Details of Disease

Disease Name

Common variable immunodeficiency

common variable hypogamma-globulinemia; common variable immune deficiency; hypogamma-globulinemia, acquired; acquired hypogammaglobulinemia; acquired agammaglobulinemia; Immunoglobulin deficiency, late-onset; common variable agammaglobulinemia; primary hypogammaglobulinemia; primary antibody deficiency; sporadic hypogammaglobulinemia; Common Variable Immune Deficiency; CVID; secondary hypogammaglobulinemia; idiopathic immunoglobulin deficiency

Definition

Common variable immunodeficiency (CVID) comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunizations and susceptibility to bacterial infections, predominantly caused by encapsulated bacteria.

Disease Hierarchy

DISS69ST: Syndromic agammaglobulinemia

DISGXLG5: Hereditary neoplastic syndrome

DISHE7JQ: Common variable immunodeficiency

Disease Identifiers

MONDO ID

MONDO_0015517

MESH ID

D017074

UMLS CUI

C0009447

MedGen ID

40407

Orphanet ID

1572

SNOMED CT ID

23238000

General Information of Disease (ID: DISHE7JQ)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 49 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
CACNA1C	TTZIFHC	Limited	Genetic Variation	[1]
CD40LG	TTIJP3Q	Limited	Biomarker	[2]
FGF14	TTKJX1V	Limited	Genetic Variation	[1]
ICOS	TTE5VP6	Limited	Altered Expression	[3]
IL21	TT9QEJ6	Limited	Autosomal recessive	[4]
NFKB2	TTKLNRV	Limited	Genetic Variation	[5]
TNFRSF13B	TTL9OD4	Limited	Genetic Variation	[6]
TNFSF13	TTOI1RM	Limited	Autosomal recessive	[4]
PRKCD	TT7A1BO	Disputed	GermlineCausalMutation	[7]
TNFSF12	TTBTDM1	Disputed	GermlineCausalMutation	[8]
CD19	TTW640A	Supportive	Autosomal dominant	[9]
CR2	TT0HUN7	Supportive	Autosomal dominant	[10]
MS4A1	TTUE541	Supportive	Autosomal dominant	[11]
NFKB1	TTUIZKC	Supportive	Autosomal dominant	[12]
NFKB2	TTKLNRV	Supportive	Autosomal dominant	[13]
PRKCD	TT9WJ8U	Supportive	Autosomal dominant	[7]
TNFRSF13B	TTL9OD4	Supportive	Autosomal dominant	[14]
TNFRSF13C	TT7NJSE	Supportive	Autosomal dominant	[9]
TNFSF12	TTBTDM1	Supportive	Autosomal dominant	[8]
DAG1	TT4X7PG	moderate	Genetic Variation	[15]
ERAP2	TTVGS1C	moderate	Genetic Variation	[15]
GPR35	TT254XD	moderate	Genetic Variation	[15]
IL23R	TT6H4QR	moderate	Genetic Variation	[15]
LRRK2	TTK0FEA	moderate	Genetic Variation	[15]
TNFSF15	TTEST6I	moderate	Genetic Variation	[15]
AICDA	TTKRTP6	Strong	Biomarker	[2]
APCS	TTB7VAT	Strong	Altered Expression	[16]
BCL6	TTC9YX5	Strong	Genetic Variation	[17]
BLK	TTNDSC3	Strong	Altered Expression	[18]
BTK	TTGM6VW	Strong	Biomarker	[2]
CD19	TTW640A	Strong	Biomarker	[19]
CD27	TTDO1MV	Strong	Biomarker	[13]
CD40	TT1ERKL	Strong	Biomarker	[12]
CD86	TT53XHB	Strong	Altered Expression	[20]
CR2	TT0HUN7	Strong	Biomarker	[21]
DUSP5	TTZN92A	Strong	Genetic Variation	[22]
FCGR2A	TTXT21W	Strong	Genetic Variation	[23]
FCGRT	TTKLPHO	Strong	Genetic Variation	[24]
IL2RA	TT10Y9E	Strong	Biomarker	[19]
MBL2	TTMQDZ5	Strong	Biomarker	[25]
MS4A1	TTUE541	Strong	Genetic Variation	[26]
NFKB1	TTUIZKC	Strong	Genetic Variation	[27]
TLR9	TTSHG0T	Strong	Altered Expression	[28]
TNFRSF13C	TT7NJSE	Strong	Biomarker	[29]
TNFRSF17	TTZ3P4W	Strong	Altered Expression	[30]
TNFRSF18	TTG6LA7	Strong	Altered Expression	[31]
TNFRSF8	TT2GM5R	Strong	Altered Expression	[32]
TNFSF13B	TTWMIDN	Strong	Biomarker	[33]
ICOS	TTE5VP6	Definitive	Autosomal recessive	[4]
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⏷ Show the Full List of 49 DTT(s)

