X-linked lymphoproliferative disease due to XIAP deficiency

Summary

X-linked lymphoproliferative disease due to XIAP deficiency (MONDO:0010385) is a disease caused by XIAP (GenCC Strong), with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include tadekinig alfa, mas-825, and quercetin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: XIAP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 400
• Phenotypes (HPO): 22
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001876	Pancytopenia	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0005229	Jejunoileal ulceration	Frequent (30-79%)
HP:0012115	Hepatitis	Frequent (30-79%)
HP:0034799	Splenic hemophagocytosis	Frequent (30-79%)
HP:0100280	Crohn’s disease	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000123	Nephritis	Occasional (5-29%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0002037	Inflammation of the large intestine	Occasional (5-29%)
HP:0002583	Colitis	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0012219	Erythema nodosum	Occasional (5-29%)
HP:0030151	Cholangitis	Occasional (5-29%)
HP:0031292	Cutaneous abscess	Occasional (5-29%)
HP:0031693	Severe Epstein Barr virus infection	Occasional (5-29%)
HP:0040218	Reduced natural killer cell count	Occasional (5-29%)
HP:0001399	Hepatic failure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked lymphoproliferative disease due to XIAP deficiency
Mondo ID	MONDO:0010385
MeSH	C564469
OMIM	300635
Orphanet	538934
DOID	DOID:0060706
NCIT	C126295
UMLS	C1845076
MedGen	336848
GARD	0010916
Is cancer (heuristic)	no

Also known as: lymphoproliferative syndrome, X-linked, 2 · lymphoproliferative syndrome, X-linked, 2, X-linked recessive · lymphoproliferative syndrome, X-linked, type 2 · X-linked lymphoproliferative disease due to XIAP deficiency · X-linked lymphoproliferative syndrome type 2 · XIAP deficiency · XIAP deficiency/XLPs · XIAP-related lymphoproliferative disease, X-linked · XLP2

Data availability: 400 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked lymphoproliferative syndrome › X-linked lymphoproliferative disease due to XIAP deficiency

Related subtypes (1): X-linked lymphoproliferative disease due to SH2D1A deficiency

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

400 retrieved; paginated sample, class counts are floors:

