Lymphoproliferative syndrome 1

Summary

Lymphoproliferative syndrome 1 (MONDO:0013081) is a disease caused by ITK (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ITK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 544

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphoproliferative syndrome 1
Mondo ID	MONDO:0013081
MeSH	C567815
OMIM	613011
Orphanet	538963
DOID	DOID:0060707
NCIT	C126344
UMLS	C3552634
MedGen	765548
GARD	0017979
Is cancer (heuristic)	no

Also known as: ITK deficiency · ITK lymphoproliferative syndrome · LPFS1 · lymphoproliferative syndrome 1 · lymphoproliferative syndrome caused by mutation in ITK · lymphoproliferative syndrome type 1

Data availability: 544 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › lymphoproliferative syndrome › lymphoproliferative syndrome 1

Related subtypes (7): X-linked lymphoproliferative syndrome, Dianzani autoimmune lymphoproliferative disease, lymphoproliferative syndrome 2, Castleman disease, autoimmune lymphoproliferative syndrome, severe combined immunodeficiency due to CD70 deficiency, atypical lymphoproliferative disorder

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

544 retrieved; paginated sample, class counts are floors:

240 likely benign, 238 uncertain significance, 22 conflicting classifications of pathogenicity, 21 benign, 14 pathogenic, 6 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456681	NM_005546.4(ITK):c.49C>T (p.Gln17Ter)	ITK	Pathogenic	criteria provided, single submitter
1460222	NC_000005.9:g.(?156659330)(156667225_?)del	ITK	Pathogenic	criteria provided, single submitter
2004689	NM_005546.4(ITK):c.228T>A (p.Tyr76Ter)	ITK	Pathogenic	criteria provided, single submitter
2088804	NM_005546.4(ITK):c.380del (p.Asp127fs)	ITK	Pathogenic	criteria provided, single submitter
2109594	NM_005546.4(ITK):c.1201G>T (p.Glu401Ter)	ITK	Pathogenic	criteria provided, single submitter
2109769	NM_005546.4(ITK):c.1664del (p.Gly555fs)	ITK	Pathogenic	criteria provided, single submitter
2148272	NM_005546.4(ITK):c.742A>T (p.Lys248Ter)	ITK	Pathogenic	criteria provided, single submitter
2750136	NM_005546.4(ITK):c.389G>A (p.Trp130Ter)	ITK	Pathogenic	criteria provided, single submitter
3661212	NM_005546.4(ITK):c.871A>T (p.Lys291Ter)	ITK	Pathogenic	criteria provided, single submitter
3667792	NM_005546.4(ITK):c.925G>T (p.Glu309Ter)	ITK	Pathogenic	criteria provided, single submitter
4694433	NM_005546.4(ITK):c.175C>T (p.Arg59Ter)	ITK	Pathogenic	criteria provided, single submitter
4725764	NM_005546.4(ITK):c.819C>G (p.Tyr273Ter)	ITK	Pathogenic	criteria provided, single submitter
64371	NM_005546.4(ITK):c.1764C>G (p.Tyr588Ter)	ITK	Pathogenic	no assertion criteria provided
2425364	NC_000005.9:g.(?155338082)(156899968_?)del	TIMD4	Pathogenic	criteria provided, single submitter
12741	NM_005546.4(ITK):c.1003C>T (p.Arg335Trp)	ITK	Likely pathogenic	criteria provided, single submitter
2860481	NM_005546.4(ITK):c.139-2A>G	ITK	Likely pathogenic	criteria provided, single submitter
3064392	NM_005546.4(ITK):c.129del (p.Arg44fs)	ITK	Likely pathogenic	criteria provided, single submitter
4731821	NM_005546.4(ITK):c.455-1G>C	ITK	Likely pathogenic	criteria provided, single submitter
4846822	NM_005546.4(ITK):c.1233-1G>A	ITK	Likely pathogenic	criteria provided, single submitter
64372	NM_005546.4(ITK):c.86G>A (p.Arg29His)	ITK	Likely pathogenic	criteria provided, single submitter
1024741	NM_005546.4(ITK):c.1075G>C (p.Asp359His)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1084872	NM_005546.4(ITK):c.33C>A (p.Leu11=)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1457163	NM_005546.4(ITK):c.512C>T (p.Pro171Leu)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694291	NM_005546.4(ITK):c.810A>G (p.Ala270=)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352456	NM_005546.4(ITK):c.139-6C>T	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352457	NM_005546.4(ITK):c.150G>A (p.Thr50=)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352458	NM_005546.4(ITK):c.237G>A (p.Pro79=)	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352461	NM_005546.4(ITK):c.495+12C>T	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352462	NM_005546.4(ITK):c.496-4C>G	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352471	NM_005546.4(ITK):c.1060+12A>C	ITK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ITK	Definitive	Autosomal recessive	lymphoproliferative syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITK	Orphanet:538963	Combined immunodeficiency due to ITK deficiency

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
ITK	HGNC:6171	ENSG00000113263	Q08881	Tyrosine-protein kinase ITK/TSK	gencc,clinvar
HAVCR1	HGNC:17866	ENSG00000113249	Q96D42	Hepatitis A virus cellular receptor 1	clinvar
TIMD4	HGNC:25132	ENSG00000145850	Q96H15	T-cell immunoglobulin and mucin domain-containing protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITK	Tyrosine-protein kinase ITK/TSK	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
HAVCR1	Hepatitis A virus cellular receptor 1	Phosphatidylserine receptor that plays an important functional role in regulatory B-cell homeostasis including generation, expansion and suppressor functions.
TIMD4	T-cell immunoglobulin and mucin domain-containing protein 4	Phosphatidylserine receptor that plays different role in immune response including phagocytosis of apoptotic cells and T-cell regulation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	2	19.5×	0.007
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
HAVCR1	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_sub, Ig-like_dom
TIMD4	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set

Expression context

Cohort genes with no expression data: 0.

