To the editor:

Sequence variants in TNFRSF13B gene, encoding the transmembrane activator and CAML interactor (TACI) protein, have been associated with common variable immunodeficiency (CVID) and IgA deficiency.1-3  However, its detection among healthy persons and the absence of a phenotype-genotype segregation pattern raises the question whether they are true disease-causing mutations.4-6 

Here we report the results of TNFRSF13B genotyping in 120 Spanish CVID patients according to European Society for Immunodeficiencies criteria, and 31 healthy first-degree relatives (HFDR) of p.C104R-harboring CVID patients. We detected 14 patients (11.6%) carrying at least one TNFRSF13B variant: 7 homozygous (4 cases from 2 multiplex families), 1 compound heterozygous, and 6 simple heterozygous (Tables 12). Six different variants were detected, 3 of them already known (p.C104R, p.L171R and p.A181E) and 3 novel (p.C89Y, p.E117G and p.E140K). As in previous studies, p.C104R was the most frequently detected in our CVID cohort. Interestingly, 28 of 31 HFDR persons harbored monoallelic or biallelic TNFRSF13B variants (Table 1). Among 198 healthy, normoglobulinemic Spanish persons included as controls, only the monoallelic p.C104R was detected in 5 of them.

Table 1

Families with p.C104R variant in TNFRSF13B

Family/subject C104R variant CVID Age Sex IgG IgA IgM Other clinical manifestations 
A         
    A.I.1 het Yes 63 320 169 22 None 
    A.II.1 het No 31 906 135 110 None 
    A.II.2 het No 36 945 279 42* None 
B         
    B.I.1 het Yes 57 374 24 27 Vasculitis, splenomegaly 
    B.II.2 het No 25 898 61 126 None 
C         
    C.II.1 hom Yes 54 425 40 70 None 
    C.II.2 hom Yes 67 488 36 52 Pernicious anemia 
    C.III.1 het No 24 1250 170 118 Hashimoto thyroiditis 
    C.III.2 het No 30 687 64 52 None 
    C.III.3 het No 33 1100 219 207 None 
    C.III.4 het No 30 n.a. n.a. n.a. None 
D         
    D.I.1 het No 73 949 222 52 None 
    D.I.2 het No 73 995 212 42* None 
    D.II.1 hom Yes 45 378 27 79 None 
    D.II.2 hom No 42 581* 94 93 None 
    D.III.1 het No 24 712 117 23* None 
    D.III.2 het No 19 755 166 39* None 
E         
    E.I.1 het No 59 n.a. n.a. n.a. Exitus 
    E.I.2 het No 58 989 139 65 None 
    E.II.3 hom Yes 31 275 81 16 None 
    E.II.1 het No 36 1168 234 74 None 
    E.II.2 hom No 30 533* 107 32* None 
G         
    G.I.2 het No 72 605 284 26* None 
    G.II.1 het No 57 759 131 49 None 
    G.II.2 A181E het No 57 734 98 63 None 
    G.II.3 A181E het No 55 622 127 79 None 
    G.II.4 A181E het No 54 768 137 55 None 
    G.III.1 C104R/A181E Yes 17 131 14 13 None 
    G.III.2 C104R/A181E No 26 487* 68 53 None 
M         
    M.I.1 het No 77 1300 104 174 n.a. 
    M.I.2 het No 77 1070 243 69 n.a. 
    M.II.1 hom Yes 32 473 88 62 Crohn 
    M.II.2 hom Yes 30 310 34 15 Splenomegaly 
    M.II.3 hom No 25 820 52 104 n.a. 
    M.III.1 het No 1190 106 55 n.a. 
    M.III.2 het No 903 154 66 n.a. 
    M.III.3 het No 920 59 55 n.a. 
Family/subject C104R variant CVID Age Sex IgG IgA IgM Other clinical manifestations 
A         
    A.I.1 het Yes 63 320 169 22 None 
    A.II.1 het No 31 906 135 110 None 
    A.II.2 het No 36 945 279 42* None 
B         
    B.I.1 het Yes 57 374 24 27 Vasculitis, splenomegaly 
    B.II.2 het No 25 898 61 126 None 
C         
    C.II.1 hom Yes 54 425 40 70 None 
    C.II.2 hom Yes 67 488 36 52 Pernicious anemia 
    C.III.1 het No 24 1250 170 118 Hashimoto thyroiditis 
    C.III.2 het No 30 687 64 52 None 
    C.III.3 het No 33 1100 219 207 None 
    C.III.4 het No 30 n.a. n.a. n.a. None 
D         
    D.I.1 het No 73 949 222 52 None 
    D.I.2 het No 73 995 212 42* None 
    D.II.1 hom Yes 45 378 27 79 None 
    D.II.2 hom No 42 581* 94 93 None 
    D.III.1 het No 24 712 117 23* None 
    D.III.2 het No 19 755 166 39* None 
E         
    E.I.1 het No 59 n.a. n.a. n.a. Exitus 
    E.I.2 het No 58 989 139 65 None 
    E.II.3 hom Yes 31 275 81 16 None 
    E.II.1 het No 36 1168 234 74 None 
    E.II.2 hom No 30 533* 107 32* None 
G         
    G.I.2 het No 72 605 284 26* None 
    G.II.1 het No 57 759 131 49 None 
    G.II.2 A181E het No 57 734 98 63 None 
    G.II.3 A181E het No 55 622 127 79 None 
    G.II.4 A181E het No 54 768 137 55 None 
    G.III.1 C104R/A181E Yes 17 131 14 13 None 
    G.III.2 C104R/A181E No 26 487* 68 53 None 
M         
    M.I.1 het No 77 1300 104 174 n.a. 
    M.I.2 het No 77 1070 243 69 n.a. 
    M.II.1 hom Yes 32 473 88 62 Crohn 
    M.II.2 hom Yes 30 310 34 15 Splenomegaly 
    M.II.3 hom No 25 820 52 104 n.a. 
    M.III.1 het No 1190 106 55 n.a. 
    M.III.2 het No 903 154 66 n.a. 
    M.III.3 het No 920 59 55 n.a. 