155 uncertain significance, 78 benign, 73 likely benign, 59 pathogenic, 19 conflicting classifications of pathogenicity, 10 likely pathogenic, 5 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071347	NM_001167.4(XIAP):c.1012dup (p.Tyr338fs)	XIAP	Pathogenic	criteria provided, single submitter
1072889	NM_001167.4(XIAP):c.978-2A>G	XIAP	Pathogenic	criteria provided, single submitter
1073250	NM_001167.4(XIAP):c.60del (p.Glu21fs)	XIAP	Pathogenic	criteria provided, single submitter
1162913	NM_001167.4(XIAP):c.894_898del (p.Lys299fs)	XIAP	Pathogenic	criteria provided, multiple submitters, no conflicts
11645	NM_001167.4(XIAP):c.292del (p.Glu99fs)	XIAP	Pathogenic	no assertion criteria provided
11646	NM_001167.4(XIAP):c.352G>T (p.Glu118Ter)	XIAP	Pathogenic	no assertion criteria provided
11647	NG_007264.1:g.(31343_33421)_(33522_36040)del	XIAP	Pathogenic	no assertion criteria provided
1375770	NM_001167.4(XIAP):c.755dup (p.Asn252fs)	XIAP	Pathogenic	criteria provided, single submitter
1418323	NM_001167.4(XIAP):c.1315G>T (p.Glu439Ter)	XIAP	Pathogenic	criteria provided, single submitter
1452964	NM_001167.4(XIAP):c.921_924del (p.Thr308fs)	XIAP	Pathogenic	criteria provided, single submitter
1456269	NM_001167.4(XIAP):c.1048G>T (p.Glu350Ter)	XIAP	Pathogenic	criteria provided, single submitter
1479537	NM_001167.4(XIAP):c.609TGG[1] (p.Gly205del)	XIAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1482523	NM_001167.4(XIAP):c.1386del (p.Phe462fs)	XIAP	Pathogenic	criteria provided, single submitter
1701610	NM_001167.4(XIAP):c.345C>G (p.Tyr115Ter)	XIAP	Pathogenic	criteria provided, multiple submitters, no conflicts
2019044	NM_001167.4(XIAP):c.990_991del (p.Leu331fs)	XIAP	Pathogenic	criteria provided, single submitter
2048465	NM_001167.4(XIAP):c.1009G>T (p.Glu337Ter)	XIAP	Pathogenic	criteria provided, multiple submitters, no conflicts
2138713	NM_001167.4(XIAP):c.145C>T (p.Arg49Ter)	XIAP	Pathogenic	criteria provided, single submitter
2700917	NM_001167.4(XIAP):c.664_665insTGTC (p.Arg222fs)	XIAP	Pathogenic	criteria provided, single submitter
2836709	NM_001167.4(XIAP):c.371del (p.Arg124fs)	XIAP	Pathogenic	criteria provided, single submitter
2867274	NM_001167.4(XIAP):c.481del (p.Tyr161fs)	XIAP	Pathogenic	criteria provided, single submitter
3068635	NM_001167.4(XIAP):c.985del (p.Tyr329fs)	XIAP	Pathogenic	criteria provided, multiple submitters, no conflicts
3244551	NC_000023.10:g.(?123010866)(123025086_?)del	XIAP	Pathogenic	criteria provided, single submitter
3244562	NC_000023.10:g.(?123025068)(123041031_?)del	XIAP	Pathogenic	criteria provided, single submitter
3255350	NM_001167.4(XIAP):c.969G>A (p.Trp323Ter)	XIAP	Pathogenic	criteria provided, single submitter
3255351	NM_001167.4(XIAP):c.1057-600_1300+79del	XIAP	Pathogenic	criteria provided, single submitter
3642311	NM_001167.4(XIAP):c.218G>A (p.Trp73Ter)	XIAP	Pathogenic	criteria provided, single submitter
3645202	NM_001167.4(XIAP):c.568dup (p.Tyr190fs)	XIAP	Pathogenic	criteria provided, single submitter
3653116	NM_001167.4(XIAP):c.416_417del (p.Tyr139fs)	XIAP	Pathogenic	criteria provided, single submitter
3663962	NM_001167.4(XIAP):c.764dup (p.Asn255fs)	XIAP	Pathogenic	criteria provided, single submitter
3664415	NM_001167.4(XIAP):c.64G>T (p.Glu22Ter)	XIAP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
XIAP	Strong	X-linked	X-linked lymphoproliferative disease due to XIAP deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
XIAP	Orphanet:538934	X-linked lymphoproliferative disease due to XIAP deficiency
STAG2	Orphanet:220386	Semilobar holoprosencephaly
STAG2	Orphanet:521258	Xq25 microduplication syndrome
STAG2	Orphanet:93925	Alobar holoprosencephaly

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
XIAP	HGNC:592	ENSG00000101966	P98170	E3 ubiquitin-protein ligase XIAP	gencc,clinvar
STAG2	HGNC:11355	ENSG00000101972	Q8N3U4	Cohesin subunit SA-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
XIAP	E3 ubiquitin-protein ligase XIAP	Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis.
STAG2	Cohesin subunit SA-2	Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
XIAP	Transcription factor	no		BIR_rpt, Znf_RING, DEATH-like_dom_sf
STAG2	Other/Unknown	no		STAG, ARM-type_fold, SCD

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
buccal mucosa cell	1
ileal mucosa	1
kidney epithelium	1
calcaneal tendon	1
mucosa of paranasal sinus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
XIAP	256	ubiquitous	marker	kidney epithelium, ileal mucosa, buccal mucosa cell
STAG2	299	ubiquitous	marker	mucosa of paranasal sinus, calcaneal tendon, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XIAP	5,252
STAG2	2,945

