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Table 1.

Discoveries of single-gene defects underlying inborn errors of immunity in single patients

Gene producta Inheritance and alleleb Mousec References Citations (10/2014), ISI 
Combined immunodeficiencies     
CD45 ARg, LOF Prior Kung et al., 2000  179 
CD3-ε ARg, hM/LOF Prior Soudais et al., 1993  62 
CD3-ζ AR, LOFh Prior Rieux-Laucat et al., 2006  48 
Coronin 1A ARg, LOF Concomitantly Shiow et al., 2008  80 
DNA-PK ARf, hM Prior van der Burg et al., 2009  83 
CD8-α ARf, LOF Prior de la Calle-Martin et al., 2001  40 
Tapasin AR, LOF Prior Yabe et al., 2002  22 
LCK AR, LOF Prior Hauck et al., 2012  10 
UNC119d ADi, LOF Unrelatedi Gorska and Alam, 2012  12 
CARD11 ARf, LOF Prior Stepensky et al., 2013 k 18 
OX40 ARf, LOF Prior Byun et al., 2013  
Syndromic combined immunodeficiencies     
WIP ARf, LOF Prior Lanzi et al., 2012  23 
RNF168 ARg, LOF Later Stewart et al., 2009  295 
TYK2 ARf, LOF Prior Minegishi et al., 2006  244 
STAT5B ARf, LOF Prior Kofoed et al., 2003  236 
IKAROS ADi, hM Prior Goldman et al., 2012  
Antibody deficiencies     
λ5 ARg, LOF Prior Minegishi et al., 1998  152 
Ig-α AR, LOF Prior Minegishi et al., 1999a  111 
Ig-β AR, hM;LOF Prior Dobbs et al., 2007; Ferrari et al., 2007  30/29 
BLNK AR, LOF Concomitantly Minegishi et al., 1999b  188 
PI3K p85α ARf, LOF Prior Conley et al., 2012  33 
CD81 ARf, LOF Prior van Zelm et al., 2010  102 
CD20 ARf, LOF Prior Kuijpers et al., 2010  97 
CD21 ARg, LOF Prior Thiel et al., 2012  28 
Kappa chain ARg, LOF Prior Stavnezer-Nordgren et al., 1985  27 
PKCδ ARf, LOF Prior Kuehn et al., 2013; Salzer et al., 2013 l 9/8 
Diseases of immune dysregulation     
CD25 ARf, LOF Prior Sharfe et al., 1997  178 
Fas-ligand ADi, LOF Prior Wu et al., 1996  300 
NRASe ADi, GOF No GOF Oliveira et al., 2007  81 
Phagocyte disorders     
Rac2 ADi, LOF Prior Ambruso et al., 2000  223 
C/EBPε AR, LOF Prior Lekstrom-Himes et al., 1999  105 
P40 phox ARg, LOF Prior Matute et al., 2009  125 
IL12p40 ARf, LOF Prior Altare et al., 1998  263 
IFN-γR1 ARf, LOF Prior Jouanguy et al., 1996 m 552 
IFN-γR2 AR, LOF Prior Dorman and Holland, 1998  286 
IRF8 AR, LOF Prior Hambleton et al., 2011 n 128 
Defects of innate immunity     
IκBα ADi, GOF No GOF Courtois et al., 2003  148 
STAT2 ARf, LOFo Prior Hambleton et al., 2013  
TRAF3 ADi, LOF Prior Pérez de Diego et al., 2010  81 
IL17RA ARf, LOF Prior Puel et al., 2011 p 218 
APOL1 ARg, LOF Absent Vanhollebeke et al., 2006  63 
Auto-inflammatory disorders     
IL1RN ARf, LOF Prior Reddy et al., 2009 q 139 
Complement deficiencies     
C1qB AR, LOF Later McAdam et al., 1988  41 
C1qC AR, LOF Later Petry et al., 1995  27 
C1s AR, LOF Not done Inoue et al., 1998  11 
C3 ARf, LOF Later Botto et al., 1990  41 
C9 ARg, LOF Not done Witzel-Schlömp et al., 1997  18 
Factor B ARg, LOF Prior Slade et al., 2013  
Factor H ARg, LOF Later Ault et al., 1997  98 
MASP2 AR, LOF Not done Stengaard-Pedersen et al., 2003  119 
