Combined immunodeficiency with skin granulomas

Summary

Combined immunodeficiency with skin granulomas (MONDO:0009306) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 1,227

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency with skin granulomas
Mondo ID	MONDO:0009306
MeSH	C567115
OMIM	233650
Orphanet	157949
DOID	DOID:0112253
UMLS	C2673536
MedGen	435945
GARD	0013587
Is cancer (heuristic)	no

Also known as: CCHIDG · CID due to RAG 1/2 deficiency · combined cellular and humoral immune defects with granulomas · combined immunodeficiency due to RAG 1/2 deficiency

Data availability: 1,227 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B- severe combined immunodeficiency › combined immunodeficiency with skin granulomas

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

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

600 retrieved; paginated sample, class counts are floors:

236 uncertain significance, 224 likely benign, 54 pathogenic, 34 pathogenic/likely pathogenic, 26 likely pathogenic, 15 conflicting classifications of pathogenicity, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13157	NM_000448.2(RAG1):c.[1519C>T;2210G>A]		Pathogenic	no assertion criteria provided
1034220	NM_000448.3(RAG1):c.2487_2488delinsTT (p.Arg829_Lys830delinsSerTer)	RAG1	Pathogenic	reviewed by expert panel
1072413	NM_000448.3(RAG1):c.1211G>A (p.Arg404Gln)	RAG1	Pathogenic	reviewed by expert panel
1072942	NM_000448.3(RAG1):c.2615T>G (p.Leu872Ter)	RAG1	Pathogenic	criteria provided, single submitter
1075542	NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076023	NM_000448.3(RAG1):c.1798del (p.Glu600fs)	RAG1	Pathogenic	criteria provided, single submitter
13139	NM_000448.3(RAG1):c.2164G>A (p.Glu722Lys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13140	NM_000448.3(RAG1):c.2320G>T (p.Glu774Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13143	NM_000448.3(RAG1):c.1682G>A (p.Arg561His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13144	NM_000448.3(RAG1):c.1186C>T (p.Arg396Cys)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13146	NM_000448.3(RAG1):c.1187G>A (p.Arg396His)	RAG1	Pathogenic	reviewed by expert panel
13148	NM_000448.3(RAG1):c.1681C>T (p.Arg561Cys)	RAG1	Pathogenic	reviewed by expert panel
13149	NM_000448.3(RAG1):c.2210G>A (p.Arg737His)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13150	NM_000448.3(RAG1):c.1612_1624del (p.Ile538fs)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13154	NM_000448.3(RAG1):c.2521C>T (p.Arg841Trp)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13156	NM_000448.3(RAG1):c.940C>T (p.Arg314Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13158	NM_000448.3(RAG1):c.2333G>A (p.Arg778Gln)	RAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13159	NM_000448.3(RAG1):c.2923C>T (p.Arg975Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13160	NM_000448.3(RAG1):c.983G>A (p.Cys328Tyr)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13161	NM_000448.3(RAG1):c.2326C>T (p.Arg776Trp)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323517	NM_000448.3(RAG1):c.2850del (p.Ile950fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353693	NM_000448.3(RAG1):c.2736_2737del (p.Tyr912_Ser913delinsTer)	RAG1	Pathogenic	criteria provided, single submitter
1458103	NM_000448.3(RAG1):c.2475del (p.Glu827fs)	RAG1	Pathogenic	criteria provided, single submitter
1505484	NM_000448.3(RAG1):c.2882_2891del (p.Ser961fs)	RAG1	Pathogenic	criteria provided, single submitter
1704499	NM_000448.3(RAG1):c.2327G>A (p.Arg776Gln)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1997718	NM_000448.3(RAG1):c.539G>A (p.Trp180Ter)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2022529	NM_000448.3(RAG1):c.2065G>T (p.Glu689Ter)	RAG1	Pathogenic	criteria provided, single submitter
2042280	NM_000448.3(RAG1):c.1653C>G (p.Tyr551Ter)	RAG1	Pathogenic	criteria provided, single submitter
2095853	NM_000448.3(RAG1):c.1366del (p.Ala456fs)	RAG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2108168	NM_000448.3(RAG1):c.354del (p.Phe118fs)	RAG1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RSPH9	Orphanet:244	Primary ciliary dyskinesia
RBPJ	Orphanet:974	Adams-Oliver syndrome
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn syndrome
RAG2	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG2	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG2	Orphanet:39041	Omenn syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RSPH9	HGNC:21057	ENSG00000172426	Q9H1X1	Radial spoke head protein 9 homolog	clinvar
RBPJ	HGNC:5724	ENSG00000168214	Q06330	Recombining binding protein suppressor of hairless	clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RSPH9	Radial spoke head protein 9 homolog	Functions as part of axonemal radial spoke complexes that play an important part in the motility of sperm and cilia.
RBPJ	Recombining binding protein suppressor of hairless	Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.
RAG2	V(D)J recombination-activating protein 2	Core component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	3	6.2×	0.013
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RSPH9	Other/Unknown	no		RSP9
RBPJ	Transcription factor	no		p53-like_TF_DNA-bd_sf, Ig-like_fold, Ig_E-set
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RAG2	Transcription factor	no		RAG2, Znf_FYVE_PHD, Gal_Oxase/kelch_b-propeller