3 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
blood	1
granulocyte	1
thymus	1
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
rectum	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITK	198	broad	marker	granulocyte, thymus, blood
HAVCR1	123	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, adult mammalian kidney, rectum
TIMD4	154	tissue_specific	marker	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITK	2,670
TIMD4	1,536
HAVCR1	1,528

Intra-cohort edges

A	B	Sources
HAVCR1	TIMD4	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITK	Q08881	37
TIMD4	Q96H15	3
HAVCR1	Q96D42	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 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
Dengue Virus Attachment and Entry	2	173.0×	4e-04	HAVCR1, TIMD4
Attachment and Entry	1	200.3×	0.016	HAVCR1
TCR signaling	1	165.5×	0.016	ITK
FCERI mediated Ca+2 mobilization	1	119.0×	0.016	ITK
Generation of second messenger molecules	1	115.3×	0.016	ITK
Fc epsilon receptor (FCERI) signaling	1	90.6×	0.016	ITK
Adaptive Immune System	1	9.9×	0.125	ITK
Innate Immune System	1	8.5×	0.127	ITK
Immune System	1	4.3×	0.214	ITK

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
cytoskeletal rearrangement involved in phagocytosis, engulfment	1	5617.3×	0.002	TIMD4
NK T cell differentiation	1	1404.3×	0.004	ITK
positive regulation of mast cell activation	1	1123.5×	0.004	HAVCR1
gamma-delta T cell activation	1	702.2×	0.005	ITK
apoptotic cell clearance	1	295.6×	0.009	TIMD4
phagocytosis, engulfment	1	224.7×	0.010	HAVCR1
B cell receptor signaling pathway	1	133.8×	0.015	ITK
cellular defense response	1	106.0×	0.016	ITK
positive regulation of cytokine production	1	90.6×	0.016	ITK
T cell activation	1	86.4×	0.016	ITK
T cell receptor signaling pathway	1	50.6×	0.025	ITK
adaptive immune response	1	28.1×	0.041	ITK
intracellular signal transduction	1	12.7×	0.083	ITK
signal transduction	1	5.3×	0.176	ITK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
ITK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITK	39	4
HAVCR1	0	0
TIMD4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ITK
AXITINIB	4	ITK
IBRUTINIB	4	ITK
BOSUTINIB	4	ITK
ACALABRUTINIB	4	ITK
ZANUBRUTINIB	4	ITK
RITLECITINIB	4	ITK
NINTEDANIB	4	ITK
SUNITINIB	4	ITK
DASATINIB	4	ITK
QUIZARTINIB	4	ITK
CRIZOTINIB	4	ITK
CANERTINIB	3	ITK
EVOBRUTINIB	3	ITK
REMIBRUTINIB	3	ITK
DOVITINIB	3	ITK
LESTAURTINIB	3	ITK
FORETINIB	2	ITK
TANDUTINIB	2	ITK
SU-014813	2	ITK
REBASTINIB	2	ITK
CENISERTIB	2	ITK
ILORASERTIB	2	ITK
OSI-632	2	ITK
SPEBRUTINIB	2	ITK
BMS-986142	2	ITK
BMS-919373	2	ITK
ATUZABRUTINIB	2	ITK
CERDULATINIB	2	ITK
BRANEBRUTINIB	2	ITK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ITK	563	Binding:547, Functional:10, ADMET:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ITK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ITK	563

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

30 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)
FEDRATINIB	4	ITK
AXITINIB	4	ITK
IBRUTINIB	4	ITK
BOSUTINIB	4	ITK
ACALABRUTINIB	4	ITK
ZANUBRUTINIB	4	ITK
RITLECITINIB	4	ITK
NINTEDANIB	4	ITK
SUNITINIB	4	ITK
DASATINIB	4	ITK
QUIZARTINIB	4	ITK
CRIZOTINIB	4	ITK
CANERTINIB	3	ITK
EVOBRUTINIB	3	ITK
REMIBRUTINIB	3	ITK
DOVITINIB	3	ITK
LESTAURTINIB	3	ITK
FORETINIB	2	ITK
TANDUTINIB	2	ITK
SU-014813	2	ITK
REBASTINIB	2	ITK
CENISERTIB	2	ITK
ILORASERTIB	2	ITK
OSI-632	2	ITK
SPEBRUTINIB	2	ITK
BMS-986142	2	ITK
BMS-919373	2	ITK
ATUZABRUTINIB	2	ITK
CERDULATINIB	2	ITK
BRANEBRUTINIB	2	ITK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ITK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	HAVCR1, TIMD4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
HAVCR1	0	—
TIMD4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.