X-linked lymphoproliferative disease due to SH2D1A deficiency

Summary

X-linked lymphoproliferative disease due to SH2D1A deficiency (MONDO:0024551) is a disease caused by SH2D1A (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SH2D1A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 151

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

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked lymphoproliferative disease due to SH2D1A deficiency
Mondo ID	MONDO:0024551
OMIM	308240
Orphanet	538931
UMLS	C5399825
MedGen	1770239
GARD	0007906
Is cancer (heuristic)	no

Also known as: lymphoproliferative syndrome, X-linked, 1, X-linked recessive · X-linked lymphoproliferative disease due to SH2D1A deficiency · XLP1

Data availability: 151 ClinVar variants · 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 › X-linked disease › X-linked lymphoproliferative syndrome › X-linked lymphoproliferative disease due to SH2D1A deficiency

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

151 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 36 pathogenic, 26 likely benign, 14 benign, 11 conflicting classifications of pathogenicity, 11 likely pathogenic, 6 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076142	NC_000023.10:g.(?123480147)(123480649_?)del	SH2D1A	Pathogenic	criteria provided, single submitter
10898	NM_002351.5(SH2D1A):c.163C>T (p.Arg55Ter)	SH2D1A	Pathogenic	criteria provided, multiple submitters, no conflicts
10899	NM_002351.5(SH2D1A):c.172C>T (p.Gln58Ter)	SH2D1A	Pathogenic	no assertion criteria provided
10900	NM_002351.5(SH2D1A):c.149_201+106del	SH2D1A	Pathogenic	no assertion criteria provided
10901	NM_002351.5(SH2D1A):c.95G>C (p.Arg32Thr)	SH2D1A	Pathogenic	no assertion criteria provided
10902	NM_002351.5(SH2D1A):c.138-1G>T	SH2D1A	Pathogenic	no assertion criteria provided
10903	NM_002351.5(SH2D1A):c.385T>A (p.Ter129Arg)	SH2D1A	Pathogenic	no assertion criteria provided
10904	NM_002351.5(SH2D1A):c.302C>T (p.Pro101Leu)	SH2D1A	Pathogenic	no assertion criteria provided
10906	NM_002351.5(SH2D1A):c.-10C>T	SH2D1A	Pathogenic	no assertion criteria provided
10907	NC_000023.11:g.(?124346562)(124346780_124365760)del	SH2D1A	Pathogenic	no assertion criteria provided
10908	NM_002351.5(SH2D1A):c.3G>T (p.Met1Ile)	SH2D1A	Pathogenic	no assertion criteria provided
10910	NM_002351.5(SH2D1A):c.164G>T (p.Arg55Leu)	SH2D1A	Pathogenic	no assertion criteria provided
1455661	NM_002351.5(SH2D1A):c.2T>C (p.Met1Thr)	SH2D1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458979	NM_002351.5(SH2D1A):c.191G>A (p.Trp64Ter)	SH2D1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1459603	NM_002351.5(SH2D1A):c.245dup (p.Asn82fs)	SH2D1A	Pathogenic	criteria provided, single submitter
1459977	NC_000023.10:g.(?123480493)(123505241_?)del	SH2D1A	Pathogenic	criteria provided, single submitter
1518501	NM_002351.5(SH2D1A):c.201+2T>C	SH2D1A	Pathogenic	criteria provided, single submitter
1686182	NM_002351.5(SH2D1A):c.160T>A (p.Tyr54Asn)	SH2D1A	Pathogenic	criteria provided, single submitter
1686183	NM_002351.5(SH2D1A):c.202-1G>C	SH2D1A	Pathogenic	criteria provided, single submitter
1805004	NM_002351.5(SH2D1A):c.251T>C (p.Ile84Thr)	SH2D1A	Pathogenic	criteria provided, single submitter
2138715	NM_002351.5(SH2D1A):c.261dup (p.Gln88fs)	SH2D1A	Pathogenic	criteria provided, single submitter
2138716	NM_002351.5(SH2D1A):c.295C>T (p.Gln99Ter)	SH2D1A	Pathogenic	criteria provided, single submitter
2424418	NC_000023.10:g.(?123499591)(123499694_?)del	SH2D1A	Pathogenic	criteria provided, single submitter
2424420	NC_000023.10:g.(?123494030)(123499653_?)del	SH2D1A	Pathogenic	criteria provided, single submitter
2442798	NM_002351.5(SH2D1A):c.1A>G (p.Met1Val)	SH2D1A	Pathogenic	criteria provided, single submitter
2706624	NM_002351.5(SH2D1A):c.126C>A (p.Cys42Ter)	SH2D1A	Pathogenic	criteria provided, single submitter
2737364	NM_002351.5(SH2D1A):c.138-1G>A	SH2D1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2737365	NM_002351.5(SH2D1A):c.201+1G>A	SH2D1A	Pathogenic	criteria provided, single submitter
3244970	NC_000023.10:g.(?123499591)(123505241_?)del	SH2D1A	Pathogenic	criteria provided, single submitter
3244981	NC_000023.10:g.(?123504006)(123505241_?)del	SH2D1A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
SH2D1A	Definitive	X-linked	X-linked lymphoproliferative disease due to SH2D1A deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH2D1A	Orphanet:538931	X-linked lymphoproliferative disease due to SAP deficiency
XIAP	Orphanet:538934	X-linked lymphoproliferative disease due to XIAP deficiency
NTRK1	Orphanet:146	Differentiated thyroid carcinoma
NTRK1	Orphanet:642	Hereditary sensory and autonomic neuropathy type 4
NTRK1	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
NTRK1	Orphanet:99361	Isolated familial medullary thyroid carcinoma