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
thymus	2
bronchial epithelial cell	1
bronchus	1
mucosa of paranasal sinus	1
calcaneal tendon	1
inferior olivary complex	1
nipple	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
bone marrow	1
left lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RSPH9	167	broad	marker	bronchial epithelial cell, bronchus, mucosa of paranasal sinus
RBPJ	295	ubiquitous	marker	inferior olivary complex, nipple, calcaneal tendon
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
RAG2	119	tissue_specific	marker	thymus, bone marrow, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBPJ	4,036
RAG1	3,549
RAG2	2,319
RSPH9	1,230

Intra-cohort edges

A	B	Sources
RAG1	RAG2	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBPJ	Q06330	4
RSPH9	Q9H1X1	1
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-7 signaling	2	211.5×	1e-03	RAG1, RAG2
MAPK6/MAPK4 signaling	2	90.6×	0.003	RAG1, RAG2
NOTCH2 intracellular domain regulates transcription	1	317.2×	0.016	RBPJ
RUNX3 regulates NOTCH signaling	1	271.9×	0.016	RBPJ
Regulation of beta-cell development	1	237.9×	0.016	RBPJ
Signaling by NOTCH2	1	237.9×	0.016	RBPJ
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	237.9×	0.016	RBPJ
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.016	RBPJ
Signaling by NOTCH3	1	173.0×	0.016	RBPJ
Signaling by NOTCH4	1	165.5×	0.016	RBPJ
NOTCH3 Intracellular Domain Regulates Transcription	1	146.4×	0.016	RBPJ
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	135.9×	0.016	RBPJ
Signaling by NOTCH1 in Cancer	1	135.9×	0.016	RBPJ
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	135.9×	0.016	RBPJ
Notch-HLH transcription pathway	1	135.9×	0.016	RBPJ
Formation of paraxial mesoderm	1	135.9×	0.016	RBPJ
Pre-NOTCH Expression and Processing	1	122.8×	0.016	RBPJ
Signaling by NOTCH1	1	119.0×	0.016	RBPJ
Transcriptional regulation by RUNX3	1	90.6×	0.020	RBPJ
Gastrulation	1	86.5×	0.020	RBPJ
NOTCH1 Intracellular Domain Regulates Transcription	1	79.3×	0.020	RBPJ
Somitogenesis	1	77.7×	0.020	RBPJ
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	65.6×	0.021	RBPJ
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	65.6×	0.021	RBPJ
Signaling by NOTCH	1	58.6×	0.023	RBPJ
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.027	RBPJ
Pre-NOTCH Transcription and Translation	1	40.9×	0.031	RBPJ
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.063	RBPJ
RNA Polymerase II Transcription	1	7.5×	0.149	RBPJ
Gene expression (Transcription)	1	6.0×	0.180	RBPJ

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pre-B cell allelic exclusion	2	2808.7×	1e-05	RAG1, RAG2
B cell differentiation	3	164.1×	2e-05	RBPJ, RAG1, RAG2
V(D)J recombination	2	1053.2×	3e-05	RAG1, RAG2
T cell differentiation in thymus	2	205.5×	7e-04	RAG1, RAG2
arterial endothelial cell fate commitment	1	4213.0×	0.003	RBPJ
blood vessel endothelial cell fate specification	1	4213.0×	0.003	RBPJ
positive regulation of ERBB signaling pathway	1	4213.0×	0.003	RBPJ
positive regulation of ephrin receptor signaling pathway	1	4213.0×	0.003	RBPJ
B cell homeostatic proliferation	1	2106.5×	0.004	RAG2
endocardium morphogenesis	1	2106.5×	0.004	RBPJ
blood vessel lumenization	1	2106.5×	0.004	RBPJ
defense response to bacterium	2	54.0×	0.004	RBPJ, RAG2
auditory receptor cell fate commitment	1	1404.3×	0.004	RBPJ
regulation of generation of precursor metabolites and energy	1	1404.3×	0.004	RBPJ
regulation of cell adhesion involved in heart morphogenesis	1	1404.3×	0.004	RBPJ
radial spoke assembly	1	1404.3×	0.004	RSPH9
mature B cell differentiation involved in immune response	1	1053.2×	0.004	RAG2
pulmonary valve development	1	1053.2×	0.004	RBPJ
regulation of timing of cell differentiation	1	1053.2×	0.004	RBPJ
DN2 thymocyte differentiation	1	1053.2×	0.004	RAG2
regulation of behavioral fear response	1	1053.2×	0.004	RAG1
B cell lineage commitment	1	842.6×	0.004	RAG2
T cell lineage commitment	1	842.6×	0.004	RAG2
aortic valve development	1	842.6×	0.004	RBPJ
epidermal cell fate specification	1	842.6×	0.004	RBPJ
club cell differentiation	1	842.6×	0.004	RBPJ
cardiac muscle cell fate commitment	1	842.6×	0.004	RBPJ
positive regulation of cell proliferation involved in heart morphogenesis	1	842.6×	0.004	RBPJ
negative regulation of T cell differentiation in thymus	1	702.2×	0.004	RAG2
axonemal central apparatus assembly	1	702.2×	0.004	RSPH9

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RSPH9	0	0
RBPJ	0	0
RAG1	0	0
RAG2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RBPJ	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RSPH9, RBPJ, RAG1, RAG2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RSPH9	0	—
RBPJ	8	—
RAG1	0	—
RAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.