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NT5C	DE4E31Z	Strong	Altered Expression	[34]
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This Disease Is Related to 63 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CDK14	OT385ZH1	Limited	Genetic Variation	[1]
CLDN15	OT9K0KI7	Limited	Altered Expression	[35]
CLDN2	OTRF3D6Y	Limited	Biomarker	[35]
CTNNBL1	OT6KLHPA	Limited	Autosomal recessive	[4]
HAVCR1	OT184CRZ	Limited	Genetic Variation	[1]
IL21	OTABCY4W	Limited	Autosomal recessive	[4]
IRF2BP2	OTSSRRCA	Limited	Biomarker	[36]
LAMB4	OT0NOOB2	Limited	Genetic Variation	[1]
MAN1C1	OT44TM7D	Limited	Genetic Variation	[1]
OR14J1	OTFIHZ4O	Limited	Genetic Variation	[1]
SNX31	OTMUGVSY	Limited	Genetic Variation	[1]
SRPX	OT5B9LXS	Limited	Genetic Variation	[1]
TAB3	OT1ECMDL	Limited	Genetic Variation	[1]
TNFSF13	OT90OWIO	Limited	Autosomal recessive	[4]
CD19	OTCPF9NF	Supportive	Autosomal dominant	[9]
CD81	OTQFXNAZ	Supportive	Autosomal dominant	[37]
CR2	OT90NDLY	Supportive	Autosomal dominant	[10]
MS4A1	OTZTVUBX	Supportive	Autosomal dominant	[11]
NFKB1	OTNRRD8I	Supportive	Autosomal dominant	[12]
NFKB2	OTS231V7	Supportive	Autosomal dominant	[13]
PRKCD	OTSEH90E	Supportive	Autosomal dominant	[7]
TNFRSF13B	OTBYKL89	Supportive	Autosomal dominant	[14]
TNFRSF13C	OTW0DE8Q	Supportive	Autosomal dominant	[9]
TNFSF12	OT6FQ02V	Supportive	Autosomal dominant	[8]
ADCY7	OTAWMGP3	moderate	Genetic Variation	[15]
ADGRL2	OTCXD2YR	moderate	Genetic Variation	[15]
ANKRD30A	OTJXYAE5	moderate	Genetic Variation	[15]
ANKRD55	OT62KZII	moderate	Genetic Variation	[15]
ATG16L1	OTEOYC5D	moderate	Genetic Variation	[15]
ATXN2L	OTP5M3R9	moderate	Genetic Variation	[15]
C1orf141	OTASPHL0	moderate	Genetic Variation	[15]
CARD9	OTJ81AWD	moderate	Genetic Variation	[15]
CRB1	OTXYUNG0	moderate	Genetic Variation	[15]
FNBP1	OTSJ5KKA	moderate	Genetic Variation	[15]
FUT2	OTLXM6WI	moderate	Genetic Variation	[15]
INS-IGF2	OTZR74BO	moderate	Genetic Variation	[15]
LURAP1L	OTSJ29M5	moderate	Genetic Variation	[15]
NKD1	OTY3MO97	moderate	Genetic Variation	[15]
SUOX	OTEJQ9FC	moderate	Genetic Variation	[15]
SWAP70	OTPHT2QD	moderate	Biomarker	[38]
CAMLG	OTTSRY39	Strong	Genetic Variation	[39]
CARD11	OTRCTLYC	Strong	Biomarker	[26]
CELSR3	OT8P6QNJ	Strong	Biomarker	[40]
CENPX	OTG1RAKJ	Strong	Altered Expression	[41]
CLEC16A	OTLGV5SV	Strong	Biomarker	[42]
HLA-DRB3	OT5PM9N7	Strong	Biomarker	[43]
IFNK	OTO2WDPX	Strong	Genetic Variation	[44]
IKZF1	OTCW1FKL	Strong	Altered Expression	[45]
LRBA	OTOUZN9G	Strong	Biomarker	[46]
MSH5	OTDARQT3	Strong	Genetic Variation	[47]
MTA2	OTCCYIQJ	Strong	Biomarker	[48]
NEIL1	OTHBU5DJ	Strong	Biomarker	[49]
NLRP12	OTGR132Z	Strong	Genetic Variation	[50]
ORC4	OT3ACTST	Strong	Genetic Variation	[1]
POU2AF1	OTOO6WHL	Strong	Biomarker	[26]
RAG1	OTV131E4	Strong	Genetic Variation	[51]
SBDS	OTHDCCIB	Strong	Genetic Variation	[52]
SH2D1A	OTLU49I5	Strong	Altered Expression	[16]
TBX19	OTXEMR2U	Strong	Genetic Variation	[53]
TCOF1	OT4BOYTM	Strong	Biomarker	[54]
TOLLIP	OTYEO4NR	Strong	Altered Expression	[55]
ICOS	OT82PDEY	Definitive	Autosomal recessive	[4]
SCYL1	OTQ0IN7P	Definitive	Biomarker	[12]
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⏷ Show the Full List of 63 DOT(s)

