Omenn syndrome

Summary

Omenn syndrome (MONDO:0011338) is a disease caused by variants in DCLRE1C, RAG1, and RAG2, with 10 cohort genes and 3 clinical trials. The dominant Reactome pathway is Interleukin-7 signaling (4 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: DCLRE1C (GenCC Definitive), RAG1 (GenCC Definitive), RAG2 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 598
• Phenotypes (HPO): 28
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001019	Erythroderma	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002028	Chronic diarrhea	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0004332	Abnormal lymphocyte morphology	Very frequent (80-99%)
HP:0004430	Severe combined immunodeficiency	Very frequent (80-99%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001880	Eosinophilia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0007549	Desquamation of skin soon after birth	Frequent (30-79%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Frequent (30-79%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000944	Abnormal metaphysis morphology	Occasional (5-29%)
HP:0001831	Short toe	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002960	Autoimmunity	Occasional (5-29%)
HP:0100646	Thyroiditis	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Omenn syndrome
Mondo ID	MONDO:0011338
OMIM	603554
Orphanet	39041
DOID	DOID:0060010
NCIT	C61240
SNOMED CT	722067005
UMLS	C2700553
MedGen	398130
GARD	0008198
MedDRA	10069097
Is cancer (heuristic)	no

Also known as: combined immunodeficiency with hypereosinophilia · Omenn syndrome · reticuloendotheliosis familial with eosinophilia

Data availability: 598 ClinVar variants · 15 GenCC gene-disease records · 1 cell line.

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 › Omenn syndrome

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, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, 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

598 retrieved; paginated sample, class counts are floors:

260 uncertain significance, 105 likely pathogenic, 61 conflicting classifications of pathogenicity, 45 pathogenic/likely pathogenic, 45 benign, 41 pathogenic, 32 likely benign, 8 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071466	NM_001033855.3(DCLRE1C):c.671del (p.Gly224fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322192	NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)	DCLRE1C	Pathogenic	reviewed by expert panel
1324212	NM_001033855.3(DCLRE1C):c.1628_1632del (p.Ile543fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368634	NM_001033855.3(DCLRE1C):c.816T>A (p.Cys272Ter)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388521	NM_001033855.3(DCLRE1C):c.310_313del	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453673	NM_001033855.3(DCLRE1C):c.1442del (p.Lys481fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674742	NM_001033855.3(DCLRE1C):c.330_331del (p.Leu111fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674744	NM_001033855.3(DCLRE1C):c.1238del (p.Pro413fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674751	NM_001033855.3(DCLRE1C):c.1574_1575del (p.Asp524_Ser525insTer)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674764	NM_001033855.3(DCLRE1C):c.184_191del (p.Ser62fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2707873	NM_001033855.3(DCLRE1C):c.1103del (p.Lys368fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241289	NM_001033855.3(DCLRE1C):c.879G>A (p.Trp293Ter)	DCLRE1C	Pathogenic	criteria provided, single submitter
3251745	NM_001033855.3(DCLRE1C):c.353G>T (p.Gly118Val)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4665	NM_001033855.3(DCLRE1C):c.241C>T (p.Arg81Ter)	DCLRE1C	Pathogenic	reviewed by expert panel
4670	NM_001033855.3(DCLRE1C):c.362+1G>T	DCLRE1C	Pathogenic	criteria provided, multiple submitters, no conflicts
4673	NM_001033855.3(DCLRE1C):c.597C>A (p.Tyr199Ter)	DCLRE1C	Pathogenic	reviewed by expert panel
4674	NM_001033855.3(DCLRE1C):c.103C>G (p.His35Asp)	DCLRE1C	Pathogenic	reviewed by expert panel
4675	NM_001033855.3(DCLRE1C):c.1350_1356del (p.Asp451fs)	DCLRE1C	Pathogenic	criteria provided, multiple submitters, no conflicts
666082	NM_001033855.3(DCLRE1C):c.754C>T (p.Gln252Ter)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
852821	NM_001033855.3(DCLRE1C):c.352G>T (p.Gly118Ter)	DCLRE1C	Pathogenic	reviewed by expert panel
872164	NM_001033855.3(DCLRE1C):c.464+1G>A	DCLRE1C	Pathogenic	criteria provided, multiple submitters, no conflicts
936913	NM_001033855.3(DCLRE1C):c.461del (p.Gly154fs)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
958957	NM_001033855.3(DCLRE1C):c.1265C>A (p.Ser422Ter)	DCLRE1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
969751	NM_001033855.3(DCLRE1C):c.109+1G>T	DCLRE1C	Pathogenic	reviewed by expert panel
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
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
13145	NM_000448.3(RAG1):c.2735A>G (p.Tyr912Cys)	RAG1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 58 · Orphanet: 22 · 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
DCLRE1C	Definitive	Autosomal recessive	Omenn syndrome	7
RAG1	Definitive	Autosomal recessive	Omenn syndrome	11
RAG2	Definitive	Autosomal recessive	Omenn syndrome	7
ADA	Supportive	Autosomal recessive	Omenn syndrome	7
CHD7	Supportive	Autosomal recessive	Omenn syndrome	8
IL2RG	Supportive	Autosomal recessive	Omenn syndrome	6
IL7R	Supportive	Autosomal recessive	Omenn syndrome	6
LIG4	Supportive	Autosomal recessive	Omenn syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCLRE1C	Orphanet:275	Severe combined immunodeficiency due to DCLRE1C deficiency
DCLRE1C	Orphanet:39041	Omenn syndrome
IL7R	Orphanet:169154	T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
IL7R	Orphanet:39041	Omenn 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
ADA	Orphanet:277	Severe combined immunodeficiency due to adenosine deaminase deficiency
ADA	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
IL2RG	Orphanet:276	T-B+ severe combined immunodeficiency due to gamma chain deficiency
IL2RG	Orphanet:39041	Omenn syndrome
LIG4	Orphanet:235	Dubowitz syndrome
LIG4	Orphanet:39041	Omenn syndrome
LIG4	Orphanet:99812	LIG4 syndrome

