T-B+ severe combined immunodeficiency due to gamma chain deficiency

Summary

T-B+ severe combined immunodeficiency due to gamma chain deficiency (MONDO:0010315) is a disease caused by IL2RG (GenCC Definitive), with 3 cohort genes and 11 clinical trials. Top therapeutic interventions include busulfan, palifermin, and plerixafor.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: IL2RG (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 477
• Phenotypes (HPO): 33
• Clinical trials: 11

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0032218	Decreased proportion of CD4-positive T cells	Very frequent (80-99%)
HP:0001888	Lymphopenia	Very frequent (80-99%)
HP:0001954	Recurrent fever	Very frequent (80-99%)
HP:0002090	Pneumonia	Very frequent (80-99%)
HP:0010701	Abnormal immunoglobulin level	Very frequent (80-99%)
HP:0031381	Decreased lymphocyte proliferation in response to mitogen	Very frequent (80-99%)
HP:0031397	Reduced proportion of naive T cells	Very frequent (80-99%)
HP:0040218	Reduced natural killer cell count	Very frequent (80-99%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002720	Decreased circulating IgA level	Frequent (30-79%)
HP:0004315	Decreased circulating IgG level	Frequent (30-79%)
HP:0005390	Recurrent opportunistic infections	Frequent (30-79%)
HP:0012735	Cough	Frequent (30-79%)
HP:0031545	Abnormally low T cell receptor excision circle level	Frequent (30-79%)
HP:0045080	Decreased proportion of CD3-positive T cells	Frequent (30-79%)
HP:0100806	Sepsis	Frequent (30-79%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002728	Chronic mucocutaneous candidiasis	Occasional (5-29%)
HP:0002732	Lymph node hypoplasia	Occasional (5-29%)
HP:0005353	Recurrent herpes	Occasional (5-29%)
HP:0005376	Recurrent Haemophilus influenzae infections	Occasional (5-29%)
HP:0005406	Recurrent bacterial skin infections	Occasional (5-29%)
HP:0005428	Severe recurrent varicella	Occasional (5-29%)
HP:0009098	Chronic oral candidiasis	Occasional (5-29%)
HP:0011370	Recurrent cutaneous fungal infections	Occasional (5-29%)
HP:0030813	Absent tonsils	Occasional (5-29%)
HP:0000952	Jaundice	Very rare (<1-4%)
HP:0002240	Hepatomegaly	Very rare (<1-4%)
HP:0002665	Lymphoma	Very rare (<1-4%)
HP:0003237	Increased circulating IgG level	Very rare (<1-4%)
HP:0005523	Lymphoproliferative disorder	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	T-B+ severe combined immunodeficiency due to gamma chain deficiency
Mondo ID	MONDO:0010315
EFO	EFO:0005555
OMIM	300400
Orphanet	276
DOID	DOID:0060013
NCIT	C4682
SNOMED CT	203592006
UMLS	C1279481
MedGen	220906
GARD	0005618
Is cancer (heuristic)	no

Also known as: SCIDX · SCIDX1 · severe combined immunodeficiency T- B+ due to gamma chain deficiency · severe combined immunodeficiency T- B+, X-linked · severe combined immunodeficiency, X-linked · severe combined immunodeficiency, X-linked, X-linked recessive · T-B+ SCID due to gamma chain deficiency · T-B+ severe combined immunodeficiency due to gamma chain deficiency · T-B+ severe combined immunodeficiency, X-linked · X-linked SCID · X-linked severe combined immunodeficiency · X-SCID · XSCID

Data availability: 477 ClinVar variants · 54 ClinGen variant curations · 5 GenCC gene-disease records · 2 cell lines.

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 › familial severe combined immunodeficiency › T-B+ severe combined immunodeficiency due to gamma chain deficiency

Related subtypes (13): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, MHC class II deficiency, reticular dysgenesis, T-B+ severe combined immunodeficiency due to JAK3 deficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, immunodeficiency 104, Cernunnos-XLF deficiency, immunodeficiency 18, immunodeficiency 19, immunodeficiency 49, immunodeficiency 105

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

477 retrieved; paginated sample, class counts are floors:

163 likely benign, 121 uncertain significance, 101 pathogenic, 38 likely pathogenic, 27 benign, 16 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
265194	NM_000206.3(IL2RG):c.270-15A>G	CXorf65	Pathogenic	criteria provided, multiple submitters, no conflicts
3244127	NC_000023.10:g.(?70326254)(70332481_?)del	CXorf65	Pathogenic	criteria provided, single submitter
10016	NM_000206.3(IL2RG):c.355A>T (p.Lys119Ter)	IL2RG	Pathogenic	no assertion criteria provided
10018	NM_000206.3(IL2RG):c.923C>A (p.Ser308Ter)	IL2RG	Pathogenic	no assertion criteria provided
10019	NM_000206.3(IL2RG):c.186T>A (p.Cys62Ter)	IL2RG	Pathogenic	reviewed by expert panel
10020	NM_000206.3(IL2RG):c.341G>A (p.Gly114Asp)	IL2RG	Pathogenic	no assertion criteria provided
10021	NM_000206.3(IL2RG):c.454+1G>A	IL2RG	Pathogenic	no assertion criteria provided
10022	NM_000206.3(IL2RG):c.458T>A (p.Ile153Asn)	IL2RG	Pathogenic	no assertion criteria provided
10023	NM_000206.3(IL2RG):c.878T>A (p.Leu293Gln)	IL2RG	Pathogenic	criteria provided, single submitter
10024	NM_000206.3(IL2RG):c.703_711dup (p.Gln235_Trp237dup)	IL2RG	Pathogenic	no assertion criteria provided
10025	NM_000206.3(IL2RG):c.343T>C (p.Cys115Arg)	IL2RG	Pathogenic	reviewed by expert panel
10026	NM_000206.3(IL2RG):c.854G>A (p.Arg285Gln)	IL2RG	Pathogenic	criteria provided, multiple submitters, no conflicts
10027	NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)	IL2RG	Pathogenic	reviewed by expert panel
1028611	NM_000206.3(IL2RG):c.269+1G>T	IL2RG	Pathogenic	reviewed by expert panel
1066149	NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg)	IL2RG	Pathogenic	reviewed by expert panel
1066800	NM_000206.3(IL2RG):c.594+5G>T	IL2RG	Pathogenic	criteria provided, single submitter
1067389	NM_000206.3(IL2RG):c.340G>T (p.Gly114Cys)	IL2RG	Pathogenic	criteria provided, single submitter
1068066	NM_000206.3(IL2RG):c.116-1G>A	IL2RG	Pathogenic	reviewed by expert panel
1068144	NM_000206.3(IL2RG):c.854+2T>C	IL2RG	Pathogenic	criteria provided, single submitter
1068145	NM_000206.3(IL2RG):c.713G>A (p.Ser238Asn)	IL2RG	Pathogenic	criteria provided, single submitter
1068146	NM_000206.3(IL2RG):c.675C>A (p.Ser225Arg)	IL2RG	Pathogenic	criteria provided, single submitter
1069444	NM_000206.3(IL2RG):c.302_384dup (p.Val129fs)	IL2RG	Pathogenic	criteria provided, single submitter
1070717	NC_000023.10:g.(?70328107)(70328216_?)del	IL2RG	Pathogenic	criteria provided, single submitter
1074635	NM_000206.3(IL2RG):c.148del (p.Leu50fs)	IL2RG	Pathogenic	criteria provided, single submitter
1075157	NM_000206.3(IL2RG):c.758-2A>G	IL2RG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175096	NM_000206.3(IL2RG):c.816_819del (p.Ile273fs)	IL2RG	Pathogenic	criteria provided, single submitter
1251965	NM_000206.3(IL2RG):c.922del (p.Ser308fs)	IL2RG	Pathogenic	criteria provided, single submitter
1323112	NM_000206.3(IL2RG):c.115+1G>T	IL2RG	Pathogenic	reviewed by expert panel
1351468	NM_000206.3(IL2RG):c.359dup (p.Glu121fs)	IL2RG	Pathogenic	criteria provided, single submitter
1355530	NM_000206.3(IL2RG):c.598C>T (p.Gln200Ter)	IL2RG	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
IL2RG	Definitive	X-linked	T-B+ severe combined immunodeficiency due to gamma chain deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL2RG	Orphanet:276	T-B+ severe combined immunodeficiency due to gamma chain deficiency
IL2RG	Orphanet:39041	Omenn syndrome
GJB1	Orphanet:101075	X-linked Charcot-Marie-Tooth disease type 1
GJB1	Orphanet:1175	X-linked progressive cerebellar ataxia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL2RG	HGNC:6010	ENSG00000147168	P31785	Cytokine receptor common subunit gamma	gencc,clinvar
CXorf65	HGNC:33713	ENSG00000204165	A6NEN9	Uncharacterized protein CXorf65	clinvar
GJB1	HGNC:4283	ENSG00000169562	P08034	Gap junction beta-1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL2RG	Cytokine receptor common subunit gamma	Common subunit for the receptors for a variety of interleukins.
GJB1	Gap junction beta-1 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL2RG	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
CXorf65	Other/Unknown	no		CXorf65-like
GJB1	Other/Unknown	no		Connexin, Connexin32, Connexin_N

Expression context

Cohort genes with no expression data: 0.