Ficolin 3 AR, LOF Absent Munthe-Fog et al., 2009  63 
Total: 49 of 232 (21%) proven PIDs     
Gene producta Inheritance and alleleb Mousec References Citations (10/2014), ISI 
Combined immunodeficiencies     
CD45 ARg, LOF Prior Kung et al., 2000  179 
CD3-ε ARg, hM/LOF Prior Soudais et al., 1993  62 
CD3-ζ AR, LOFh Prior Rieux-Laucat et al., 2006  48 
Coronin 1A ARg, LOF Concomitantly Shiow et al., 2008  80 
DNA-PK ARf, hM Prior van der Burg et al., 2009  83 
CD8-α ARf, LOF Prior de la Calle-Martin et al., 2001  40 
Tapasin AR, LOF Prior Yabe et al., 2002  22 
LCK AR, LOF Prior Hauck et al., 2012  10 
UNC119d ADi, LOF Unrelatedi Gorska and Alam, 2012  12 
CARD11 ARf, LOF Prior Stepensky et al., 2013 k 18 
OX40 ARf, LOF Prior Byun et al., 2013  
Syndromic combined immunodeficiencies     
WIP ARf, LOF Prior Lanzi et al., 2012  23 
RNF168 ARg, LOF Later Stewart et al., 2009  295 
TYK2 ARf, LOF Prior Minegishi et al., 2006  244 
STAT5B ARf, LOF Prior Kofoed et al., 2003  236 
IKAROS ADi, hM Prior Goldman et al., 2012  
Antibody deficiencies     
λ5 ARg, LOF Prior Minegishi et al., 1998  152 
Ig-α AR, LOF Prior Minegishi et al., 1999a  111 
Ig-β AR, hM;LOF Prior Dobbs et al., 2007; Ferrari et al., 2007  30/29 
BLNK AR, LOF Concomitantly Minegishi et al., 1999b  188 
PI3K p85α ARf, LOF Prior Conley et al., 2012  33 
CD81 ARf, LOF Prior van Zelm et al., 2010  102 
CD20 ARf, LOF Prior Kuijpers et al., 2010  97 
CD21 ARg, LOF Prior Thiel et al., 2012  28 
Kappa chain ARg, LOF Prior Stavnezer-Nordgren et al., 1985  27 
PKCδ ARf, LOF Prior Kuehn et al., 2013; Salzer et al., 2013 l 9/8 
Diseases of immune dysregulation     
CD25 ARf, LOF Prior Sharfe et al., 1997  178 
Fas-ligand ADi, LOF Prior Wu et al., 1996  300 
NRASe ADi, GOF No GOF Oliveira et al., 2007  81 
Phagocyte disorders     
Rac2 ADi, LOF Prior Ambruso et al., 2000  223 
C/EBPε AR, LOF Prior Lekstrom-Himes et al., 1999  105 
P40 phox ARg, LOF Prior Matute et al., 2009  125 
IL12p40 ARf, LOF Prior Altare et al., 1998  263 
IFN-γR1 ARf, LOF Prior Jouanguy et al., 1996 m 552 
IFN-γR2 AR, LOF Prior Dorman and Holland, 1998  286 
IRF8 AR, LOF Prior Hambleton et al., 2011 n 128 
Defects of innate immunity     
IκBα ADi, GOF No GOF Courtois et al., 2003  148 
STAT2 ARf, LOFo Prior Hambleton et al., 2013  
TRAF3 ADi, LOF Prior Pérez de Diego et al., 2010  81 
IL17RA ARf, LOF Prior Puel et al., 2011 p 218 
APOL1 ARg, LOF Absent Vanhollebeke et al., 2006  63 
Auto-inflammatory disorders     
IL1RN ARf, LOF Prior Reddy et al., 2009 q 139 
Complement deficiencies     
C1qB AR, LOF Later McAdam et al., 1988  41 
C1qC AR, LOF Later Petry et al., 1995  27 
C1s AR, LOF Not done Inoue et al., 1998  11 
C3 ARf, LOF Later Botto et al., 1990  41 
C9 ARg, LOF Not done Witzel-Schlömp et al., 1997  18 
Factor B ARg, LOF Prior Slade et al., 2013  
Factor H ARg, LOF Later Ault et al., 1997  98 
MASP2 AR, LOF Not done Stengaard-Pedersen et al., 2003  119 
Ficolin 3 AR, LOF Absent Munthe-Fog et al., 2009  63 
Total: 49 of 232 (21%) proven PIDs     