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DCLRE1C	HGNC:17642	ENSG00000152457	Q96SD1	Protein artemis	gencc,clinvar
IL7R	HGNC:6024	ENSG00000168685	P16871	Interleukin-7 receptor subunit alpha	gencc,clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	gencc,clinvar
RAG2	HGNC:9832	ENSG00000175097	P55895	V(D)J recombination-activating protein 2	gencc,clinvar
ADA	HGNC:186	ENSG00000196839	P00813	Adenosine deaminase	gencc
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	gencc
IL2RG	HGNC:6010	ENSG00000147168	P31785	Cytokine receptor common subunit gamma	gencc
LIG4	HGNC:6601	ENSG00000174405	P49917	DNA ligase 4	gencc
SUV39H2	HGNC:17287	ENSG00000152455	Q9H5I1	Histone-lysine N-methyltransferase SUV39H2	clinvar
IFTAP	HGNC:25142	ENSG00000166352	Q86VG3	Intraflagellar transport-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCLRE1C	Protein artemis	Nuclease involved in DNA non-homologous end joining (NHEJ); required for double-strand break repair and V(D)J recombination.
IL7R	Interleukin-7 receptor subunit alpha	Receptor for interleukin-7.
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.
ADA	Adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
IL2RG	Cytokine receptor common subunit gamma	Common subunit for the receptors for a variety of interleukins.
LIG4	DNA ligase 4	DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination.
SUV39H2	Histone-lysine N-methyltransferase SUV39H2	Histone methyltransferase that specifically mediates trimethylation of ‘Lys-9’ of histone H3 (H3K9me3) using monomethylated H3 ‘Lys-9’ (H3K9me1) as substrate.
IFTAP	Intraflagellar transport-associated protein	Seems to play a role in ciliary BBSome localization, maybe through interaction with IFT-A complex.

