Table 1. Distribution of PAD genes... | Rockefeller University Press

Table 1.

Distribution of PAD genes across the IUIS classification tables for IEIs

PAD gene	Inheritance	PAD mechanism
Section I. Immunodeficiencies affecting cellular and humoral immunity
I-1. T-B + SCID
IL2RG	XL, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
IL7R	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
I-2. T-B- SCID
ADA	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
DCLRE1C	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
LIG4	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
RAG1	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
RAG2	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
I-3. CID, generally less profound than SCID
DOCK8	AR, LOF	Defects in actin cytoskeleton
MSN	XL, LOF	Defects in actin cytoskeleton
STK4	AR, LOF	Defects in actin cytoskeleton
MALT1	AR, LOF	Attenuated antigen receptor signaling, altered cellular metabolism
RFXANK	AR, LOF	Attenuated antigen receptor signaling
ZAP70	AR, LOF/GOF	Abnormal T cell development and/or restriction of the TCR repertoire
Section II. CIDs with associated or syndromic features
II-1. Immunodeficiency with congenital thrombocytopenia
ARPC1B	AR, LOF	Defects in actin cytoskeleton
IKZF2	AD, DN-GOF	Failure of immune tolerance
WAS	XL, LOF	Defects in actin cytoskeleton
WIPF1	AR, LOF	Defects in actin cytoskeleton
II-2. DNA repair defects other than those listed inTable 1
No PADs
II-3. Thymic defects with additional congenital anomalies
CHD7	AD, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
TBX1	AD	Abnormal T cell development and/or restriction of the TCR repertoire
22q11.2 deletion syndrome—large deletion (3 Mb) typically in chromosome 22 (TBX1)	AD	Abnormal T cell development and/or restriction of the TCR repertoire
II-4. Immuno-osseous dysplasias
No PADs
II-5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [7])
SPINK5	AR, LOF	Skin barrier dysfunction
CARD11	AD, DN	Attenuated antigen receptor signaling, altered cellular metabolism
ERBIN	AD	Abnormal cytokine signaling
IL6R	AR, LOF	Abnormal cytokine signaling
IL6ST	AR, LOF	Abnormal cytokine signaling
STAT3	AD, DN-LOF	Abnormal cytokine signaling
STAT6	AD, GOF	Abnormal cytokine signaling
TGFBR1	AD	Abnormal cytokine signaling
TGFBR2	AD	Abnormal cytokine signaling
ZNF341	AR, LOF	Abnormal cytokine signaling
PGM3	AR, LOF	Altered cellular metabolism
II-6. Defects of vitamin B12 and folate metabolism
No PADs
II-7. EDA-ID
No PADs
II-8. Calcium channel defects
No PADs
II-9. Other defects
STAT5B	AR, LOF and AD, DN-LOF	Abnormal cytokine signaling
Section III. Predominantly antibody deficiencies
No PADs
Section IV. Diseases of immune dysregulation
IV-1. FHL syndromes
No PADs
IV-2. FHL syndromes with hypopigmentation
No PADs
IV-3. Tregdefects
FOXP3	XL, LOF	Failure of immune tolerance
CTLA4	AD, haploinsufficiency	Failure of immune tolerance
IKZF1	AD, GOF	Abnormal T cell development and/or restriction of the TCR repertoire
IL2RA	AR, LOF	Failure of immune tolerance
IL2RB	AR, LOF	Failure of immune tolerance
STAT3	AD, GOF	Abnormal cytokine signaling
IV-4. Autoimmunity with or without lymphoproliferation
NCKAP1L	AR, LOF	Defects in actin cytoskeleton
JAK1	AD, GOF	Abnormal cytokine signaling
SOCS1	AD, LOF	Abnormal cytokine signaling
IV-5. Immune dysregulation with colitis
RHBDF2	AR, LOF	Skin barrier dysfunction
IV-6. ALPS (Canale–Smith syndrome)
No PADs
IV-7. Susceptibility to EBV and lymphoproliferative conditions
CARMIL2	AR, LOF	Attenuated antigen receptor signaling
Section V. Congenital defects of phagocyte number or function
No PADs
Section VI. Defects in intrinsic and innate immunity
VI-1. MSMD
TBX21	AR, LOF	Abnormal cytokine signaling, abnormal T cell development, and/or restriction of the TCR repertoire
TYK2	AR, LOF	Abnormal cytokine signaling
VI-2. Epidermodysplasia verruciformis (HPV)
No PADs
VI-3. Predisposition to severe viral infection
No PADs
VI-4. HSE
No PADs
VI-5. Predisposition to invasive fungal diseases
No PADs
VI-6. Predisposition to mucocutaneous candidiasis
STAT1	AD, GOF	Abnormal cytokine signaling
VI-7. TLR signaling pathway deficiency
No PADs
VI-8. Other IEIs related to nonhematopoietic tissues
No PADs
VI-9. Other IEIs related to leukocytes
No PADs
Section VII. Autoinflammatory disorders
VII-1. Type 1 interferonopathies
No PADs
VII-2. Defects affecting the inflammasome
PLCG2	AD, GOF/LOF	Abnormal immune signaling
VII-3. Non–inflammasome-related conditions
LYN	AD, GOF	Abnormal immune signaling
Section VIII. Complement deficiencies
No PADs
Section IX. Bone marrow failure
No PADs
Section X. Phenocopies of IEIs associated with autoantibodies or somatic variants
X-1. Associated with somatic variants
STAT5B	Somatic, GOF	Abnormal cytokine signaling
Genes not included in the IUIS 2024-update table
CARD14	AD, LOF	Attenuated antigen receptor signaling
CDSN	AR, LOF	Skin barrier dysfunction
DSG1	AR, LOF	Skin barrier dysfunction
DSP	AD, LOF	Skin barrier dysfunction
FLG	AD or AR, LOF	Skin barrier dysfunction
OSMR	AR, LOF	Abnormal cytokine signaling
ZBTB7B	AD	Abnormal T cell development and/or restriction of the TCR repertoire