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
lymph node	1
vermiform appendix	1
left testis	1
testis	1
C1 segment of cervical spinal cord	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL2RG	213	broad	marker	granulocyte, lymph node, vermiform appendix
CXorf65	122	tissue_specific	yes	granulocyte, left testis, testis
GJB1	207	broad	marker	right lobe of liver, C1 segment of cervical spinal cord, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL2RG	2,470
GJB1	1,494
CXorf65	207

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB1	P08034	15
IL2RG	P31785	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CXorf65	A6NEN9	82.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oligomerization of connexins into connexons	1	1903.3×	0.003	GJB1
Transport of connexins along the secretory pathway	1	1903.3×	0.003	GJB1
Interleukin-9 signaling	1	634.4×	0.005	IL2RG
Interleukin-21 signaling	1	571.0×	0.005	IL2RG
STAT3 nuclear events downstream of ALK signaling	1	519.1×	0.005	IL2RG
Interleukin-2 signaling	1	475.8×	0.005	IL2RG
Interleukin-15 signaling	1	380.7×	0.005	IL2RG
Interleukin receptor SHC signaling	1	203.9×	0.008	IL2RG
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.008	GJB1
Interleukin-7 signaling	1	158.6×	0.008	IL2RG
Gap junction assembly	1	146.4×	0.008	GJB1
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.021	IL2RG
RAF/MAP kinase cascade	1	30.5×	0.032	IL2RG

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mature B cell differentiation	1	5617.3×	0.004	IL2RG
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1872.4×	0.004	IL2RG
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1123.5×	0.004	IL2RG
lymphocyte differentiation	1	936.2×	0.004	IL2RG
interleukin-4-mediated signaling pathway	1	802.5×	0.004	IL2RG
gap junction assembly	1	702.2×	0.004	GJB1
interleukin-2-mediated signaling pathway	1	702.2×	0.004	IL2RG
interleukin-7-mediated signaling pathway	1	702.2×	0.004	IL2RG
interleukin-9-mediated signaling pathway	1	702.2×	0.004	IL2RG
interleukin-15-mediated signaling pathway	1	561.7×	0.004	IL2RG
positive regulation of T cell differentiation in thymus	1	510.7×	0.004	IL2RG
positive regulation of B cell differentiation	1	374.5×	0.005	IL2RG
cellular homeostasis	1	267.5×	0.007	IL2RG
positive regulation of immunoglobulin production	1	160.5×	0.010	IL2RG
T cell differentiation in thymus	1	137.0×	0.011	IL2RG
positive regulation of phagocytosis	1	106.0×	0.014	IL2RG
cytokine-mediated signaling pathway	1	43.5×	0.031	IL2RG
gene expression	1	26.6×	0.047	IL2RG
transcription by RNA polymerase II	1	23.5×	0.049	CXorf65
cell-cell signaling	1	23.2×	0.049	GJB1
immune response	1	15.7×	0.067	IL2RG
nervous system development	1	15.3×	0.067	GJB1
signal transduction	1	5.3×	0.176	IL2RG

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL2RG	0	0
CXorf65	0	0
GJB1	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
GJB1	1	Binding:1

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	1	IL2RG
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CXorf65, GJB1

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)
IL2RG	0	—
CXorf65	0	—
GJB1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	5
Not specified	4
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01306019	PHASE1/PHASE2	RECRUITING	Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
NCT03311503	PHASE1/PHASE2	RECRUITING	Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning
NCT06851767	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy
NCT00490100	PHASE1/PHASE2	TERMINATED	Treatment for Growth Failure in Patients With X-Linked Severe Combined Immunodeficiency: Phase 2 Study of Insulin-Like Growth Factor-1
NCT01410019	PHASE1/PHASE2	COMPLETED	Gene Therapy for X-linked Severe Combined Immunodeficiency
NCT03601286	PHASE1	RECRUITING	Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01175239	Not specified	UNKNOWN	Gene Therapy for X-linked Severe Combined Immunodeficiency (SCID-X1)
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUSULFAN	4	2
PALIFERMIN	4	2
PLERIXAFOR	4	2
MECASERMIN	4	1