SelectiveIgAdeficiency
Unknown
?AbsentIgA
with
otherisotypes
norm
al,
norm
alsubclasses
andspecificantib
odies
May
beasym
ptom
aticBacterialinfections,
autoim
munity
mild
lyincreased
Specificantib
odydeficiency
with
norm
alIg
levelsandnorm
alBcells
Unknown
?Normal
Reduced
ability
toproduceantib
odiesto
specificantig
ens
Transient
hypogammaglobulinem
iaof
infancy
Unknown
?IgGandIgAdecreased
Normalability
toproduceantibodiesto
vaccineantigens,usually
notassociated
with
significantinfectio
nsCARD11
GOF
CARD11
ADGOF
616452
PolyclonalBcelllymphocytosisdue
toconstitutiveNF-κB
activ
ation
Splenomegaly,lymphadenopathy,poor
vaccineresponse
SelectiveIgM
deficiency
Unknown
?Absentserum
IgM
Pneumococcal/b
acterial
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
ODI(Table2),thymom
awith
immunodeficiency(G
oodsyndrome),orm
yelodysplasiaare
firstseenby
anim
munologistb
ecause
ofrecurrentinfectio
ns,hypogam
maglobulin
emia,and
norm
alor
reducednumbersof
Bcells
Totaln
umberof
disordersin
Table3:
46
Totaln
umberof
mutantg
enes
inTable3:
39
New
disorders:9:
ARPIK3C
D[35,36,66];A
RTC
F3[31,32];SL
C39A7[67];T
OP2B
[68];A
RHGEF1[69];S
H3K
BP1[70];S
EC61A1[71];A
RLO
FRAC2[41];A
DAICDA
EBVEpstein-Barrvirus,COPDchronicobstructivepulm
onarydisease
#Heterozygousvariantsin
TNFRSF
13Bhave
been
detected
inhealthyindividuals,thus
such
variantsarelik
elyto
bedisease-modifying
rather
than
disease-causing
J Clin Immunol (2020) 40:24–64 41
Table4
Diseasesof
immunedysregulation
Disease
Genetic
defect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gB
cells
Functio
nald
efect
Associatedfeatures
1.Fam
ilial
hemop
hagocyticlymph
ohistiocytosis(FHLsynd
romes)
Perforin
deficiency
(FHL2)
PRF1
AR
170280
Increasedactiv
ated
Tcells
Normal
Decreased
toabsent
NKandCTL
activ
ities
cytotoxicity
Fever,HSM
,hem
ophagocytic
lymphohistio
cytosis
(HLH),cytopenias
UNC13D/M
unc13–4
deficiency
(FHL3)
UNC13D
AR
608897
Increasedactiv
ated
Tcells
Normal
Decreased
toabsent
NKandCTL
activ
ities
(cytotoxicity
and/or
degranulation)
Fever,HSM
,HLH,cytopenias,
Syntaxin11
deficiency
(FHL4)
STX11
AR
605014
STXBP2
/Munc18–2
deficiency
(FHL5)
STXBP2
ARor
AD
601717
FAAP2
4deficiency
FAAP24
AR
610884
Increasedactiv
ated
Tcells
Normal
Failu
reto
killautologous
EBV
transformed
Bcells.N
ormalNKcell
functio
n
EBV-drivenlymphoproliferativedisease
SLC7A
7deficiency
SLC7A
7AR
222700
Normal
Normal
Hyper-inflammatoryresponse
ofmacrophages
NormalNKcellfunctio
n
Lysinuricproteinintolerance,bleeding
tendency,
alveolarproteinosis
2.FHLsynd
romes
withhy
popigm
entation
Chediak-H
igashi
syndrome
LYST
AR
606897
Increasedactiv
ated
Tcells
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Partialalbinism,recurrent
infections,fever,H
SM,
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-Pu
dlak
syndrome,type
2AP3B
1AR
603401
Normal
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Partialalbinism,recurrent
infections,pulmonary
fibrosis,increased
bleeding,neutropenia,H
LH
Hermansky-Pu
dlak
syndrome,type
10AP3D
1AR
617050
Normal
Normal
Decreased
NKandCTLactiv
ities
(cytotoxicity
and/or
degranulation)
Oculocutaneousalbinism
,severeneutropenia,
recurrentinfectio
ns,seizures,hearingloss
and
neurodevelopmentald
elay
3.RegulatoryTcelldefects
IPEX,immune
dysregulation,
polyendocrinopathy,
enteropathyX-linked
FOXP3
XL
300292
Normal
Normal
Lackof
(and/orim
paired
functio
nof)
CD4+
CD25
+FO
XP3
+regulatory
Tcells
(Tregs)
Autoimmuneenteropathy,earlyonsetd
iabetes,
thyroiditis
hemolyticanem
ia,throm
bocytopenia,
eczema,elevated
IgEandIgA
CD25
deficiency
IL2R
AAR
147730
Normalto
decreased
Normal
NoCD4+C25+cells
with
impaired
functio
nof
Tregs
cells
Lymphoproliferation,autoim
munity,impaired
Tcell
proliferationin
vitro
CD122deficiency
IL2R
BAR
618495
Increasedmem
oryCD8Tcells,
decreasedTregs
Increased
mem
oryB
cells
Dim
inishedIL2R
βexpression,
dysregulated
signalingin
response
toIL-2/IL-15;
increasedim
matureNK
cells
Lymphoproliferation,lymphadenopathy,
hepatosplenomegaly,autoim
munehemolytic
anem
ia,dermatitis,enteropathy,
hypergam
maglobulin
emia,recurrent
viral(EBV,
CMV)infections
CTLA4
haploinsufficiency
(ALPS
-V)
CTL
A4
AD
123890
Decreased
Decreased
Impaired
functio
nof
Tregs.
Autoimmunecytopenias,enteropathy,interstitial
lung
disease,extra-lymphoidlymphocytic
infiltration,recurrentinfectio
ns
J Clin Immunol (2020) 40:24–6442
Tab
le4
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gB
cells
Functio
nald
efect
Associatedfeatures
LRBAdeficiency
LRBA
AR
606453
Normalor
decreasedCD4
numbersTcelldysregulation
Low
ornorm
alnumbersof
Bcells
Reduced
IgGandIgAin
most
Recurrent
infections,inflammatoryboweldisease,
autoim
munity
DEF6
deficiency
DEF6
AR
610094
Mild
CD4andCD8
lymphopenia
Low
ornorm
alnumbersof
Bcells
Impaired
Tregfunctio
nEnteropathy,hepatosplenom
egaly,cardiomyopathy,
recurrentinfectio
ns
STAT3GOFmutation
STAT
3ADGOF
102582
Decreased
Decreased
EnhancedST
AT3signaling,leadingto
increasedTh17celldifferentiatio
n,lymphoproliferationand
autoim
munity.D
ecreased
Tregs
and
impaired
functio
n
Lymphoproliferation,solid
organautoim
munity,
recurrentinfectio
ns
BACH2deficiency
BACH2
AD
605394
ProgressiveTcelllymphopenia
Impaired
mem
oryB
cell
developm
ent
Haploinsufficiencyforacriticallineage
specificationtranscriptionfactor
Lymphocyticcolitis,sinopulmonaryinfections
FERMT1deficiency
FERMT1
AR
173650
Normal
Normal
Intracellularaccumulationof
IgG,IgM
,IgA,and
C3in
colloid
bodies
under
thebasementm
embrane
Dermatosischaracterizedby
congenitalb
listering,
skin
atrophy,photosensitivity,skinfragility,and
scaling
4.Autoimmun
itywithor
witho
utlymph
oproliferation
APE
CED(A
PS-1),
autoim
mune
polyendocrinopathy
with
candidiasisand
ectoderm
aldystrophy
AIRE
ARor
AD
240300
Normal
Normal
AIREserves
ascheck-pointinthe
thym
usfornegativ
eselectionof
autoreactiv
eTcells
andforg
eneration
ofTregs
Autoimmunity
:hypoparathyroidism,
hypothyroidism
,adrenalinsufficiency,diabetes,
gonadald
ysfunctionandotherendocrine
abnorm
alities;dentalenamelhypoplasia,alopecia
areataenteropathy,pernicious
anem
ia;chronic
mucocutaneous
candidiasis
ITCHdeficiency
ITCH
AR
606409
Not
assessed
Not
assessed
Itch
deficiency
may
causeim
mune
dysregulationby
affectingboth
anergy
inductionin
auto-reactive
effector
Tcells
andgeneratio
nof
Tregs
Early-onsetchroniclung
disease(interstitial
pneumonitis),autoimmunity
(thyroiditis,type
Idiabetes,chronicdiarrhea/enteropathy,and
hepatitis),failu
reto
thrive,developmentald
elay,
dysm
orphicfacialfeatures
Tripeptidyl-peptid
aseII
deficiency
TPP2
AR
190470
Decreased
Decreased
TPP
2deficiency
results
inprem
ature
immunosenescenceandim
mune
dysregulation
Variablelymphoproliferation,severe
autoim
mune
cytopenias,hypergammaglobulin
emia,recurrent
infections
JAK1GOF
JAK1
ADGOF
147795
Not
assessed
Not
assessed
Hyperactiv
eJA
K1
HSM
,eosinophilia,eosinophilic
enteritis,thyroid
disease,poor
grow