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
SH2D1A	HGNC:10820	ENSG00000183918	O60880	SH2 domain-containing protein 1A	gencc,clinvar
XIAP	HGNC:592	ENSG00000101966	P98170	E3 ubiquitin-protein ligase XIAP	clinvar
NTRK1	HGNC:8031	ENSG00000198400	P04629	High affinity nerve growth factor receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH2D1A	SH2 domain-containing protein 1A	Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7.
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.
NTRK1	High affinity nerve growth factor receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · 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
Kinase	1	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SH2D1A	Scaffold/PPI	no		SH2, SH2_prot_1A, SH2D1A_SH2
XIAP	Transcription factor	no		BIR_rpt, Znf_RING, DEATH-like_dom_sf
NTRK1	Kinase	yes	2.7.10.1	Cys-rich_flank_reg_C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

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
granulocyte	1
lymph node	1
thymus	1
buccal mucosa cell	1
ileal mucosa	1
kidney epithelium	1
apex of heart	1
dorsal root ganglion	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH2D1A	170	broad	marker	thymus, lymph node, granulocyte
XIAP	256	ubiquitous	marker	kidney epithelium, ileal mucosa, buccal mucosa cell
NTRK1	160	broad	marker	dorsal root ganglion, apex of heart, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTRK1	9,181
XIAP	5,252
SH2D1A	1,548