het indicates heterozygous; hom, homozygous; and n.a., not available.

*

Immunoglobulin (mg/dL) values below normal range for age in non-CVID relatives.

Table 2

Frequencies, significance for monoallelic and biallelic TNFRSF13B variants in patients and control group: presence of variants in healthy first-degree relatives (HFDR)

Genotype CVID Controls P HFDR 
p.C104R/p.C104R 6/120 0/198 .006 
p.C104/wt 2/120 5/198 n.s. 21 
p.C104R/A181E 1/120 0/198 n.s. 
p.L171R/p.L171R 1/120 0/198 n.s. n.a. 
p.L171R/wt 1/120 0/198 n.s. n.a. 
p.E140K/wt 1/120 0/198 n.s. n.a. 
p.C89Y/wt 1/120 0/198 n.s. n.a. 
p.E117G/wt 1/120 0/198 n.s. n.a. 
p.A181E/wt 0/120 0/198 n.s. 
Genotype CVID Controls P HFDR 
p.C104R/p.C104R 6/120 0/198 .006 
p.C104/wt 2/120 5/198 n.s. 21 
p.C104R/A181E 1/120 0/198 n.s. 
p.L171R/p.L171R 1/120 0/198 n.s. n.a. 
p.L171R/wt 1/120 0/198 n.s. n.a. 
p.E140K/wt 1/120 0/198 n.s. n.a. 
p.C89Y/wt 1/120 0/198 n.s. n.a. 
p.E117G/wt 1/120 0/198 n.s. n.a. 
p.A181E/wt 0/120 0/198 n.s. 

χ2 test compared CVID and control group.

n.s. indicates not significant; and n.a., not available.