References

1	Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6. doi: 10.1016/j.jaci.2011.02.039. Epub 2011 Apr 17.
2	Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.J Allergy Clin Immunol Pract. 2019 Mar;7(3):864-878.e9. doi: 10.1016/j.jaip.2018.09.004. Epub 2018 Sep 19.
3	The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first-degree relatives.Haematologica. 2017 Jan;102(1):192-202. doi: 10.3324/haematol.2016.149112. Epub 2016 Sep 15.
4	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
5	Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency.Clin Immunol. 2019 Jun;203:23-27. doi: 10.1016/j.clim.2019.03.010. Epub 2019 Apr 3.
6	Rare TACI Mutation in a 3-Year-Old Boy With CVID Phenotype.Front Pediatr. 2019 Oct 15;7:418. doi: 10.3389/fped.2019.00418. eCollection 2019.
7	B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C . Blood. 2013 Apr 18;121(16):3112-6. doi: 10.1182/blood-2012-10-460741. Epub 2013 Jan 14.
8	Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5127-32. doi: 10.1073/pnas.1221211110. Epub 2013 Mar 14.
9	Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
10	Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol. 2012 Mar;129(3):801-810.e6. doi: 10.1016/j.jaci.2011.09.027. Epub 2011 Oct 27.
11	CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest. 2010 Jan;120(1):214-22. doi: 10.1172/JCI40231. Epub 2009 Dec 21.
12	Haploinsufficiency of the NF-B1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015 Sep 3;97(3):389-403. doi: 10.1016/j.ajhg.2015.07.008. Epub 2015 Aug 13.
13	Novel NFKB2 mutation in early-onset CVID. J Clin Immunol. 2014 Aug;34(6):686-90. doi: 10.1007/s10875-014-0064-x. Epub 2014 Jun 3.
14	TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. doi: 10.1038/ng1601. Epub 2005 Jul 10.
15	Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
16	Skewed Invariant Natural Killer T (iNKT) Cells, Impaired iNKT:B Cell Help and Decreased SAP Expression in Blood Lymphocytes from Patients with Common Variable Immunodeficiency.Scand J Immunol. 2017 Sep;86(3):171-178. doi: 10.1111/sji.12576.
17	Common-variable immunodeficiency-related lymphomas associate with mutations and rearrangements of BCL-6: pathogenetic and histogenetic implications.Hum Pathol. 2000 Jul;31(7):871-3. doi: 10.1053/hupa.2000.7626.
18	Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.Oncotarget. 2015 May 10;6(13):10759-71. doi: 10.18632/oncotarget.3577.
19	Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21(low) B cells.Allergol Immunopathol (Madr). 2019 Sep-Oct;47(5):457-466. doi: 10.1016/j.aller.2019.01.003. Epub 2019 May 15.
20	TLR9 activation is defective in common variable immune deficiency.J Immunol. 2006 Feb 1;176(3):1978-87. doi: 10.4049/jimmunol.176.3.1978.