PAD gene	Inheritance	PAD mechanism
Section I. Immunodeficiencies affecting cellular and humoral immunity
I-1. T-B + SCID
IL2RG	XL, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
IL7R	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
I-2. T-B- SCID
ADA	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
DCLRE1C	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
LIG4	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
RAG1	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
RAG2	AR, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
I-3. CID, generally less profound than SCID
DOCK8	AR, LOF	Defects in actin cytoskeleton
MSN	XL, LOF	Defects in actin cytoskeleton
STK4	AR, LOF	Defects in actin cytoskeleton
MALT1	AR, LOF	Attenuated antigen receptor signaling, altered cellular metabolism
RFXANK	AR, LOF	Attenuated antigen receptor signaling
ZAP70	AR, LOF/GOF	Abnormal T cell development and/or restriction of the TCR repertoire
Section II. CIDs with associated or syndromic features
II-1. Immunodeficiency with congenital thrombocytopenia
ARPC1B	AR, LOF	Defects in actin cytoskeleton
IKZF2	AD, DN-GOF	Failure of immune tolerance
WAS	XL, LOF	Defects in actin cytoskeleton
WIPF1	AR, LOF	Defects in actin cytoskeleton
II-2. DNA repair defects other than those listed inTable 1
No PADs
II-3. Thymic defects with additional congenital anomalies
CHD7	AD, LOF	Abnormal T cell development and/or restriction of the TCR repertoire
TBX1	AD	Abnormal T cell development and/or restriction of the TCR repertoire
22q11.2 deletion syndrome—large deletion (3 Mb) typically in chromosome 22 (TBX1)	AD	Abnormal T cell development and/or restriction of the TCR repertoire
II-4. Immuno-osseous dysplasias
No PADs
II-5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [7])
SPINK5	AR, LOF	Skin barrier dysfunction
CARD11	AD, DN	Attenuated antigen receptor signaling, altered cellular metabolism
ERBIN	AD	Abnormal cytokine signaling
IL6R	AR, LOF	Abnormal cytokine signaling
IL6ST	AR, LOF	Abnormal cytokine signaling
STAT3	AD, DN-LOF	Abnormal cytokine signaling
STAT6	AD, GOF	Abnormal cytokine signaling
TGFBR1	AD	Abnormal cytokine signaling
TGFBR2	AD	Abnormal cytokine signaling
ZNF341	AR, LOF	Abnormal cytokine signaling
PGM3	AR, LOF	Altered cellular metabolism
II-6. Defects of vitamin B12 and folate metabolism
No PADs
II-7. EDA-ID
No PADs
II-8. Calcium channel defects
No PADs
II-9. Other defects
STAT5B	AR, LOF and AD, DN-LOF	Abnormal cytokine signaling
Section III. Predominantly antibody deficiencies
No PADs
Section IV. Diseases of immune dysregulation
IV-1. FHL syndromes
No PADs
IV-2. FHL syndromes with hypopigmentation
No PADs
IV-3. Tregdefects
FOXP3	XL, LOF	Failure of immune tolerance
CTLA4	AD, haploinsufficiency	Failure of immune tolerance
IKZF1	AD, GOF	Abnormal T cell development and/or restriction of the TCR repertoire
IL2RA	AR, LOF	Failure of immune tolerance
IL2RB	AR, LOF	Failure of immune tolerance
STAT3	AD, GOF	Abnormal cytokine signaling
IV-4. Autoimmunity with or without lymphoproliferation
NCKAP1L	AR, LOF	Defects in actin cytoskeleton