Phenotype-genotype correlation in p.C104R/p.C104R persons revealed a continuum spectrum of disease severity, ranging from the absence of clinical symptoms (3 HFDR persons), minor clinical manifestations (4 CVID patients), and moderate to severe forms in 2 CVID patients, (1 with Crohn-like disease and the other with recurrent infections, bronchiectasis, and splenomegaly). Twenty-six clinically asymptomatic persons harbored the monoallelic p.C104R variant (21 HFDR and 5 controls), whereas only 1 of 2 monoallelic p.C104R CVID patients presented autoimmune and lymphoproliferative manifestations. In previous studies, autoimmunity and lymphoid hyperplasia was associated with TNFRSF13B variants,7,8  in particular with heterozygosity for C104R.3  However, in our CVID cohort we did not find them, maybe due to the lower frequencies of monoallelic p.C104R patients in our cohort.

Previous studies usually detected monoallelic TNFRSF13B variants among CVID patients and in low percentages of asymptomatic patient's relatives and controls.1-3  This suggests a potential autosomal dominant inheritance pattern with low penetrance. However, we detected a higher number of biallelic CVID patients, a higher than expected number of asymptomatic mono- and biallelic carriers among patients' relatives, and a higher frequency of monoallelic p.C104R variant in controls than in previous studies.1-5  These results support the fact that monoallelic p.C104R variant is not a true CVID-causing mutation. This is in concordance with previously reported data, on the basis of their presence in healthy normoglobulinemic controls, the absence of a clear Mendelian inheritance pattern, and the absence of a clear phenotype-genotype segregation pattern in a given family. However, the absence of homozygous p.C104R/p.C104R persons in the control group suggests a potential role for p.C104R variant in homozygous state as a risk factor to CVID, which might be exerted separately or in conjunction with other unidentified genetic factors. In this sense, it is interesting to note that we have observed low immunoglobulin plasma levels in 2 of 3 p.C104R/p.C104R asymptomatic HFDR persons, which might be a first step toward CVID development. Further studies are needed to evaluate the precise role of these TNFRSF13B variants in TACI signaling pathway and in the dysregulated immunoglobulin production observed in CVID.

Authorship

Approval was obtained from the hospital institutional review board for these studies. Informed consent was provided according to the Declaration of Helsinki.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Natalia Martínez-Pomar, Hospital Son Dureta, Andrea Doria, 55, Palma de Mallorca, 07014 Spain; e-mail: natalia.martinez@ssib.es.

References

References
1
Salzer
U
Chapel
HM
Webster
AD
, et al. 
Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.
Nat Genet
2005
, vol. 
37
 
8
(pg. 
820
-
828
)
2
Castigli
E
Wilson
SA
Garibyan
L
, et al. 
TACI is mutant in common variable immunodeficiency and IgA deficiency.
Nat Genet
2005
, vol. 
37
 
8
(pg. 
829
-
834
)
3
Salzer
U
Bacchelli
C
Buckridge
S
, et al. 
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.
Blood
2009
, vol. 
113
 
9
(pg. 
1967
-
1976
)
4
Pan-Hammarström
Q
Salzer
U
Du
L
, et al. 
Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency.
Nat Genet
2007
, vol. 
39
 
4
(pg. 
429
-
430
)
5
Castigli
E
Wilson
S
Garibyan
L
, et al. 
Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency.
Nat Genet
2007
, vol. 
39
 
4
(pg. 
430
-
431
)
6
Conley
ME
Dobbs
AK
Farmer
DM
, et al. 
Primary B Cell Immunodeficiencies: Comparisons and Contrasts.
Annu Rev Immunol
2009
, vol. 
27
 (pg. 
199
-
227
)
7
Bacchelli
C
Buckridge
S
Thrasher
AJ
, et al. 
Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency.
Clin Exp Immunol
2007
, vol. 
149
 
3
(pg. 
401
-
409
)
8
Zhan
L
Radigan
L
Salzer
U
, et al. 
Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozyogotes.
J Allergy Clin Immunol
2007
, vol. 
120
 
5
(pg. 
1178
-
1185
)