th,viralinfections
Prolidasedeficiency
PEPD
AR
613230
Normal
Normal
PeptidaseD
Autoantibodiescommon,chronicskin
ulcers,
eczema,infections
5.Im
mun
edy
sregulationwithcolitis
IL-10deficiency
IL10
AR
124092
Normal
Normal
Nofunctio
nalIL-10secretion
Inflam
matoryboweldisease(IBD),folliculitis,
recurrentrespiratory
diseases,arthritis,
IL-10R
deficiency
IL10RA
AR
146933
Normal
Normal
Leukocytesunresponsive
toIL-10
IBD,folliculitis,recurrentrespiratory
diseases,
arthritis,lym
phom
a
J Clin Immunol (2020) 40:24–64 43
Tab
le4
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gB
cells
Functio
nald
efect
Associatedfeatures
IL10RB
AR
123889
Normal
Normal
Leukocytesunresponsive
toIL-10,and
IL-22,IL-26,IL-28A
,IL-28B
and
IL-29
NFA
T5
haploinsufficiency
NFA
T5AD
604708
Normal
Normal
Decreased
mem
oryBcells
and
plasmablasts
IBD,recurrent
sinopulm
onaryinfections
TGFB
1deficiency
TGFB1
AR
618213
Normal
Normal
Decreased
Tcellproliferationin
response
toanti-CD3
IBD,immunodeficiency,recurrentv
iralinfections,
microcephaly,andencephalopathy
RIPK1
RIPK1
AR
618108
Reduced
Normal/reduced
Reduced
activ
ationof
MAPK
,NFk
Bpathways
Recurrent
infections,early-onsetIBD,progressive
polyarthritis
6.Autoimmun
elymph
oproliferativesynd
rome(A
LPS,
Can
ale-Sm
ithsynd
rome)
ALPS
-FAS
TNFRSF
6AD
AR
134637
IncreasedTCRα/β+
CD4−CD8−
doublenegativ
e(D
N)Tcells
Normal,low
mem
oryB
cells
ApoptosisdefectFA
Smediated
Splenomegaly,adenopathies,autoimmune
cytopenias,increased
lymphom
arisk,IgG
andA
norm
alor
increased,elevated
serum
FasL,IL-10,
vitamin
B12
ALPS
-FASL
GTN
FSF
6AR
134638
IncreasedDNTcells
Normal
ApoptosisdefectFA
SLmediated
Splenomegaly,adenopathies,autoimmune
cytopenias,S
LE,solubleFasL
isnotelevated
ALPS
-Caspase10
CASP
10AD
601762
IncreasedDNTcells
Normal
Defectiv
elymphocyteapoptosis
Adenopathies,splenomegaly,autoim
munity
ALPS
-Caspase
8CASP
8AR
601763
Slightly
increasedDNTcells
Normal
Defectiv
elymphocyteapoptosisand
activ
ation
Adenopathies,splenomegaly,bacterialand
viral
infections,hypogam
maglobulinem
iaFA
DDdeficiency
FADD
AR
602457
IncreasedDNTcells
Normal
Defectiv
elymphocyteapoptosis
Functio
nalh
yposplenism,bacterialandviral
infections,recurrent
episodes
ofencephalopathy
andliver
dysfunction
7.Su
sceptibilityto
EBVan
dlymph
oproliferativecond
itions
SAPdeficiency
(XLP1
)SH
2D1A
XL
300490
Normalor
Increasedactiv
ated
Tcells
Reduced
Mem
oryB
cells
Reduced
NKcellandCTLcytotoxic
activ
ityClin
icalandim
munologicfeatures
triggeredby
EBVinfection:
HLH,L
ymphoproliferation,
Aplastic
anem
ia,L
ymphom
a.Hypogam
maglobulin
emia,A
bsentiNKTcells
XIA
Pdeficiency
(XLP2
)XIAP
XL
300079
Normalor
Increasedactiv
ated
Tcells;low
/normaliNKT
cells
Normalor
reduced
Mem
oryB
cells
IncreasedTcells
susceptib
ility
toapoptosisto
CD95
andenhanced
activ
ation-inducedcelldeath(A
ICD)
EBVinfection,Sp
lenomegaly,lymphoproliferation
HLH,C
olitis,IBD,hepatitis
Low
iNKTcells
CD27
deficiency
CD27
AR
615122
Normal
Nomem
oryB
cells
hypogammaglobulin
emia;p
oorAb
responsestosomevaccines/in
fections
Features
triggeredby
EBVinfection,HLH,aplastic
anem
ia,low
iNKTcells,B
-lym
phom
aCD70
deficiency
CD70
AR
602840
Normalnumber,lowTreg,poor
activ
ationandfunctio
nDecreased
mem
oryB
cells
hypogammaglobulin
emia;p
oorAb
responsestosomevaccines/in
fections
EBVsusceptib
ility,H
odgkin
lymphom
a;autoim
munity
insomepatients
CTPS
1deficiency
CTP
S1AR
615897
Normalto
low,but
reduced
activ
ation,proliferation
Decreased
mem
oryB
cells
Normal/highIgGpoor
proliferationto
antig
enRecurrent/chronicbacterialand
viralinfectio
ns(EBV,V
ZV),EBVlymphoproliferation,Bcell
non-Hodgkin
lymphom
aCD137deficiency
(41B
B)
TNFRSF
9AR
602250
Normal
Normal
Low
IgG,low
IgA,poorresponsesto
Tcell-dependentand
Tcellindependent
EBVlymphoproliferation,Bcelllymphom
a,chronicactiv
eEBVinfection
J Clin Immunol (2020) 40:24–6444
Tab
le4
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Circulatin
gTcells
Circulatin
gB
cells
Functio
nald
efect
Associatedfeatures
antig
ens,decreasedTcell
proliferation,
IFNγsecretion,
cytotoxicity
RASG
RP1
deficiency
RASG
RP1
AR
603962
Poor
activation,proliferation,
motility.R
educed
naïveT
cells
Poor
activ
ation,
proliferation,
motility
NormalIgM,IgG
,increased
IgA
Recurrent
pneumonia,herpesvirus
infections,E
BV
associated
lymphom
aDecreased
NKcellfunctio
nRLT
PRdeficiency
CARMIL2
AR
610859
Normalnumber,high
CD4,
increasednaïveCD4+
and
CD8+
Tcells,low
Tregand
MAIT,poorCD28-induced
functio
n
NormalBcell
numbers,
reduced
mem
oryB
cells
Normalto
low,poorTdependent
antib
odyresponse
Recurrent
bacterial,fungalandmycobacterial
infections,viralwarts,m
olluscum
andEBV
lymphoproliferativeandothermalignancy,atopy
X-linkedmagnesium
EBVandneoplasia
(XMEN)
MAGT1
XL
300853
Low
CD4Low
recent
thym
icem
igrant
cels,inverted
CD4/CD8ratio
,reduced
MAIT
cells,poor
proliferationto
CD3
Normalbut
decreased
mem
oryB
cells
Progressivehypogammaglobulin
emia
Reduced
NKcellandCTLcytotoxic
activ
ityduetoim
paired
expression
ofNKG2D
EBVinfection,lymphom
a,viralinfections,
respiratoryandGIinfections
Glycosylatio
ndefects
PRKCDdeficiency
PRKCD
AR
615559
Normal
Low
mem
oryB
cells,high
CD5Bcells
Apoptoticdefectin
Bcells
Recurrent
infections,E
BVchronicinfection,
lymphoproliferation,SL
E-likeautoim
munity
(nephroticandantip
hospholip
idsyndromes),low
IgG
Totaln
umberof
disordersin
Table4:
44
Totaln
umberof
mutantg
enes
inTable4:
45
New
disorders:7;
SLC7A
7[72];IL2
RB[73,74];DEF6[48];F
ERMT1
[75];T
GFB1[76];R
IPK1[77,78];TN
FRSF
9[66,79,80]
FHLfamilialhemophagocytic
lymphohistio
cytosis,HLH
hemophagocytic
lymphohistio
cytosis,HSM
hepatosplenomegaly,DNdouble-negative,SL
Esystem
iclupuserythematous,IBD
Inflam
matory
boweldisease
J Clin Immunol (2020) 40:24–64 45
Table5
Congenitald
efectsof
phagocytenumberor
functio
n
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
1.Con
genitaln
eutrop
enias
Elastasedeficiency
(Severecongential
neutropenia[SCN]1)
ELA
NE
AD
130130
NMyeloid
differentiatio
nSu
sceptib
ility
toMDS/leukem
iaSeverecongenitaln
eutropeniaor
cyclic
neutropenia
GFI
1deficiency
(SCN2)
GFI1
AD
600871
NMyeloid
differentiatio
nB/T
lymphopenia
HAX1deficiency
(Kostm
ann
Disease)(SCN3)
HAX1
AR
605998
NMyeloid
differentiatio
nCognitiv
eandneurologicaldefectsin
patientswith
defectsin
both
HAX1
isoforms,susceptib
ility
toMDS/leukem
iaG6P
C3deficiency
(SCN4)
G6P
C3
AR
611045
NMyeloid
differentiatio
n,chem
otaxis,O
2−production
Structuralheartd
efects,urogenital
abnorm
alities,innereardeafness,and
venous
angiectasias
oftrunks
andlim
bsVPS
45deficiency
(SCN5)
VPS45
AR
610035
NMyeloid
differentiatio
n,migratio
nExtramedullary
hematopoiesis,bone
marrowfibrosis,nephrom
egaly
Glycogenstoragediseasetype
1bG6P
T1AR
602671
N+M
Myeloid
differentiatio
n,chem
otaxis,O
2−production
Fastinghypoglycem
ia,lactic
acidosis,
hyperlipidem
ia,hepatom
egaly
X-linkedneutropenia/myelodysplasia
WAS
XLGOF
300299
NDifferentiatio
n,mito
sis.
