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. Tangyes.tangye@garvan.org.au

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