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XIAP	P98170	74
STAG2	Q8N3U4	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. 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
Activation of caspases through apoptosome-mediated cleavage	1	951.7×	0.008	XIAP
SMAC (DIABLO) binds to IAPs	1	815.7×	0.008	XIAP
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	815.7×	0.008	XIAP
SMAC, XIAP-regulated apoptotic response	1	815.7×	0.008	XIAP
Mitotic Telophase/Cytokinesis	1	713.8×	0.008	STAG2
Cohesin Loading onto Chromatin	1	571.0×	0.008	STAG2
Establishment of Sister Chromatid Cohesion	1	519.1×	0.008	STAG2
Regulation of PTEN localization	1	519.1×	0.008	XIAP
Regulation of the apoptosome activity	1	519.1×	0.008	XIAP
RIPK1-mediated regulated necrosis	1	228.4×	0.014	XIAP
TNFR1-induced proapoptotic signaling	1	219.6×	0.014	XIAP
Regulation of necroptotic cell death	1	219.6×	0.014	XIAP
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.017	XIAP
Meiosis	1	142.8×	0.019	STAG2
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.021	XIAP
Regulation of TNFR1 signaling	1	112.0×	0.021	XIAP
Reproduction	1	95.2×	0.021	STAG2
Regulation of PTEN stability and activity	1	92.1×	0.021	XIAP
S Phase	1	90.6×	0.021	STAG2
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.021	STAG2
SUMOylation	1	81.6×	0.021	STAG2
Activation of STAT3 by cadherin engagement	1	81.6×	0.021	XIAP
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.022	STAG2
Meiotic synapsis	1	70.5×	0.022	STAG2
ESR-mediated signaling	1	64.2×	0.024	STAG2
Signaling by Nuclear Receptors	1	51.0×	0.028	STAG2
Mitotic Metaphase and Anaphase	1	48.4×	0.028	STAG2
Mitotic Anaphase	1	48.4×	0.028	STAG2
Resolution of Sister Chromatid Cohesion	1	43.3×	0.030	STAG2
Estrogen-dependent gene expression	1	37.8×	0.033	STAG2

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
positive regulation of protein linear polyubiquitination	1	4213.0×	0.004	XIAP
regulation of apoptosis involved in tissue homeostasis	1	2808.7×	0.004	XIAP
copper ion homeostasis	1	2106.5×	0.004	XIAP
regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	1685.2×	0.004	XIAP
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1685.2×	0.004	XIAP
establishment of mitotic sister chromatid cohesion	1	1203.7×	0.004	STAG2
quinolinate biosynthetic process	1	766.0×	0.005	XIAP
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.005	XIAP
regulation of BMP signaling pathway	1	601.9×	0.006	XIAP
sister chromatid cohesion	1	383.0×	0.008	STAG2
regulation of innate immune response	1	324.1×	0.008	XIAP
negative regulation of tumor necrosis factor-mediated signaling pathway	1	227.7×	0.011	XIAP
positive regulation of type I interferon production	1	210.7×	0.011	XIAP
mitotic spindle assembly	1	172.0×	0.012	STAG2
protein K63-linked ubiquitination	1	133.8×	0.015	XIAP
meiotic cell cycle	1	122.1×	0.015	STAG2
positive regulation of protein ubiquitination	1	106.7×	0.017	XIAP
neuron apoptotic process	1	92.6×	0.018	XIAP
regulation of inflammatory response	1	84.3×	0.018	XIAP
positive regulation of JNK cascade	1	81.8×	0.018	XIAP
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.018	XIAP
response to lipopolysaccharide	1	62.4×	0.022	XIAP
defense response to bacterium	1	54.0×	0.024	XIAP
Wnt signaling pathway	1	49.9×	0.025	XIAP
regulation of apoptotic process	1	41.7×	0.029	XIAP
regulation of cell cycle	1	37.3×	0.030	XIAP
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.030	XIAP
DNA damage response	1	26.8×	0.040	XIAP
cell division	1	23.1×	0.044	STAG2
negative regulation of apoptotic process	1	17.4×	0.057	XIAP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XIAP	6	3
STAG2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
XIAP	499	Binding:468, Functional:24, ADMET:7

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
XIAP	499

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

6 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)
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

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	1	XIAP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	STAG2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03113760	PHASE3	COMPLETED	Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency
NCT03512314	PHASE3	COMPLETED	Therapeutic Use of Tadekinig Alfa in NLRC4 Mutation and XIAP Deficiency As Open Label Extension
NCT06309823	PHASE3	COMPLETED	A Single-patient Clinical Trial of MAS825 in a Patient With XIAP Deficiency
NCT07433621	PHASE1	RECRUITING	Quercetin in Patients With XIAP (X-linked Inhibitor of Apoptosis) Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TADEKINIG ALFA	3	2
MAS-825	3	1
QUERCETIN	3	1