Resultsfrom
GOFmutations
inGTPase
bindingdomainof
WASp
Neutropenia,m
yeloid
maturationarrest,
monocytopenia,variablelymphoid
anom
alies
P14/LAMTOR2deficiency
LAMTO
R2
AR
610389
N+M
Endosom
albiogenesis
Neutropenia
Hypogam
maglobulin
emia↓C
D8
cytotoxicity,partialalbinism,
grow
thfailu
reBarth
Syndrome(3-M
ethylglutaconic
aciduriatype
II)
TAZ
XL
300394
N+L
Mel
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,developmentald
elay,
facialdysm
orphisms,poikilo
derm
aJA
GN1deficiency
JAGN1
AR
616012
NMyeloid
differentiatio
nMyeloid
maturationarrest,osteopenia
3-Methylglutaconicaciduria
CLP
BAR
616254
NMyeloid
differentiatio
nMito
chondrialp
rotein
Neurocognitive
developm
ental
aberratio
ns,m
icrocephaly,
hypoglycem
ia,hypotonia,ataxia,
seizures,cataracts,IUGR
G-CSF
receptor
deficiency
CSF
3RAR
138971
NStress
granulopoiesisdisturbed
SMARCD2deficiency
SMARCD2
AR
601736
NChrom
atin
remodeling,Myeloid
differentiatio
nandneutrophil
functio
nald
efect
Neutropenia,developmental
aberratio
ns,bones,hem
atopoietic
stem
cells,m
yelodysplasia
Specificgranuledeficiency
CEBPE
AR
189965
NTerm
inalmaturationand
globaldysfunction
Neutropenia,N
eutrophilswith
bilobednuclei
Shwachm
an-D
iamondSy
ndrome
SBDS
AR
607444
NNeutrophilm
aturation,chem
otaxis,
ribosomalbiogenesis
Pancytopenia,exocrinepancreatic
insufficiency,chondrodysplasia
DNAJC
21AR
617052
N+HSC
Pancytopenia,exocrinepancreatic
insufficiency
EFL1
AR
617941
N+HSC
HYOU1deficiency
HYO
U1
AR
601746
NUnfoldedproteinresponse
Hypoglycemia,inflammatory
complications
SRP5
4deficiency
SRP54
AD
604857
NProteintranslocationto
ER,
myeloid
differentiationand
neutrophilfunctio
nald
efect
Neutropenia,exocrinepancreaticinsufficiency
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
J Clin Immunol (2020) 40:24–6446
Tab
le5
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
Leukocyteadhesion
deficiency
type
2(LAD2)
SLC35C1
AR
605881
N+M
Rolling,chem
otaxis
Mild
LADtype
1features
with
hh-blood
group,grow
thretardation,
developm
entald
elay
Leukocyteadhesion
deficiency
type
3(LAD3)
FERMT3
AR
607901
N+M
+L+NK
Adherence,chemotaxis
LADtype
1plus
bleeding
tendency
Rac2deficiency
RAC2
ADLOF
608203
NAdherence,chemotaxis
O2−productio
nPo
orwound
healing,leukocytosis
βactin
deficiency
ACTB
AD
102630
N+M
Motility
Mentalretardatio
n,shortstature
Localized
juvenileperiodontitis
FPR1
AR
136537
NFo
rmylpeptideinducedchem
otaxis
Periodontitisonly
Papillo
n-Lefèvre
syndrome
CTS
CAR
602365
N+M
Chemotaxis
Periodontitis,palmoplantar
hyperkeratosisin
somepatients
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
Neutropeniawith
combined
immunedeficiency
dueto
MKL1deficiency
MKL1
AR
606078
N+M
+L+NK
Impaired
expression
ofcytoskeletalgenes
Mild
thrombocytopenia
3.Defectsof
respiratorybu
rst
X-linkedchronicgranulom
atous
disease(CGD),gp91phox
CYB
BXL
306400
N+M
Killing(faulty
O2−productio
n)Infections,autoinflammatory
phenotype,IBD
McL
eodphenotypein
patientswith
deletions
extendinginto
the
contiguous
Kelllocus
Autosom
alrecessiveCGD
CYB
AAR
608508
Infections,autoinflammatoryphenotype
CYB
C1
618334
NCF1
608512
NCF2
608515
NCF4
613960
G6P
Ddeficiency
classI
G6P
DXL
305900
NReduced
O2−
productio
nInfections
4.Other
non-lymph
oiddefects
GATA
2deficiency
GAT
A2
AD
137295
Monocytes
+peripheralDC
Multilineage
cytopenias
Susceptib
ility
tomycobacteria,HPV
,histoplasm
osis,alveolarproteinosis,
MDS/AML/CMML,lym
phedem
aPu
lmonaryalveolarproteinosis
CSF
2RA
XL(Biallelic
mutations
inpseudo-autosom
algene)
300770
Alveolar
macrophages
GM-CSF
signaling
Alveolarproteinosis
CSF
R2B
AR
614370
Totaln
umberof
disordersin
Table5:
34
Totaln
umberof
mutantg
enes
inTable5:
41
New
disorders:3;
SRP54
[81,82];DNAJC
21[83];C
YBC1[84,85]
Rem
oved:C
yclic
neutropeniawas
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
J Clin Immunol (2020) 40:24–64 47
Table6
Defectsin
intrinsicandinnateim
munity
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
1.Mendelia
nsusceptibilityto
mycob
acterial
disease(M
SMD)
IL-12andIL-23receptor
β1chaindeficiency
IL12RB1
AR
601604
L+NK
IFN-γ
secretion
Susceptibility
tomycobacteria
andSalmonella
IL-12p40
(IL-12andIL-23)
deficiency
IL12B
AR
161561
MIL-12R
β2deficiency
IL12RB2
AR
601642
L+NK
IL-23R
deficiency
IL23R
AR
607562
L+NK
IFN-γ
receptor
1deficiency
IFNGR1
AR
209950
M+L
IFN-γ
bindingandsignaling
AD
615978
M+L
IFN-γ
receptor
2deficiency
IFNGR2
AR
147569
M+L
IFN-γ
signaling
STAT1deficiency
STAT
1ADLOF
614892
M+L
Macrophagegp91
phox
deficiency
CYB
BXL
300645
Macrophageonly
Killing(faulty
O2−productio
n)Isolated
susceptib
ility
tomycobacteria
IRF8
deficiency
IRF8
AD
614893
M+L
Impaired
developm
ento
fcD
Csand
Th1*cells
Susceptibility
tomycobacteria
AR
226990
MLackof
circulatingmonocytes
and
DCs,reducedNKcellnumbers
andfunctio
nreported
insomepatients
Susceptibility
tomycobacteriaand
multip
leotherinfectious
agents
includingEBV
SPPL
2adeficiency
SPPL2
AAR
608238
M+L
Impaired
developm
ento
fcD
Cs
andTh1*cells
Susceptibility
tomycobacteriaandSalmonella
Tyk2
deficiency
TYK2
AR
611521
M+L
Impaired
cellu
larresponsesto
IL-10,IL-12,IL-23,andtype
IIFNs
Susceptibility
tointracellularbacteria
(mycobacteria,Salmonella),andviruses
P1104A
TYK2homozygosity
TYK2
AR
176941
LIm
paired
cellu
larresponsesto
IL-23
MSM
Dor
tuberculosis
ISG15
deficiency
ISG15
AR
147571
IFNγproductio
ndefect
Susceptibility
tomycobacteria(BCG),
braincalcification
RORγtd
eficiency
RORC
AR
602943
L+NK
Lackof
functio
nalR
ORγTprotein,
IFNγproductio
ndefect,com
plete
absenceof
IL-17A
/F-producing
Tcells