Intra-cohort edges

A	B	Sources
SH2D1A	XIAP	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XIAP	P98170	74
NTRK1	P04629	65
SH2D1A	O60880	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. 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
TRKA activation by NGF	1	1903.3×	0.005	NTRK1
PLC-gamma1 signalling	1	1268.9×	0.005	NTRK1
Signalling to STAT3	1	1268.9×	0.005	NTRK1
NGF-independant TRKA activation	1	761.3×	0.005	NTRK1
Signalling to p38 via RIT and RIN	1	761.3×	0.005	NTRK1
Activation of caspases through apoptosome-mediated cleavage	1	634.4×	0.005	XIAP
SMAC (DIABLO) binds to IAPs	1	543.8×	0.005	XIAP
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	543.8×	0.005	XIAP
SMAC, XIAP-regulated apoptotic response	1	543.8×	0.005	XIAP
ARMS-mediated activation	1	543.8×	0.005	NTRK1
PI3K/AKT activation	1	423.0×	0.006	NTRK1
Regulation of PTEN localization	1	346.1×	0.006	XIAP
Regulation of the apoptosome activity	1	346.1×	0.006	XIAP
Frs2-mediated activation	1	317.2×	0.006	NTRK1
Retrograde neurotrophin signalling	1	271.9×	0.007	NTRK1
Signalling to RAS	1	223.9×	0.008	NTRK1
RIPK1-mediated regulated necrosis	1	152.3×	0.010	XIAP
TNFR1-induced proapoptotic signaling	1	146.4×	0.010	XIAP
Regulation of necroptotic cell death	1	146.4×	0.010	XIAP
TNFR1-induced NF-kappa-B signaling pathway	1	112.0×	0.012	XIAP
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.016	XIAP
Regulation of TNFR1 signaling	1	74.6×	0.016	XIAP
Regulation of PTEN stability and activity	1	61.4×	0.019	XIAP
Activation of STAT3 by cadherin engagement	1	54.4×	0.021	XIAP
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	29.1×	0.037	SH2D1A
Adaptive Immune System	1	9.9×	0.101	SH2D1A
Immune System	1	4.3×	0.214	SH2D1A

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
programmed cell death involved in cell development	1	2808.7×	0.006	NTRK1
positive regulation of protein linear polyubiquitination	1	2808.7×	0.006	XIAP
olfactory nerve development	1	1872.4×	0.006	NTRK1
regulation of apoptosis involved in tissue homeostasis	1	1872.4×	0.006	XIAP
behavioral response to formalin induced pain	1	1872.4×	0.006	NTRK1
response to hydrostatic pressure	1	1404.3×	0.006	NTRK1
copper ion homeostasis	1	1404.3×	0.006	XIAP
mechanoreceptor differentiation	1	1123.5×	0.006	NTRK1
regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	1123.5×	0.006	XIAP
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1123.5×	0.006	XIAP
neuron apoptotic process	2	123.5×	0.006	XIAP, NTRK1
cellular response to nicotine	1	702.2×	0.009	NTRK1
peptidyl-tyrosine autophosphorylation	1	624.1×	0.009	NTRK1
axonogenesis involved in innervation	1	561.7×	0.009	NTRK1
quinolinate biosynthetic process	1	510.7×	0.009	XIAP
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	510.7×	0.009	XIAP
nerve growth factor signaling pathway	1	432.1×	0.009	NTRK1
regulation of BMP signaling pathway	1	401.2×	0.009	XIAP
positive regulation of programmed cell death	1	374.5×	0.009	NTRK1
detection of mechanical stimulus involved in sensory perception of pain	1	374.5×	0.009	NTRK1
Sertoli cell development	1	374.5×	0.009	NTRK1
negative regulation of apoptotic process	2	23.2×	0.009	XIAP, NTRK1
neurotrophin TRK receptor signaling pathway	1	351.1×	0.009	NTRK1
sympathetic nervous system development	1	312.1×	0.010	NTRK1
positive regulation of Ras protein signal transduction	1	295.6×	0.010	NTRK1
detection of temperature stimulus involved in sensory perception of pain	1	280.9×	0.010	NTRK1
regulation of innate immune response	1	216.1×	0.013	XIAP
response to electrical stimulus	1	216.1×	0.013	NTRK1
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.013	NTRK1
natural killer cell activation	1	193.7×	0.013	SH2D1A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
NTRK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NTRK1	66	4
XIAP	6	3
SH2D1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	NTRK1
FEDRATINIB	4	NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	NTRK1
SUNITINIB	4	NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
CRENOLANIB	3	NTRK1
LINIFANIB	3	NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	NTRK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
XIAP	499	Binding:468, Functional:24, ADMET:7
SH2D1A	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTRK1	2.7.10.1	receptor 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
XIAP	499
NTRK1	1,194

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)
PONATINIB	4	NTRK1
FEDRATINIB	4	NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	NTRK1
SUNITINIB	4	NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
CRENOLANIB	3	NTRK1
LINIFANIB	3	NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	NTRK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NTRK1
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	SH2D1A

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)
SH2D1A	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.