Protein-family classification

Druggable: 4 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.4

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	5.8×	0.176
Enzyme (other)	2	2.4×	0.401
Transcription factor	2	1.6×	0.461
Other/Unknown	4	0.7×	0.907

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCLRE1C	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro
IL7R	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
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
ADA	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, A/AMP_deam_AS
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
IL2RG	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
LIG4	Enzyme (other)	yes	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, DNA_ligase_ATP-dep_N
SUV39H2	Other/Unknown	no		Chromo/chromo_shadow_dom, SET_dom, Post-SET_dom
IFTAP	Other/Unknown	no		IFTAP

Expression context

Cohort genes with no expression data: 0.

9 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
thymus	3
secondary oocyte	3
buccal mucosa cell	2
granulocyte	2
lymph node	2
epithelium of nasopharynx	1
tendon of biceps brachii	1
right lung	1
male germ line stem cell (sensu Vertebrata) in testis	1
bone marrow	1
left lobe of thyroid gland	1
duodenum	1
jejunal mucosa	1
cerebellar vermis	1
sural nerve	1
vermiform appendix	1
endothelial cell	1
oocyte	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCLRE1C	284	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, epithelium of nasopharynx
IL7R	220	ubiquitous	marker	right lung, granulocyte, lymph node
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
ADA	202	ubiquitous	marker	jejunal mucosa, duodenum, thymus
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
IL2RG	213	broad	marker	granulocyte, lymph node, vermiform appendix
LIG4	275	ubiquitous	yes	endothelial cell, oocyte, secondary oocyte
SUV39H2	216	ubiquitous	marker	sperm, secondary oocyte, male germ cell
IFTAP	247	ubiquitous	marker	left ventricle myocardium, bronchial epithelial cell, myocardium

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD7	4,819
RAG1	3,549
IL7R	3,412
ADA	3,187
SUV39H2	2,654
IL2RG	2,470
LIG4	2,352
RAG2	2,319
DCLRE1C	1,756
IFTAP	479

Intra-cohort edges

A	B	Sources
DCLRE1C	IL2RG	string_interaction
DCLRE1C	LIG4	intact, string_interaction
DCLRE1C	RAG1	string_interaction
DCLRE1C	RAG2	string_interaction
IL2RG	IL7R	intact, string_interaction
IL2RG	RAG1	string_interaction
IL2RG	RAG2	string_interaction
IL7R	RAG1	string_interaction
RAG1	RAG2	biogrid_interaction, string_interaction