Susceptibility
tomycobacteriaandcandida
JAK1deficiency
JAK1
ARLOF
147795
N+L
Reduced
JAK1activ
ationto
cytokines,
Reduced
IFNγproductio
nSusceptibility
tomycobacteriaand
viruses,urothelialcarcinoma
2.Epiderm
odysplasia
verruciformis(H
PV)
EVER1deficiency
TMC6
AR
605828
Keratinocytes
EVER1,EVER2andCIB1form
acomplex
inkeratin
ocytes
Hum
anpapillo
mavirus
(HPV
)(group
B1)
infections
andcancer
oftheskin
(typicalEV)
EVER2deficiency
TMC8
605829
CIB1deficiency
CIB1
618267
WHIM
(warts,hypogam
maglobulin
emia,
infections,m
yelokathexis)syndrome
CXCR4
ADGOF
162643
Leukocytes
Increasedresponse
oftheCXCR4
chem
okinereceptor
toits
ligand
CXCL12
(SDF-1)
Warts(H
PV)infection,neutropenia,
lowBcellnumber,
hypogammaglobulinem
ia3.Predispo
sition
tosevere
viralinfection
STAT1deficiency
STAT
1ARLOF
600555
Leukocytesandothercells
STAT1-dependent
IFN-α/β,γ
andλresponses
Severeviralinfectio
ns,
mycobacterialinfection
STAT2deficiency
STAT
2AR
600556
Leukocytesandothercells
STAT2-dependent
IFN-α/β
andλresponse
Severeviralinfectio
ns(disseminated
vaccine-strain
measles)
IRF9
deficiency
IRF9
AR
147574*
Leukocytesandothercells
IRF9
-andISGF3
-dependent
IFN-α/β
andλresponses
Severeinfluenzadisease
IRF7
deficiency
IRF7
AR
605047
Leukocytes,plasmacytoid
dendritic
cells,
non-hematopoieticcells
IFN-α,β
andγproductio
nandIFN-λ
productio
n
IFNAR1deficiency
IFNAR1
AR
107450*
Leukocytesandothercells
IFNAR1-dependent
responsesto
IFN-α/β
Severediseasecaused
byYellowFever
vaccineandMeasles
vaccine
IFNAR2deficiency
IFNAR2
AR
602376
Broadly
expressed
IFNAR2-dependent
responsesto
IFN-α/β
Severeviralinfectio
ns(disseminated
vaccine-strain
measles,H
HV6)
J Clin Immunol (2020) 40:24–6448
Tab
le6
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
CD16
deficiency
FCGR3A
AR
146740
NKcells
AlteredNKcells
functio
nSevereherpes
viralinfectio
ns,particularly
VZV,E
pstein-Barrvirus(EBV),
and(H
PV)
MDA5deficiency
IFIH
1ARLOF
606951
Broadly
expressed
Viralrecognition
andIFN
induction
RhinovirusandotherRNAviruses
RNApolymeraseIIIdeficiency
POLR
3AAD
614258
Leukocytesandothercells
Impaired
viralrecognitio
nand
IFNinductionin
response
toVZVor
poly
I:C
SevereVZVinfection
POLR
3CAD
617454
POLR
3FAD
617455
4.Herpessimplex
enceph
alitis(H
SE)
TLR3deficiency
TLR3
AD
613002
Centralnervoussystem
(CNS)
resident
cells
andfibroblasts
TLR3-dependentIFN
-α,
βandγresponse
Herpessimplex
virus1encephalitis
(incom
pleteclinicalpenetrance
for
alletio
logies
listedhere);severe
pulm
onaryinfluenza;VZV
AR
UNC93B1deficiency
UNC93B1
AR
608204
UNC-93B
-dependent
IFN-α,
βandγresponse
Herpessimplex
virus1encephalitis
TRAF3
deficiency
TRAF3
AD
601896
TRAF3
-dependent
IFN-α,
βandγresponse
TRIF
deficiency
TICAM1
AD
607601
TRIF-dependent
IFN-α,
βandγresponse
AR
TBK1deficiency
TBK1
AD
604834
TBK1-dependent
IFN-α,β
andγresponse
IRF3
deficiency
IRF3
AD
616532
Low
IFN-α/β
productio
nin
response
toHSV
1and
decreasedIRF3
phosphorylation
DBR1deficiency
DBR1
AR
607024
Impaired
productio
nof
anti-viralIFN
sHSE
ofthebrainstem.O
ther
viral
infections
ofthebrainstem.
5.Predispo
sition
toinvasive
fung
aldiseases
CARD9deficiency
CARD9
AR
607212
Mononuclear
phagocytes
CARD9signalingpathway
Invasive
candidiasisinfection,deep
derm
atophytoses,otherinvasive
fungalinfections
6.Predispo
sition
tomucocutan
eous
cand
idiasis
IL-17R
Adeficiency
IL17RA
AR
605461
Epithelialcells,fibroblasts,
mononuclear
phagocytes
IL-17R
Asignalingpathway
CMC,folliculitis
IL-17R
Cdeficiency
IL17RC
AR
610925
IL-17R
Csignalingpathway
CMC
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,auto-im
munity
(thyroiditis,diabetes,cytopenias),
enteropathy
ACT1deficiency
TRAF3IP2
AR
607043
Tcells,fibroblasts
Fibroblastsfailto
respondto
IL-17A
andIL-17F,and
theirTcells
toIL-17E
CMC,blepharitis,folliculitis,and
macroglossia
7.TLRsign
alingpa
thway
deficiency
withba
cterialsusceptibility
IRAK4deficiency
IRAK4
AR
606883
Lymphocytes
+granulocytes+monocytes
TIR-IRAK4signalingpathway
Bacterialinfections
(pyogens)
MyD
88deficiency
MYD
88AR
602170
Lymphocytes
+granulocytes
+monocytes
TIR-M
yD88
signalingpathway
J Clin Immunol (2020) 40:24–64 49
Tab
le6
(contin
ued)
Disease
Geneticdefect
Inheritance
OMIM
Affectedcells
Affectedfunctio
nAssociatedfeatures
IRAK1deficiency
IRAK1
XL
300283
Lymphocytes
+granulocytes
+monocytes
TIR-IRAK1signalingpathway
Bacterialinfections,X
-linkedMECP2
deficiency-related
syndromedue
toalargede
novo
Xq28chromosom
aldeletionencompassingboth
MECP2
andIRAK1
TIRAPdeficiency
TIRAP
AR
614382
Lymphocytes
+granulocytes
+monocytes
TIRAP-
signalingpathway,
TLR1/2,TLR2/6,
andTLR4
agonistswereim
paired
inthe
fibroblastsandleukocytes
Staphylococcald
isease
during
child
hood
8.Other
inbo
rnerrors
ofim
mun
ityrelatedto
non
-hem
atop
oietictissues
Isolated
congenitalasplenia(ICA)
RPSA
AD
271400
Nospleen
RPS
Aencodesribosomalprotein
SA,a
component
ofthesm
all
subunito
ftheribosome
Bacteremia(encapsulatedbacteria)
HMOX
AR
141250
Macrophages
HO-1
regulatesiron
recycling
andheme-dependentd
amageoccurs
Hem
olysis,nephritis,inflam
mation
Trypanosomiasis
APOL1
AD
603743
Somatic
Poreform
ingserum
protein
Trypanosomiasis
Acuteliv
erfailu
redueto
NBASdeficiency
NBAS
AR
608025
Somaticandhematopoietic
ERstress
Fever
inducesliv
erfailu
reAcutenecrotizingencephalopathy
Osteopetrosis
RANBP2
AR
601181
Ubiquito
usexpression
Nuclear
pore
Fever
inducesacuteencephalopathy
CLC
N7
AR
602727
Osteoclasts
Secretorylysosomes
Osteopetrosiswith
hypocalcem
ia,
neurologicfeatures
SNX10
AR
614780
Osteopetrosiswith
visualim
pairment
OST
M1
AR