The IUIS committee for PIDs has compiled 234 genetic etiologies of PIDs into eight tables, corresponding to the eight categories in this table (Al-Herz et al., 2014). There are in fact only 232 monogenic PIDs, excluding UNC119 and NRAS deficiencies. Only loss- and gain-of-function alleles were considered to define distinct disorders; no difference was made between truly loss-of-function and hypomorphic alleles, despite their definition of distinct clinical phenotypes. We restricted our bibliographic analysis to reports of genetic lesions; some PIDs were biochemically defined before the identification of mutations, including in single patients.

a

The 51 mutated gene products are indicated for 53 unrelated patients (two conditions were simultaneously described each in two families). With 15 exceptions (Tapasin, Lck, UNC119, WIP, Ikaros, PI3K p85α, CD81, CD20, CD21, p40 phox, IRF8, STAT2, TRAF3, APOL1, and factor B), a second or more patients were subsequently identified (references available upon request; unpublished data). In some families listed herein, one or more deceased siblings were not genetically tested.

b

Mode of inheritance and nature of the morbid alleles. AR, autosomal recessive (bi-allelic mutations); AD, autosomal dominant; LOF, loss-of-function; hM, hypomorphic; GOF, gain-of-function.

c

The corresponding knockout mouse was made prior to, concomitantly with, or after the human deficit was described, or not at all.

d

The UNC119 mutation is not disease-causing as it is in fact a common polymorphism (>1%) in several human populations (http://useast.ensembl.org/Homo_sapiens/Variation/Population?db=core;g=ENSG00000109103;r=17:28546707-28552668;v=rs199714731;vdb=variation;vf=54110701).

e

The NRAS mutation is disease-causing but was later found to be somatic, not germline, consistent with the previous discovery of NRAS germline mutations in patients with Noonan syndrome (Niemela et al., 2011).

f

Known consanguineous family and homozygous patients (18 conditions and 18 patients).

g

Compound heterozygous patients (12 conditions and 12 patients); the others are homozygous but not known to be born to consanguineous parents (15 conditions and 16 patients). PCKδ deficiency was described simultaneously in a consanguineous and in a non-consanguineous family.

h

Somatic mutations rescued one of the two mutant alleles in a proportion of T cells.

i

The UNC199, Fas-ligand mutations’ familial segregation were not tested, whereas the Ikaros, NRAS, Rac2, IκBα, and TRAF3 mutations occurred de novo.

j

The UC119 mutant mouse was made previously but not studied for immunological phenotypes. The human gene had been previously shown to be important for T cell activation.

k

Another report was published shortly thereafter yet was quoted as unpublished data in this paper (Greil et al., 2013).

l

Another report was published shortly thereafter (Belot et al., 2013).

m

Another report was published concomitantly in a multiplex family (Newport et al., 1996).

n

Two patients with AD IRF8 deficiency and a different immunological and clinical phenotype were reported jointly.

o

The STAT2 allele might be severely hypomorphic or completely loss-of-function.

p

AD IL-17F deficiency (in a multiplex family) was reported together with AR IL-17RA deficiency.

q

Another report was published concomitantly in a multiplex family (Aksentijevich et al., 2009).

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