21	Idiopathic, Refractory Sweet's Syndrome Associated with Common Variable Immunodeficiency: a Case Report and Literature Review.Curr Allergy Asthma Rep. 2019 May 14;19(6):32. doi: 10.1007/s11882-019-0864-4.
22	Restricted use of fetal VH3 immunoglobulin genes by unselected B cells in the adult. Predominance of 56p1-like VH genes in common variable immunodeficiency.J Clin Invest. 1992 May;89(5):1395-402. doi: 10.1172/JCI115728.
23	A novel FcRIIa Q27W gene variant is associated with common variable immune deficiency through defective FcRIIa downstream signaling.Clin Immunol. 2014 Nov;155(1):108-117. doi: 10.1016/j.clim.2014.09.006. Epub 2014 Sep 19.
24	Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.Clin Exp Immunol. 2013 Feb;171(2):186-94. doi: 10.1111/cei.12002.
25	Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms.Rheumatol Int. 2011 Apr;31(4):537-41. doi: 10.1007/s00296-009-1209-8. Epub 2009 Oct 23.
26	Evaluation of CARMA1/CARD11 and Bob1 as candidate genes in common variable immunodeficiency.J Investig Allergol Clin Immunol. 2011;21(5):348-53.
27	Loss-of-function nuclear factor B subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.J Allergy Clin Immunol. 2018 Oct;142(4):1285-1296. doi: 10.1016/j.jaci.2018.01.039. Epub 2018 Mar 2.
28	Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).Eur Cytokine Netw. 2018 Nov 1;29(4):153-158. doi: 10.1684/ecn.2018.0420.
29	Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.Int J Immunogenet. 2015 Aug;42(4):239-53. doi: 10.1111/iji.12217. Epub 2015 Jun 19.
30	Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency.Int J Mol Med. 2008 Feb;21(2):233-8.
31	Frequency and expression of inhibitory markers of CD4(+) CD25(+) FOXP3(+) regulatory T cells in patients with common variable immunodeficiency.Scand J Immunol. 2013 May;77(5):405-12. doi: 10.1111/sji.12040.
32	Soluble CD26 and CD30 levels in patients with common variable immunodeficiency.J Investig Allergol Clin Immunol. 2013;23(2):120-4.
33	BAFF-driven B cell hyperplasia underlies lung disease in common variable immunodeficiency.JCI Insight. 2019 Mar 7;4(5):e122728. doi: 10.1172/jci.insight.122728. eCollection 2019 Mar 7.
34	Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers.Hum Immunol. 2013 Dec;74(12):1531-5. doi: 10.1016/j.humimm.2013.08.266. Epub 2013 Aug 28.
35	Differential regulation of claudin-2 and claudin-15 expression in children and adults with malabsorptive disease.Lab Invest. 2020 Mar;100(3):483-490. doi: 10.1038/s41374-019-0324-8. Epub 2019 Oct 11.
36	Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J Allergy Clin Immunol. 2016 Aug;138(2):544-550.e4. doi: 10.1016/j.jaci.2016.01.018. Epub 2016 Mar 23.
37	"A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011?. Adv Immunol. 2011;111:47-107. doi: 10.1016/B978-0-12-385991-4.00002-7.
38	Analysis of SWAP-70 as a candidate gene for non-X-linked hyper IgM syndrome and common variable immunodeficiency.Clin Immunol. 2001 Dec;101(3):270-5. doi: 10.1006/clim.2001.5116.
