Recurrent infections associated with rare immunoglobulin isotypes deficiency

Summary

Recurrent infections associated with rare immunoglobulin isotypes deficiency (MONDO:0013576) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• ClinVar variants: 2
• Phenotypes (HPO): 47

Clinical features

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0002099	Asthma	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002783	Recurrent lower respiratory tract infections	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0032169	Severe infection	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000403	Recurrent otitis media	Occasional (5-29%)
HP:0001047	Atopic dermatitis	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0002110	Bronchiectasis	Occasional (5-29%)
HP:0002720	Decreased circulating IgA level	Occasional (5-29%)
HP:0002725	Systemic lupus erythematosus	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0002850	Decreased circulating total IgM	Occasional (5-29%)
HP:0003193	Allergic rhinitis	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0004315	Decreased circulating IgG level	Occasional (5-29%)
HP:0005231	Chronic gastritis	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0011109	Chronic sinusitis	Occasional (5-29%)
HP:0011110	Recurrent tonsillitis	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0012387	Bronchitis	Occasional (5-29%)
HP:0020096	Recurrent streptococcal infections	Occasional (5-29%)
HP:0000031	Epididymitis	Very rare (<1-4%)
HP:0000819	Diabetes mellitus	Very rare (<1-4%)
HP:0000988	Skin rash	Very rare (<1-4%)
HP:0001082	Cholecystitis	Very rare (<1-4%)
HP:0001370	Rheumatoid arthritis	Very rare (<1-4%)
HP:0002608	Celiac disease	Very rare (<1-4%)
HP:0002665	Lymphoma	Very rare (<1-4%)
HP:0003765	Psoriasiform dermatitis	Very rare (<1-4%)
HP:0005353	Recurrent herpes	Very rare (<1-4%)
HP:0006562	Viral hepatitis	Very rare (<1-4%)
HP:0012476	Specific pneumococcal antibody deficiency	Very rare (<1-4%)
HP:0030151	Cholangitis	Very rare (<1-4%)
HP:0030998	Cerebrospinal fluid rhinorrhoea	Very rare (<1-4%)
HP:0032262	Pulmonary tuberculosis	Very rare (<1-4%)
HP:0032275	Recurrent shingles	Very rare (<1-4%)
HP:0100324	Scleroderma	Very rare (<1-4%)
HP:0100523	Liver abscess	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)
HP:0500093	Food allergy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	recurrent infections associated with rare immunoglobulin isotypes deficiency
Mondo ID	MONDO:0013576
MeSH	C564131
OMIM	614102
Orphanet	183675
UMLS	C3279824
MedGen	481454
GARD	0017086
Is cancer (heuristic)	no

Also known as: IgG subclass deficiency with IgA subclass deficiency · IGKCD · IMMUNOGLOBULIN kappa LIGHT chain deficiency · isolated IgG subclass deficiency · kappa-chain deficiency · recurrent infections associated with rare immunoglobulin isotypes deficiency

Data availability: 2 ClinVar variants · 3 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › recurrent infections associated with rare immunoglobulin isotypes deficiency

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29758	NC_000002.12:g.88857564A>G	IGK	Pathogenic	no assertion criteria provided
29759	NC_000002.12:g.88857564A>C	IGK	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IGKC	Moderate	Autosomal recessive	recurrent infections associated with rare immunoglobulin isotypes deficiency	2
IGHG2	Supportive	Unknown	recurrent infections associated with rare immunoglobulin isotypes deficiency

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGHG2	Orphanet:183675	Recurrent infections associated with rare immunoglobulin isotypes deficiency
IGKC	Orphanet:183675	Recurrent infections associated with rare immunoglobulin isotypes deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IGHG2	HGNC:5526	ENSG00000211893	P01859	Immunoglobulin heavy constant gamma 2	gencc
IGKC	HGNC:5716	ENSG00000211592	P01834	Immunoglobulin kappa constant	gencc
IGK	HGNC:5715			immunoglobulin kappa locus	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGHG2	Immunoglobulin heavy constant gamma 2	Constant region of immunoglobulin (Ig) heavy chains.
IGKC	Immunoglobulin kappa constant	Constant region of immunoglobulin light chains.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	2	19.5×	0.007
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGHG2	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
IGKC	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
IGK	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	1

Top tissues across cohort

Tissue	Cohort genes
vermiform appendix	2
bone marrow cell	1
spleen	1
caecum	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGHG2	126	tissue_specific	marker	vermiform appendix, spleen, bone marrow cell
IGKC	263	tissue_specific	marker	rectum, caecum, vermiform appendix
IGK

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGKC	179
IGHG2	121
IGK	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IGKC	P01834	98
IGHG2	P01859	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Classical antibody-mediated complement activation	1	1903.3×	0.004	IGHG2
FCGR activation	1	878.5×	0.004	IGHG2
Initial triggering of complement	1	601.0×	0.004	IGHG2
Role of phospholipids in phagocytosis	1	456.8×	0.004	IGHG2
FCGR3A-mediated IL10 synthesis	1	292.8×	0.005	IGHG2
Regulation of Complement cascade	1	233.1×	0.005	IGHG2
FCGR3A-mediated phagocytosis	1	187.2×	0.005	IGHG2
Regulation of actin dynamics for phagocytic cup formation	1	184.2×	0.005	IGHG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell receptor signaling pathway	2	401.2×	4e-05	IGHG2, IGKC
adaptive immune response	2	84.3×	4e-04	IGHG2, IGKC
immunoglobulin mediated immune response	1	351.1×	0.006	IGKC
complement activation, classical pathway	1	271.8×	0.006	IGHG2
antibacterial humoral response	1	165.2×	0.007	IGHG2
immune response	1	23.5×	0.042	IGKC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IGHG2	0	0
IGKC	0	0
IGK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	IGHG2, IGKC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IGK

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IGHG2	0	—
IGKC	0	—
IGK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.