Immunodeficiency 126, susceptibility to

Summary

Immunodeficiency 126, susceptibility to (MONDO:0975761) is a disease caused by PTCRA (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PTCRA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 126, susceptibility to
Mondo ID	MONDO:0975761
OMIM	620931
UMLS	C5975362
MedGen	1874892
Is cancer (heuristic)	no

Also known as: combined immunodeficiency due to autosomal recessive pre-TCR alpha deficiency

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 126, susceptibility to

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

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

4 retrieved; paginated sample, class counts are floors:

2 risk factor, 1 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3338636	NM_138296.3(PTCRA):c.296_299del (p.Leu99fs)	PTCRA	Pathogenic	no assertion criteria provided
3338634	NM_138296.3(PTCRA):c.446G>A (p.Trp149Ter)	PTCRA	risk factor	no assertion criteria provided
3338635	NM_138296.3(PTCRA):c.429del (p.Pro144fs)	PTCRA	risk factor	no assertion criteria provided
4813606	NM_138576.4(BCL11B):c.1142C>T (p.Ser381Phe)	BCL11B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
PTCRA	Strong	Autosomal recessive	immunodeficiency 126, susceptibility to	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCL11B	Orphanet:662829	Intellectual disability-speech delay-dysmorphic features-T cell abnormalities syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTCRA	HGNC:21290	ENSG00000171611	Q6ISU1	Pre T-cell antigen receptor alpha	gencc,clinvar
BCL11B	HGNC:13222	ENSG00000127152	Q9C0K0	B-cell lymphoma/leukemia 11B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTCRA	Pre T-cell antigen receptor alpha	Component of the pre-T-cell receptor complex (composed of PTCRA, TCRB and the CD3 complex) that has a crucial role in early T-cell development, particularly alpha-beta T cell differentiation.
BCL11B	B-cell lymphoma/leukemia 11B	Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	14.6×	0.135
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTCRA	Antibody/Immunoglobulin	yes		Ig-like_fold, PTCRA, Ig-like_dom_sf
BCL11B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
olfactory bulb	1
type B pancreatic cell	1
cortical plate	1
thymus	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTCRA	198	tissue_specific	marker	type B pancreatic cell, olfactory bulb, monocyte
BCL11B	211	broad	marker	thymus, upper leg skin, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCL11B	2,523
PTCRA	1,051

Intra-cohort edges

A	B	Sources
BCL11B	PTCRA	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTCRA	Q6ISU1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BCL11B	Q9C0K0	51.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Formation of the embryonic stem cell BAF (esBAF) complex	1	300.5×	0.005	BCL11B
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	228.4×	0.005	BCL11B
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.005	PTCRA

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
alpha-beta T cell differentiation	2	1872.4×	3e-06	PTCRA, BCL11B
negative regulation of thymocyte apoptotic process	2	1685.2×	3e-06	PTCRA, BCL11B
olfactory bulb axon guidance	1	8426.0×	9e-04	BCL11B
positive T cell selection	1	4213.0×	0.001	BCL11B
lymphoid lineage cell migration into thymus	1	4213.0×	0.001	BCL11B
striatal medium spiny neuron differentiation	1	2106.5×	0.001	BCL11B
post-embryonic camera-type eye development	1	2106.5×	0.001	BCL11B
T cell receptor V(D)J recombination	1	2106.5×	0.001	BCL11B
hematopoietic stem cell migration	1	2106.5×	0.001	BCL11B
commitment of neuronal cell to specific neuron type in forebrain	1	1404.3×	0.002	BCL11B
keratinocyte development	1	766.0×	0.002	BCL11B
regulation of keratinocyte proliferation	1	766.0×	0.002	BCL11B
thymocyte apoptotic process	1	702.2×	0.002	BCL11B
epithelial cell morphogenesis	1	468.1×	0.003	BCL11B
regulation of neuron differentiation	1	366.4×	0.004	BCL11B
regulation of lipid metabolic process	1	216.1×	0.006	BCL11B
T cell differentiation in thymus	1	205.5×	0.006	BCL11B
thymus development	1	168.5×	0.007	BCL11B
odontogenesis of dentin-containing tooth	1	150.5×	0.008	BCL11B
transcription by RNA polymerase II	1	35.3×	0.031	BCL11B
negative regulation of cell population proliferation	1	21.1×	0.049	BCL11B
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	BCL11B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
PTCRA	0	0
BCL11B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	PTCRA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BCL11B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTCRA	0	—
BCL11B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.