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIG4	P49917	31
DCLRE1C	Q96SD1	14
IL2RG	P31785	14
IL7R	P16871	8
CHD7	Q9P2D1	3
ADA	P00813	2
SUV39H2	Q9H5I1	2
RAG2	P55895	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68
IFTAP	Q86VG3	66.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 10 evidence-associated genes (9 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 9 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	4	141.0×	3e-07	IL7R, RAG1, RAG2, IL2RG
Defective ADA disrupts (deoxy)adenosine deamination	1	1268.9×	0.009	ADA
Nucleotide salvage defects	1	634.4×	0.009	ADA
Diseases of nucleotide metabolism	1	634.4×	0.009	ADA
Nonhomologous End-Joining (NHEJ)	2	37.3×	0.009	DCLRE1C, LIG4
MAPK6/MAPK4 signaling	2	30.2×	0.009	RAG1, RAG2
2-LTR circle formation	1	181.3×	0.021	LIG4
Interleukin-9 signaling	1	141.0×	0.021	IL2RG
Nucleotide salvage	1	126.9×	0.021	ADA
Interleukin-21 signaling	1	126.9×	0.021	IL2RG
STAT3 nuclear events downstream of ALK signaling	1	115.3×	0.021	IL2RG
Ribavirin ADME	1	115.3×	0.021	ADA
Interleukin-2 signaling	1	105.7×	0.021	IL2RG
Purine salvage	1	97.6×	0.021	ADA
Interleukin-15 signaling	1	84.6×	0.023	IL2RG
Interleukin receptor SHC signaling	1	45.3×	0.040	IL2RG
Metabolism of nucleotides	1	33.4×	0.050	ADA
Drug ADME	1	25.4×	0.062	ADA
PKMTs methylate histone lysines	1	17.9×	0.083	SUV39H2
CHD6, CHD7, CHD8, CHD9 subfamily	1	16.5×	0.086	CHD7
Cargo recognition for clathrin-mediated endocytosis	1	11.6×	0.111	IL7R
Interleukin-4 and Interleukin-13 signaling	1	11.4×	0.111	IL2RG
Clathrin-mediated endocytosis	1	9.5×	0.124	IL7R
Chromatin organization	1	9.1×	0.124	SUV39H2
Diseases of metabolism	1	8.9×	0.124	ADA
Chromatin modifying enzymes	1	8.0×	0.131	SUV39H2
RAF/MAP kinase cascade	1	6.8×	0.148	IL2RG
Disease	1	1.4×	0.530	ADA
Metabolism	1	1.3×	0.555	ADA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
T cell differentiation in thymus	6	246.6×	6e-12	IL7R, RAG1, RAG2, ADA, IL2RG, LIG4
V(D)J recombination	4	842.6×	4e-10	DCLRE1C, RAG1, RAG2, LIG4
positive regulation of T cell differentiation in thymus	3	459.6×	2e-06	IL7R, ADA, IL2RG
pre-B cell allelic exclusion	2	1123.5×	5e-05	RAG1, RAG2
DN2 thymocyte differentiation	2	842.6×	7e-05	RAG2, LIG4
interleukin-7-mediated signaling pathway	2	421.3×	3e-04	IL7R, IL2RG
B cell differentiation	3	65.7×	3e-04	DCLRE1C, RAG1, RAG2
negative regulation of thymocyte apoptotic process	2	337.0×	3e-04	RAG1, ADA
cellular homeostasis	2	160.5×	0.001	IL7R, IL2RG
B cell proliferation	2	96.3×	0.004	IL7R, ADA
T cell homeostasis	2	91.1×	0.004	IL7R, RAG1
double-strand break repair via nonhomologous end joining	2	84.3×	0.004	DCLRE1C, LIG4
mature B cell differentiation	1	1685.2×	0.006	IL2RG
mature B cell apoptotic process	1	1685.2×	0.006	ADA
right ventricular compact myocardium morphogenesis	1	1685.2×	0.006	CHD7
purine nucleotide salvage	1	1685.2×	0.006	ADA
xanthine biosynthetic process	1	1685.2×	0.006	ADA
negative regulation of adenosine receptor signaling pathway	1	1685.2×	0.006	ADA
negative regulation of penile erection	1	1685.2×	0.006	ADA
establishment of integrated proviral latency	1	1685.2×	0.006	LIG4
B cell homeostatic proliferation	1	842.6×	0.008	RAG2
positive regulation of germinal center formation	1	842.6×	0.008	ADA
penile erection	1	842.6×	0.008	ADA
purine-containing compound salvage	1	842.6×	0.008	ADA
hypoxanthine salvage	1	842.6×	0.008	ADA
dATP catabolic process	1	842.6×	0.008	ADA
negative regulation of mucus secretion	1	842.6×	0.008	ADA
positive regulation of chromosome organization	1	842.6×	0.008	LIG4
immune response	3	14.1×	0.008	IL7R, RAG1, IL2RG
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	561.7×	0.010	IL2RG

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 4 of 10 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ADA	PENTOSTATIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADA	3	4
DCLRE1C	0	0
IL7R	0	0
RAG1	0	0
RAG2	0	0
CHD7	0	0
IL2RG	0	0
LIG4	0	0
SUV39H2	0	0
IFTAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
COFORMYCIN	2	ADA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SUV39H2	62	Binding:61, Functional:1
ADA	40	Binding:35, ADMET:5
LIG4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADA	3.5.4.4	adenosine deaminase
LIG4	6.5.1.1	DNA ligase (ATP)

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
PENTOSTATIN	4	ADA
AFAMELANOTIDE	4	ADA
COFORMYCIN	2	ADA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	IL7R, IL2RG, LIG4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	DCLRE1C, RAG1, RAG2, CHD7, SUV39H2, IFTAP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DCLRE1C	0	—
IL7R	0	—
RAG1	0	—
RAG2	0	—
CHD7	0	—
IL2RG	0	—
LIG4	2	—
SUV39H2	62	—
IFTAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)