JAK1	AD, GOF	Abnormal cytokine signaling
SOCS1	AD, LOF	Abnormal cytokine signaling
IV-5. Immune dysregulation with colitis
RHBDF2	AR, LOF	Skin barrier dysfunction
IV-6. ALPS (Canale–Smith syndrome)
No PADs
IV-7. Susceptibility to EBV and lymphoproliferative conditions
CARMIL2	AR, LOF	Attenuated antigen receptor signaling
Section V. Congenital defects of phagocyte number or function
No PADs
Section VI. Defects in intrinsic and innate immunity
VI-1. MSMD
TBX21	AR, LOF	Abnormal cytokine signaling, abnormal T cell development, and/or restriction of the TCR repertoire
TYK2	AR, LOF	Abnormal cytokine signaling
VI-2. Epidermodysplasia verruciformis (HPV)
No PADs
VI-3. Predisposition to severe viral infection
No PADs
VI-4. HSE
No PADs
VI-5. Predisposition to invasive fungal diseases
No PADs
VI-6. Predisposition to mucocutaneous candidiasis
STAT1	AD, GOF	Abnormal cytokine signaling
VI-7. TLR signaling pathway deficiency
No PADs
VI-8. Other IEIs related to nonhematopoietic tissues
No PADs
VI-9. Other IEIs related to leukocytes
No PADs
Section VII. Autoinflammatory disorders
VII-1. Type 1 interferonopathies
No PADs
VII-2. Defects affecting the inflammasome
PLCG2	AD, GOF/LOF	Abnormal immune signaling
VII-3. Non–inflammasome-related conditions
LYN	AD, GOF	Abnormal immune signaling
Section VIII. Complement deficiencies
No PADs
Section IX. Bone marrow failure
No PADs
Section X. Phenocopies of IEIs associated with autoantibodies or somatic variants
X-1. Associated with somatic variants
STAT5B	Somatic, GOF	Abnormal cytokine signaling
Genes not included in the IUIS 2024-update table
CARD14	AD, LOF	Attenuated antigen receptor signaling
CDSN	AR, LOF	Skin barrier dysfunction
DSG1	AR, LOF	Skin barrier dysfunction
DSP	AD, LOF	Skin barrier dysfunction
FLG	AD or AR, LOF	Skin barrier dysfunction
OSMR	AR, LOF	Abnormal cytokine signaling
ZBTB7B	AD	Abnormal T cell development and/or restriction of the TCR repertoire

PAD genes are shown within the IUIS classification of IEIs in which disorders are currently categorized into 10 tables, with subtables segregating groups of disorders into overlapping phenotypes (2024 update) (6). For each gene, the mode of inheritance and the predominant pathogenic mechanism contributing to atopic disease are indicated. IUIS disease categories in which no PAD genes have been identified are also shown and noted accordingly. In addition, genes known to cause monogenic atopic diseases, but not yet identified within the IUIS framework, are also listed. IUIS, International Union of Immunological Societies; HPV, human papilloma virus; SCID, severe combined immunodeficiency; CID, combined immunodeficiency; EDA-ID, anhidrotic ectodermal dysplasia with immunodeficiency; FHL, familial hemophagocytic lymphohistiocytosis; ALPS, autoimmune lymphoproliferative syndrome; MSMD, Mendelian susceptibility to mycobacterial disease; HSE, herpes simplex encephalitis; AD, autosomal dominant; AR, autosomal recessive; DN, dominant negative; XL, X-linked; LOF, loss-of-function; GOF, gain-of-function.

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