607649
Osteopetrosiswith
hypocalcem
ia,
neurologicfeatures
PLE
KHM1
AR
611466
Osteopetrosis
TCIRG1
AR
604592
Osteopetrosiswith
hypocalcem
iaTN
FRSF
11A
AR
603499
Osteoclastogenesis
Osteopetrosis
TNFSF
11AR
602642
Stromal
Osteoclastogenesis
Osteopetrosiswith
severegrow
thretardation
Hidradenitis
suppurativa
NCST
NAD
605254
Epiderm
isNotch
signaling/gamma-secretase
inhairfollicleregulateskeratin
ization
Verneuil’s
disease/Hidradenitis
suppurativawith
acne
PSE
NAD
613737
Verneuil’s
disease/Hidradenitis
suppurativewith
cutaneous
hyperpigmentatio
nPSE
NEN
AD
613736
Verneuil’s
disease/Hidradenitis
suppurativa
9.Other
inbo
rnerrors
ofim
mun
ityrelatedto
leuko
cytes
IRF4
haploinsufficiency
IRF4
AD
601900
L+M
IRF4
isapleiotropictranscription
factor
Whipple’sdisease
IL-18B
Pdeficiency
IL18BP
AR
604113
Leukocytesandothercells
IL-18B
Pneutralizes
secreted
IL-18
Fulminantv
iralhepatitis
Totaln
umberof
disordersin
Table6:
53
Totaln
umberof
mutantg
enes
inTable6:
64
New
genes:13,IL1
2RB2[51];IL2
3R[51];SPPL2
A[52];T
YK2P1104Aallele[10];C
IB1[86];IRF9[46];IFNAR1[87];P
OLR
3A[88];P
OLR
3C[88];P
OLR
3F[89];D
BR1[90];IRF4[91];IL1
8BP[47]
NF-κBnuclearfactor
kappaB,TIRTo
llandInterleukin1receptor,IFNinterferon,TL
RTo
ll-lik
ereceptor,MDC
myeloid
dendritic
cell,
CNScentralnervoussystem
,CMCchronicmucocutaneous
candidiasis,HPVhuman
papillo
mavirus,V
ZVvaricella
zoster
virus,EBV,Epstein-Barrvirus
J Clin Immunol (2020) 40:24–6450
Table7
Autoinflammatorydisorders
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
Functio
nald
efect
Associatedfeatures
1.Typ
e1interferon
opathies
STIN
G-associatedvasculopathy,
infantile-onset(SAVI)
TMEM173
AR
612374
Not
assessed
Not
assessed
STIN
Gactiv
ates
both
the
NF-kappa-BandIRF3
transcriptionpathwaystoinduce
expression
ofIFN
Skin
vasculopathy,inflammatorylung
disease,system
icautoinflam
mation
andICC,F
CL
ADA2deficiency
ADA2
AR
607575
Not
assessed
Not
assessed
ADAsdeactivateextracellular
adenosineandterm
inate
signalingthroughadenosine
receptors
Polyarteritis
nodosa,childhood-onset,
early-onsetrecurrent
ischem
icstroke
andfever;somepatientsdevelop
hypogammaglobulin
emia
TREX1deficiency,
Aicardi-G
outieressyndrome1
(AGS1
)
TREX1
AR
606609
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alss
DNAspecies
leadingto
increasedtype
IIFN
productio
n
ClassicalAGS,
SLE,F
CL
RNASE
H2B
deficiency,A
GS2
RNASE
H2B
AR
610326
Not
assessed
Not
assessed
Intracellularaccumulationof
abnorm
alRNA-D
NAhybrid
speciesleadingtoincreasedtype
IIFNproductio
n
ClassicalAGS,
SPRNASE
H2C
deficiency,A
GS3
RNASE
H2C
AR
610330
Not
assessed
Not
assessed
ClassicalAGS
RNASE
H2A
deficiency,A
GS4
RNASE
H2A
AR
606034
Not
assessed
Not
assessed
ClassicalAGS
SAMHD1deficiency,A
GS5
SAMHD1
AR
606754
Not
assessed
Not
assessed
ControlsdN
TPs
inthecytosol,
failu
reof
which
leadsto
increasedtype
IIFNproduction
ClassicalAGS,
FCL
ADAR1deficiency,A
GS6
ADAR1
AR
146920
Not
assessed
Not
assessed
Catalyzes
thedeam
inationof
adenosineto
inosinein
dsRNA
substrates,failureof
which
leads
toincreasedtype
IIFN
productio
n
ClassicalAGS,
BSN
,SP
Aicardi-G
outieressyndrome7
(AGS7
)IFIH
1ADGOF
615846
Not
assessed
Not
assessed
IFIH
1gene
encodesacytoplasmic
viralR
NAreceptorthatactiv
ates
type
Iinterferon
signaling
throughtheMAVSadaptor
molecule
ClassicalAGS,
SLE,S
P,SM
S
DNAse
IIdeficiency
DNASE
2AR
126350
Not
assessed
Not
assessed
DNAse
IIdegrades
andelim
inates
DNA.L
ossof
DNaseIIactiv
ityinducestype
Iinterferon
signaling
AGS
Pediatricsystem
iclupus
erythematosus
dueto
DNASE
1L3deficiency
DNASE
1L3
AR
614420
DNASE
1L3isan
endonuclease
thatdegrades
extracellular
DNA.DNASE
1L3deficiency
decreasesclearanceof
apoptotic
cells
VeryearlyonsetS
LE,reduced
complem
entlevels,autoantibodies
(dsD
NA,A
NCA),lupusnephritis,
hypocomplem
entemicurticarial
vasculitissyndrome
Spondyloenchondro-dysplasia
with
immunedysregulation
(SPE
NCD)
ACP5
AR
171640
Not
assessed
Not
assessed
Upregulationof
IFNthrough
mechanism
possibly
relatin
gto
pDCS
Shortstature,S
P,ICC,S
LE,
thrombocytopeniaandautoim
mune
hemolyticanem
ia,possiblyrecurrent
bacterialand
viralinfectio
nsX-linkedreticulatepigm
entary
disorder
POLA
1XL
301220
Not
assessed
Not
assessed
POLA1isrequired
forsynthesisof
cytosolic
RNA:DNAandits
deficiency
leadsto
increase
productio
nof
type
Iinterferon
Hyperpigm
entation,characteristicfacies,
lung
andGIinvolvem
ent
J Clin Immunol (2020) 40:24–64 51
Tab
le7
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
Functio
nald
efect
Associatedfeatures
USP
18deficiency
USP
18AR
607057
Not
assessed
Not
assessed
Defectiv
enegativ
eregulatio
nof
ISG15
leadingto
increasedIFN
TORCH-likesyndrome
OAS1
deficiency
OAS1
ADGOF
164350
Low
Increasedinterferon
from
recognition
ofRNA
Pulm
onaryalveolar
proteinosis,
skin
rash
2.Defectsaffectingtheinflam
masom
eFamilialMediterraneanfever
MEFV
ARLOF
249100
Mature
granulocytes,
cytokine--
activ
ated
monocytes.
Increasedinflam
masom
e-mediated
inductionof
IL1β
.Recurrent
fever,serositis
andinflam
mationresponsive
tocolchicine.P
redisposes
tovasculitisandinflam
matory
boweldisease.
AD
134610
Mature
granulocytes,
cytokine--
activ
ated
monocytes.
Usually
M694delvariant.
Mevalonatekinase
deficiency
(Hyper
IgDsyndrome)
MVK
AR
260920
Somaticand
hemaotpoietic
affectingcholesterolsynthesis,
pathogenesisof
diseaseunclear
Periodicfeverandleukocytosis
with
high
IgDlevels
Muckle-Wellssyndrome
NLR
P3
ADGOF
191900
PMNsMonocytes
Defectincryopyrin,involved
inleukocyteapoptosisandNFk
BsignalingandIL-1
processing
Urticaria,S
NHL,amyloidosis.