39	Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes.J Allergy Clin Immunol. 2007 Nov;120(5):1178-85. doi: 10.1016/j.jaci.2007.10.001.
40	Evolving spectrum of LRBA deficiency-associated chronic arthritis: is there a causative role in juvenile idiopathic arthritis?.Clin Exp Rheumatol. 2017 Mar-Apr;35(2):327-329. Epub 2017 Jan 27.
41	Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity.Autoimmun Rev. 2013 Jan;12(3):430-5. doi: 10.1016/j.autrev.2012.08.016. Epub 2012 Aug 23.
42	Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.Nat Commun. 2015 Apr 20;6:6804. doi: 10.1038/ncomms7804.
43	HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID).Clin Exp Immunol. 1999 Jun;116(3):516-20. doi: 10.1046/j.1365-2249.1999.00926.x.
44	Limited role of interferon-kappa (IFNK) truncating mutations in common variable immunodeficiency.Cytokine. 2017 Aug;96:71-74. doi: 10.1016/j.cyto.2017.03.005. Epub 2017 Mar 19.
45	Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency.Front Immunol. 2019 Apr 16;10:568. doi: 10.3389/fimmu.2019.00568. eCollection 2019.
46	The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity.Allergol Immunopathol (Madr). 2019 Mar-Apr;47(2):172-178. doi: 10.1016/j.aller.2018.06.003. Epub 2018 Sep 5.
47	Role for Msh5 in the regulation of Ig class switch recombination.Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7193-8. doi: 10.1073/pnas.0700815104. Epub 2007 Apr 4.
48	Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond.Front Immunol. 2018 May 14;9:636. doi: 10.3389/fimmu.2018.00636. eCollection 2018.
49	NEIL1 is a candidate gene associated with common variable immunodeficiency in a patient with a chromosome 15q24 deletion.Clin Immunol. 2017 Mar;176:71-76. doi: 10.1016/j.clim.2017.01.006. Epub 2017 Jan 14.
50	Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency.Clin Immunol. 2014 Oct;154(2):105-11. doi: 10.1016/j.clim.2014.07.003. Epub 2014 Jul 23.
51	Advances in basic and clinical immunology in 2014.J Allergy Clin Immunol. 2015 May;135(5):1132-41. doi: 10.1016/j.jaci.2015.02.037.
52	Do ribosomopathies explain some cases of common variable immunodeficiency?.Clin Exp Immunol. 2011 Jan;163(1):96-103. doi: 10.1111/j.1365-2249.2010.04280.x. Epub 2010 Nov 9.
53	Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections.J Clin Endocrinol Metab. 2012 Jan;97(1):E121-8. doi: 10.1210/jc.2011-0407. Epub 2011 Oct 19.
54	Relative increase of T cells expressing the gamma/delta rather than the alpha/beta receptor in ataxia-telangiectasia.N Engl J Med. 1990 Jan 11;322(2):73-6. doi: 10.1056/NEJM199001113220201.
55	The Profile of Toll-like Receptor 2 (TLR2), TLR4 and Their Cytosolic Downstream Signaling Pathway in Common Variable Immunodeficiency (CVID) Patients.Iran J Allergy Asthma Immunol. 2018 Apr;17(2):188-200.