Familialcold
autoinflam
matory
syndrome1
ADGOF
120100
PMNs,monocytes
Non-pruritic
urticaria,arthritis,
chills,feverandleukocytosis
aftercold
exposure.
Neonatalo
nsetmultisystem
inflam
matorydisease(N
OMID
)or
chronicinfantile
neurologic
cutaneousandarticular
syndrome(CIN
CA)
ADGOF
607115
PMNs,
chondrocytes
Neonatalo
nsetrash,chronic
meningitis,and
arthropathy
with
feverandinflam
mation.
Familialcold
autoinflam
matory
syndrome2
NLR
P12
ADGOF
611762
PMNs,monocytes
Non-pruritic
urticaria,arthritis,
chills,feverandleukocytosis
aftercold
exposure.
NLRC4-MAS(m
acrophage
activ
atingsyndrome)
NLR
C4
ADGOF
616050
PMNsmonocytes
macrophages
Gainof
functio
nmutationinNLR
C4
results
inelevated
secretionof
IL-1βandIL-18as
wellas
macrophageactivation
Severe
enterocolitisand
macrophageactiv
ationsyndrome
Familialcold
autoinflam
matory
syndrome4
616115
PLAID
(PLCγ2associated
antib
odydeficiency
andim
mune
dysregulation)
PLC
G2
ADGOF
614878
Bcells,N
K,M
ast
cells
Mutations
activateIL-1
pathways
Coldurticariahypogammaglobulinem
ia,
impaired
humoralim
munity,
autoinflam
mation
Familialcold
autoinflam
matory
syndrome3
orAPL
AID
(c2120A>C)
614468
NLRP1
deficiency
NLR
P1
AR
617388
leukocytes
System
icelevationof
IL-18and
caspase1,suggesting
involvem
ento
fNLRP1
inflam
masom
e
Dyskeratosis,autoim
munity
andarthritis
NLRP1
GOF
NLR
P1
ADGOF
615225
Keratinocytes
IncreasedIL1β
Palm
oplantar
carcinom
a,corneal
scarring;recurrent
respiratory
papillo
matosis
J Clin Immunol (2020) 40:24–6452
Tab
le7
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
Functio
nald
efect
Associatedfeatures
3.Non
-inflammasom
e-relatedcond
itions
TNFreceptor-associatedperiodic
syndrome(TRAPS
)TN
FRSF
1AAD
142680
PMNs,monocytes
Mutations
of55-kDTNFreceptor
leadingto
intracellularreceptor
retentionor
diminishedsoluble
cytokine
receptor
availableto
bind
TNF
Recurrent
fever,serositis,rash,
andocularor
jointinflammation
Pyogenicsterile
arthritis,
pyodermagangrenosum,acne
(PAPA
)syndrome,
hyperzincemiaand
hypercalprotectin
emia
PST
PIP1
AD
604416
Hem
atopoietic
tissues,
upregulatedin
activ
ated
Tcells
Disorderedactin
reorganizatio
nleadingto
comprom
ised
physiologicsignalingduring
inflam
matoryresponse
Destructiv
earthritis,inflammatory
skin
rash,m
yositis
Blausyndrome
NOD2
AD
186580
Monocytes
Mutations
innucleotidebindingsite
ofCARD15,possiblydisruptin
ginteractions
with
lipopolysaccharides
andNF-kB
signaling
Uveitis,granulom
atoussynovitis,
camptodactyly,rashandcranial
neuropathies,30%
develop
Crohn
colitis
ADAM17
deficiency
ADAM17
AR
614328
Leukocytesand
epithelialcells
Defectiv
eTNFα
production
Early
onsetd
iarrheaandskin
lesions
Chronicrecurrentm
ultifocal
osteom
yelitisandcongenital
dyserythropoietic
anem
ia(M
ajeedsyndrome)
LPIN2
AR
609628
Neutrophils,bone
marrowcells
Undefined
Chronicrecurrentm
ultifocal
osteom
yelitis,transfusion-dependent
anem
ia,cutaneous
inflam
matory
disorders
DIRA(D
eficiencyof
the
Interleukin1Receptor
Antagonist)
IL1R
NAR
612852
PMNs,Monocytes
Mutations
intheIL1receptor
antagonistallowunopposed
actio
nof
Interleukin1
Neonatalo
nsetof
sterile
multifocal
osteom
yelitis,periostitisandpustulosis.
DITRA(D
eficiencyof
IL-36
receptor
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
entatio
nhypertrichosis,
histiocytosis-lymphadenopathy
plus
syndrome
CAMPS
(CARD14
mediated
psoriasis)
CARD14
AD
602723
Mainlyin
keratinocytes
Mutations
inCARD14
activ
atethe
NF-kB
pathway
andproductio
nof
IL-8
Psoriasis
Cherubism
SH3B
P2
AD
118400
Stromacells,bone
cells
Hyperactived
macrophageand
increase
NF-kB
Bonedegeneratio
nin
jaws
CANDLE(chronicatypical
neutrophilicderm
atitiswith
lipodystrophy)
PSM
B8*
ARandAD
256040
Keratinocytes,B
celladipose
cells
Mutations
causeincreasedIFN
signalingthroughan
undefined
mechanism
Contractures,panniculitis,ICC,fevers
PSM
G2
AR
609702
Lymphocytes
Panniculitis,lipodystrophy,autoimmune
hemolyticanem
iaCOPA
defect
COPA
AD
6011924
PMNandtissue
specificcells
Defectiv
eintracellulartransportv
iathecoatproteincomplex
I(COPI)
Autoimmuneinflam
matoryarthritis
and
interstitiallungdiseasewith
Th17
dysregulationandautoantibodyproduction
Otulipenia/ORAS
OTU
LIN
AR
615712
Leukocytes
Increase
LUBACinductionof
NF-KBactiv
ationleadingto
high
proinflamatorycytokineslevels.
Fever,diarrhea,dermatitis
J Clin Immunol (2020) 40:24–64 53
Tab
le7
(contin
ued)
Disease
Genetic
defect
Inheritance
OMIM
Tcells
Bcells
Functio
nald
efect
Associatedfeatures
A20
deficiency
TNFA
IP3
AD
616744
Lymphocytes
Defectiv
einhibitionof
NF-KB
signalingpathway
Arthralgia,mucosalulcers,ocularinflam
mation
AP1
S3deficiency
AP1S3
AR
615781
Keratinocytes
Disrupted
TLR3translocation
Pustular
psoriasis
ALPI
deficiency
ALP
IAR
171740
Intestinalepith
elial
cells
Deficient
inhibitionof
LPS
inintestine
Inflam
matoryboweldisease
TRIM
22TR
IM22
AR
606559
Macrophages,
intestinal
epithelialcells
Granulomatouscolitis
Inflam
matoryboweldisease
Tcelllymphom
asubcutaneous
panniculitis-like(TIM
3deficiency)
HAV
CR2
AR
618398
Leukocytes
Increasedinflam
masom
eactivity
dueto
defectivecheckpoint
signaling
Panniculitis,HLH,polyclonalcutaneous
Tcellinfiltrates
orTcelllymphom
a
Totaln
umberof
disordersin
Table7:
45
Totaln
umberof
mutantg
enes
inTable7:
42
New
disorders:9;
DNASE
2[93];D
NASE
1L3[94–96];OAS1
[97];A
DMEFV;
NLR
P1GOF[98,99];ALP
I[100];TR
IM22
[101];PSM
G2[102];HAV
CR2[103,104]
IFNinterferon,H
SMhepatosplenomegaly,CSF
cerebrospinalfluid,SLE
system
iclupuserythematosus,TORCHtoxoplasmosis,other,rubella,cytom
egalovirus,and
herpes
infections,SNHLsensorineural
hearingloss,A
GSAicardi-G
outièressyndrome,BSN
bilateralstriatalnecrosis,F
CLfamilialchilb
lain
lupus,ICCintracranialcalcification,
IFNinterferon
type
I,pD
Csplasmacytoiddendritic
cells,S
Pspastic
paraparesis,SM
SSingleton-Mertensyndrome,ss
single-strandedDNA
*VariantsinPSM
B4,PSM
B9,PSM
A3,andPOMPhave
been
proposed
tocauseasimilarC
ANDLEphenotypeincompoundheterozygous
monogenic(PSM
B4),digenic(PSM
A3/PSM
B8,PSM
B9/PSM
B4,
PSM
B4/PSM
B8)
andADmonogenic(POMP)models[92]
J Clin Immunol (2020) 40:24–6454
Table8
Com
plem
entd
eficiencies
Disease
Geneticdefect
Inheritance
GeneOMIM
Laboratoryfeatures
Associatedfeatures
C1q
deficiency
dueto
defects
C1Q
AAR
120550
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ationof
theclassicalp
athw
ay,dim
inished
clearanceof
apoptotic
cells
SLE,infectio
nswith
encapsulated
organism
sC1Q
BAR
120570
C1Q
CAR
120575
C1r
deficiency
C1R
AR
613785
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ationof
theclassicalp
athw
aySLE,infectio
nswith
encapsulated
organism
s,Ehlers-Danlosphenotype
C1r
PeriodontalE
hlers-Danlos
C1R
ADGOF
613785
NormalCH50
Hyperpigm
entatio
n,skin
fragility
C1s
deficiency
C1S
AR
613785
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ationof
theclassicalp
athw
aySLE,infectio
nswith
encapsulated
organism
s,Ehlers-Danlosphenotype
C1s
PeriodontalEhlers-Danlos
C1S
ADGOF
613785
NormalCH50
Hyperpigm
entatio
n,skin
fragility
Com
pleteC4deficiency
C4A
+C4B
AR
120810
AbsentC
H50
hemolyticactiv
ity,defectiv
eactiv
ationof
theclassicalp
athw
ay,com
plete
deficiency
requires
biallelic
mutations/
deletio
ns/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
ationof
theclassicalp
athw
aySLE,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
ADGOF
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
ityC7deficiency
C7
AR
217070
C8α
deficiency
C8A
AR
120950
C8γdeficiency
C8G
AR
120930
C8βdeficiency
C8B
AR
120960
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
ation
pathway
Pyogenicinfections,inflammatory
lung
disease,autoim
munity
Ficolin
3deficiency
FCN3
AR
604973
Absence
ofcomplem
entactivationby
the
Ficolin
3pathway.
Respiratory
infections,abscesses
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
ADGOF
612924
Gain-of-functionmutationwith
increased
spontaneousAH50
Atypicalh
emolytic-uremicsyndrome
FactorBdeficiency
CFB
AR
615561
Deficient
activ
ationof
thealternativepathway
Infections
with
encapsulated
organism
s
J Clin Immunol (2020) 40:24–64 55
Tab
le8
(contin
ued)
Disease
Geneticdefect
Inheritance
GeneOMIM
Laboratoryfeatures
Associatedfeatures
FactorDdeficiency
CFD
AR
134350
AbsentA
H50
hemolyticactiv
ityNeisserialinfectio
ns
Properdindeficiency
CFP
XL
300383
AbsentA
H50
hemolyticactiv
ityNeisserialinfectio
ns
FactorIdeficiency
CFI
AR
217030
Spontaneous
activ
ationof
thealternative
complem
entp
athw
aywith
consum
ptionof
C3
Infections,disseminated
neisserialinfections,
atypicalHem
olytic-uremicsyndrome,
preeclam
psia
FactorHdeficiency
CFH
ARor
AD
134370
Spontaneousactiv
ationof
thealternativecomplem
ent
pathway
with
consum
ptionof
C3
FactorH-related
proteindeficiencies
CFHR1
ARor
AD
134371,
NormalCH50,A
H50,autoantibodiesto
Factor
H.,
linkeddeletio
nsof
oneor
moreCFHRgenes
leadsto
susceptib
ility
autoantib
ody-mediatedaH
US
Older
onsetatypicalh
emolytic-uremic
syndrome,dissem
inated
neisserialinfections
CFHR2
600889,
CFHR3
605336,
CFHR4
605337,
CFHR5
608593
Throm
bomodulin
deficiency
THBD
AD
188040
NormalCH50,A
H50
Atypicalh
emolytic-uremicsyndrome
Mem
braneCofactorProtein(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
(CHAPL
Edisease)
CD55
AR
125240
Hyperactiv
ationof
complem
ento
nendothelium
Proteinlosing
enteropathy,thrombosis
Totaln
umberof
disordersin
Table8:
30
Totaln
umberof
mutantg
enes
inTable8:
36
New
disorders:2;
C1S
ADGOF[105],C1R
ADGOF[105]
MACmem
braneattack
complex,SLE
system
iclupuserythematosus
J Clin Immunol (2020) 40:24–6456
Table9
Bonemarrowfailu
re
Disease
Genetic
defect
Inheritance
Gene
OMIM
Tcells
Bcells
Other
affected
cells
Associatedfeatures
Major
Category
Subcategory
Fanconianemiatype
AFA
NCA
AR
227650
Normalto
low
Normalto
low
HSC
Normalto
lowNK,C
NS,
skeletal,skin,cardiac,
GI,urogenitalanomalies,
increasedchromosom
albreakage
Bonemarrowfailu
rewith
immune
deficiency
Fanconi
Anemia
Fanconianemiatype
BFA
NCB
XLR
300514
Fanconianemiatype
CFA
NCC
AR
227645
Fanconianemiatype
D1
BRCA2
AR
605724
Fanconianemiatype
D2
FANCD2
AR
227646
Fanconianemiatype
EFA
NCE
AR
600901
Fanconianemiatype
FFA
NCF
AR
603467
Fanconianemiatype
GXRCC9
AR
614082
Fanconianemiatype
IFA
NCI
AR
609053
Fanconianemiatype
JBRIP1
AR
609054
Fanconianemiatype
LFA
NCL
AR
614083
Fanconianemiatype
MFA
NCM
AR
618096
Fanconianemiatype
NPA
LB2
AR
610832
Fanconianemiatype
ORAD51C
AR
613390
Fanconianemiatype
PSL
X4
AR
613951
Fanconianemiatype
QERCC4
AR
615272
Fanconianemiatype
RRAD51
AR
617244
Fanconianemiatype
SBRCA1
AR
617883
Fanconianemiatype
TUBE2T
AR
616435
Fanconianemiatype
UXRCC2
AR
617247
Fanconianemiatype
VMAD2L
2AR
617243
Fanconianemiatype
WRFWD3
AR
617784
MIRAGE(m
yelodysplasia,
infection,restrictionof
grow
th,adrenalhypoplasia,
genitalp
henotypes,
enteropathy)
SAMD9
ADGOF
617053
Not
reported
Not
reported
HSC
,myeloid
cells
Intrauterine
grow
thretardation,
gonadalabnormalities,
adrenalfailure,M
DSwith
chromosom
e7aberrations,
predispositionto
infections,
enteropathy,absent
spleen
Ataxiapancytopeniasyndrome
SAMD9L
ADGOF
611170
Normal
Low
HSC
,myeloid
cells
MDS,
neurologicalfeatures
DKCX1
DKC1
XL
305000
Normalto
low
Normalto
low
HSC
Bonemarrowfailu
re,pulmonary
andhepatic
fibrosis,nail
dystrophy,leukoplakia,
reticulateskin
pigm
entatio
n;microcephaly,
neurodevelopmental
delay
Dyskeratosis
Congenita
DKCA1
TERC
AD
127550
DKCA2
TERT
AD
187270
DKCA3
TINF2
AD
604319
DKCA4
RTE
L1AD
616373
DKCA5
TINF2
AD
268130
DKCA6
ACD
AD
616553
DKCB1
NOLA
3AR
224230
DKCB2
NOLA
2AR
613987
DKCB3
WRAP53
AR
613988
DKCB4
TERT
AR
613989
DKCB5
RTE
L1AR
615190
Low
Naild
ystrophy,leukoplakia,bone
marrowfailu
re,severeBcell
immunodeficiency,intrauterine
grow
thretardation,grow
th
J Clin Immunol (2020) 40:24–64 57
Tab
le9
(contin
ued)
Disease
Genetic
defect
Inheritance
Gene
OMIM
Tcells
Bcells
Other
affected
cells
Associatedfeatures
Major
Category
Subcategory
retardation,microcephaly,
cerebellarhypoplasia,and
esophagealdysfunction
DKCB6
PARN
AR
616353
Normalto
low
Developmentald
elay,m
icrocephaly,
andcerebellarhypoplasia
DKCB7
ACD
AR
616553
Normalto
low
Bonemarrowfailu
re,pulmonary
andhepatic
fibrosis,nail
dystrophy,
leukoplakia,reticulateskin
pigm
entatio
n;microcephaly,
neurodevelopmentald
elay
BMFS
1(SRP7
2-deficiency)
SRP72
AD
602122
NA
NA
Bonemarrowfailure
andcongenital
nervedeafness
BMFS
5TP
53AD
618165
NA
Low
BErythroid
hypoplasia,B
cell
deficiency
Coatsplus
syndrome
STN1
AR
613129
Normal
Normal
Intrauterine
grow
thretardation,
prem
atureaging,pancytopenia,
hypocellu
larbone
marrow,
gastrointestinalhemorrhage
duetovascularectasia,intracranial
calcification,abnorm
altelomeres
CTC
1AR
617053
Not
reported
Not
reported
Totaln
umberof
disordersin
Table9:
43
Totaln
umberof
mutantg
enes
inTable9:
43
HSC
hematopoieticstem
cell,
NKnaturalkiller,CNScentraln
ervous
system
,GIgastrointestinal,M
DSmyelodysplasticsyndrome,DKCXX-inked
dyskeratosiscongenital,DKCAautosomaldominant
dyskeratosiscongenita,D
KCBautosomalrecessivedyskeratosiscongenita,B
MFSbone
marrowfailu
resyndrome
J Clin Immunol (2020) 40:24–6458
Table10
Phenocopiesof
inborn
errorsof
immunity
Disease
Geneticdefect/presumed
pathogenesis
Circulatin
gTcells
Circulatin
gBcells
Serum
IgAssociatedfeatures/sim
ilarPID
Associatedwithsomaticmutations
Autoimmunelymphoproliferative
syndrome(A
LPS
–SFA
S)So
maticmutationin
TNFRSF
6IncreasedCD4−CD8−double
negative(D
N)αβTcells
Normal,but
increased
numberof
CD5+
Bcells
Normalor
increased
Splenomegaly,lymphadenopathy,
autoim
munecytopenias,D
efectiv
elymphocyteapoptosis/ALPS
–FAS
(=ALPS
type
Im)
RAS-associated
autoim
mune
leukoproliferativedisease(RALD)
Somaticmutationin
KRAS(G
OF)
Normal
Bcelllymphocytosis
Normalor
increased
Splenomegaly,lymphadenopathy,
autoim
munecytopenias,
granulocytosis,m
onocytosis/ALPS
-like
RAS-associated
autoim
mune
leukoproliferativedisease
(RALD)
Somaticmutationin
NRAS(G
OF)
IncreasedCD4−
CD8−
double
negative(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
Hypereosinophilicsyndromedue
tosomaticmutations
inST
AT5b
Somaticmutationin
STAT
5B(G
OF)
Normal
Normal
Normal
Eosinophilia,atopicderm
atitis,
urticarialrash,diarrhea
Associatedwithau
toan
tibo
dies
Chronicmucocutaneous
candidiasis
AutoA
bto
IL-17and/or
IL-22
Normal
Normal
Normal
Endocrinopathy,chronic
mucocutaneous
candidiasis/CMC
Adult-onsetimmunodeficiency
with
susceptibility
tomycobacteria
AutoA
bto
IFNγ
Decreased
naiveTcells
Normal
Normal
Mycobacterial,fungal,Salmonella
VZVinfections/M
SMD,orCID
Recurrent
skin
infection
AutoA
bto
IL-6
Normal
Normal
Normal
Staphylococcalinfections/STA
T3
deficiency
Pulmonaryalveolar
proteinosis
AutoA
bto
GM-CSF
Normal
Normal
Normal
Pulmonaryalveolar
proteinosis,
cryptococcalmeningitis,
dissem
inated
nocardiosis/CSF
2RA
deficiency
Acquiredangioedema
AutoA
bto
CIinhibitor
Normal
Normal
Normal
Angioedem
a/C1INHdeficiency
(hereditary
angioedema)
Atypicalh
emolyticurem
icsyndrome
AutoA
bto
Com
plem
ent
Factor
HNormal
Normal
Normal
aHUS=Sp
ontaneousactivationof
thealternativecomplem
entp
athw
ayThymom
awith
hypogammaglobulin
emia
(Goodsyndrome)
AutoA
bto
variouscytokines
IncreasedCD8+
Tcells
NoBcells
Decreased
Invasive
bacterial,viralo
ropportunistic
infections,autoimmunity,P
RCA,
lichenplanus,cytopenia,colitis,
chronicdiarrhea
aHUSatypicalhemolyticurem
icsyndrome,XLX-linkedinheritance,ARautosomalrecessiveinheritance,ADautosomaldominantinheritance,LO
Floss-of-functio
n,GOFgain-of-functio
n,PRCApure
redcellaplasia
Totaln
umberof
conditionsforTable10:1
2
J Clin Immunol (2020) 40:24–64 59
Acknowledgments The members of the Inborn Errors of Immunity com-mittee would like to thanks the International Union of ImmunologicalSocieties (IUIS) for funding, as well as CSL Behring, Baxalta andShire/Takeda for providing educational grants to enable us to compilethis classification update.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict ofinterest.
Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adap-tation, distribution and reproduction in any medium or format, as long asyou give appropriate credit to the original author(s) and the source, pro-vide a link to the Creative Commons licence, and indicate if changes weremade. The images or other third party material in this article are includedin the article's Creative Commons licence, unless indicated otherwise in acredit line to the material. If material is not included in the article'sCreative Commons licence and your intended use is not permitted bystatutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.
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Publisher’s Note Springer Nature remains neutral with regard to jurisdic-tional claims in published maps and institutional affiliations.
J Clin Immunol (2020) 40:24–64 63
Affiliations
Stuart G. Tangye1,2 &Waleed Al-Herz3 & Aziz Bousfiha4 & Talal Chatila5 & Charlotte Cunningham-Rundles6 &
Amos Etzioni7 & Jose Luis Franco8& Steven M. Holland9
& Christoph Klein10& Tomohiro Morio11
& Hans D. Ochs12 &
Eric Oksenhendler13 & Capucine Picard14,15& Jennifer Puck16 & Troy R. Torgerson12
& Jean-Laurent Casanova17,18,19,20 &
Kathleen E. Sullivan21
1 Garvan Institute of Medical Research, Darlinghurst,
Sydney, NSW 2010, Australia
2 Faculty of Medicine, St Vincent’s Clinical School, UNSW,
Sydney, NSW, Australia
3 Department of Pediatrics, Faculty of Medicine, Kuwait University,
Kuwait City, Kuwait
4 King Hassan II University, Laboratoire d’Immunologie Clinique,
d’Inflammation et d’Allergy LICIA at Faculty of Medicine and
Pharmacy, Clinical Immunology Unit, Pediatric Infectiouse Disease
Department, Children’s Hospital, Ibn Rochd University Hospital,
Casablanca, Morocco
5 Division of Immunology, Children’s Hospital Boston, Boston, MA,
USA
6 Departments of Medicine and Pediatrics, Mount Sinai School of
Medicine, New York, NY, USA
7 Ruth’s Children’s Hospital-Technion, Haifa, Israel
8 Grupo de Inmunodeficiencias Primarias, Facultad de Medicina,
Universidad de Antioquia UdeA, Medellin, Colombia
9 Laboratory of Clinical Immunology & Microbiology, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD, USA
10 Dr von Hauner Children’s Hospital, Ludwig-Maximilians-
University Munich, Munich, Germany
11 Department of Pediatrics and Developmental Biology, Tokyo
Medical and Dental University (TMDU), Tokyo, Japan
12 Department of Pediatrics, University of Washington and Seattle
Children’s Research Institute, Seattle, WA, USA
13 Department of Clinical Immunology, Hôpital Saint-Louis, APHP,
University Paris Diderot, Sorbonne Paris Cité, Paris, France
14 Study Center for Primary Immunodeficiencies, Necker Hospital for
Sick Children, APHP, Paris, France
15 Paris University, Laboratory of Lymphocyte Activation and
Susceptibility to EBV, INSERM UMR1163, Imagine Institute,
Necker Hospital for Sick Children, Paris, France
16 Department of Pediatrics, University of California San Francisco
and UCSF Benioff Children’s Hospital, San Francisco, CA, USA
17 St. Giles Laboratory of Human Genetics of Infectious Diseases,
Rockefeller Branch, The Rockefeller University, New York, NY,
USA
18 Howard Hughes Medical Institute, New York, NY, USA
19 Laboratory of Human Genetics of Infectious Diseases, Necker
Branch, INSERM UMR1163, Imagine Institute, Necker Hospital
for Sick Children, Paris University, Paris, France
20 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick
Children, Assistance Publique-Hôpitaux de Paris (APHP),
Paris, France
21 Division of Allergy Immunology, Department of Pediatrics, The
Children’s Hospital of Philadelphia, University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA, USA
J Clin Immunol (2020) 40:24–6464