Familial hemophagocytic lymphohistiocytosis 4

Summary

Familial hemophagocytic lymphohistiocytosis 4 (MONDO:0011336) is a disease caused by STX11 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: STX11 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 388

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hemophagocytic lymphohistiocytosis 4
Mondo ID	MONDO:0011336
MeSH	C537252
OMIM	603552
DOID	DOID:0110924
UMLS	C1863728
MedGen	350245
GARD	0009929
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis 4 · familial hemophagocytic lymphohistiocytosis type 4 · FHL4 · genetic hemophagocytic lymphohistiocytosis caused by mutation in STX11 · hemophagocytic lymphohistiocytosis, familial, 4 · hemophagocytic lymphohistiocytosis, familial, type 4 · HLH4 · HPLH4 · STX11 genetic hemophagocytic lymphohistiocytosis

Data availability: 388 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › hereditary hemophagocytic lymphohistiocytosis › familial hemophagocytic lymphohistiocytosis 4

Related subtypes (10): Chediak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis type 1, familial hemophagocytic lymphohistiocytosis 2, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, familial hemophagocytic lymphohistiocytosis 3, familial hemophagocytic lymphohistiocytosis 5, Hermansky-Pudlak syndrome 9, hemophagocytic lymphohistiocytosis, familial, 6, hemophagocytic lymphohistiocytosis due to RhoG 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

388 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 141 likely benign, 20 benign, 15 pathogenic, 12 conflicting classifications of pathogenicity, 9 likely pathogenic, 6 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071172	NC_000006.11:g.(?143772160)(144508648_?)del	SF3B5	Pathogenic	criteria provided, single submitter
1412986	NM_003764.4(STX11):c.83C>A (p.Ser28Ter)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455186	NM_003764.4(STX11):c.599_602del (p.Ala200fs)	STX11	Pathogenic	criteria provided, single submitter
1686234	NM_003764.4(STX11):c.448G>T (p.Glu150Ter)	STX11	Pathogenic	criteria provided, single submitter
1686235	NM_003764.4(STX11):c.554dup (p.Trp186fs)	STX11	Pathogenic	criteria provided, multiple submitters, no conflicts
203384	NM_003764.4(STX11):c.391C>T (p.Gln131Ter)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679061	NM_003764.4(STX11):c.645dup (p.Arg216fs)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679062	NM_003764.4(STX11):c.748C>T (p.Gln250Ter)	STX11	Pathogenic	criteria provided, single submitter
2679066	NM_003764.4(STX11):c.697del (p.Val233fs)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679068	NM_003764.4(STX11):c.73G>T (p.Glu25Ter)	STX11	Pathogenic	criteria provided, multiple submitters, no conflicts
2679069	NM_003764.4(STX11):c.484C>T (p.Gln162Ter)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2744743	NM_003764.4(STX11):c.127_133del (p.Ser43fs)	STX11	Pathogenic	criteria provided, single submitter
2771358	NM_003764.4(STX11):c.334G>T (p.Glu112Ter)	STX11	Pathogenic	criteria provided, single submitter
2829742	NM_003764.4(STX11):c.490C>T (p.Gln164Ter)	STX11	Pathogenic	criteria provided, single submitter
3593212	NM_003764.4(STX11):c.396C>A (p.Tyr132Ter)	STX11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5263	NM_003764.4(STX11):c.369_376delinsTGG (p.Val124fs)	STX11	Pathogenic	criteria provided, single submitter
5264	NC_000006.12:g.144176889_144196077del	STX11	Pathogenic	no assertion criteria provided
5265	NM_003764.4(STX11):c.802C>T (p.Gln268Ter)	STX11	Pathogenic	no assertion criteria provided
583514	NC_000006.12:g.(?144186608)(144187511_?)del	STX11	Pathogenic	criteria provided, single submitter
802280	NM_003764.4(STX11):c.581_584del (p.Leu194fs)	STX11	Pathogenic	criteria provided, multiple submitters, no conflicts
97001	NM_003764.4(STX11):c.173T>C (p.Leu58Pro)	STX11	Pathogenic	criteria provided, multiple submitters, no conflicts
2679060	NM_003764.4(STX11):c.568dup (p.Ser190fs)	STX11	Likely pathogenic	criteria provided, single submitter
2679064	NM_003764.4(STX11):c.807C>A (p.Tyr269Ter)	STX11	Likely pathogenic	criteria provided, single submitter
2679065	NM_003764.4(STX11):c.551del (p.Gly184fs)	STX11	Likely pathogenic	criteria provided, single submitter
2679067	NM_003764.4(STX11):c.325G>T (p.Glu109Ter)	STX11	Likely pathogenic	criteria provided, single submitter
2679070	NM_003764.4(STX11):c.397_398del (p.Asn133fs)	STX11	Likely pathogenic	criteria provided, single submitter
3240549	NM_003764.4(STX11):c.337_352dup (p.His118delinsArgGlyTer)	STX11	Likely pathogenic	criteria provided, single submitter
3240550	NM_003764.4(STX11):c.157_160del (p.Asp53fs)	STX11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593213	NM_003764.4(STX11):c.794del (p.Lys265fs)	STX11	Likely pathogenic	criteria provided, single submitter
4077673	NM_003764.4(STX11):c.785_791del (p.Gln262fs)	STX11	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
STX11	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STX11	Orphanet:540	Familial hemophagocytic lymphohistiocytosis

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
STX11	HGNC:11429	ENSG00000135604	O75558	Syntaxin-11	gencc,clinvar
SF3B5	HGNC:21083	ENSG00000169976	Q9BWJ5	Splicing factor 3B subunit 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STX11	Syntaxin-11	SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
SF3B5	Splicing factor 3B subunit 5	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STX11	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
SF3B5	Other/Unknown	no		SF3b5/RDS3-10, Splicing_factor_3B_subunit_5

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
leukocyte	1
monocyte	1
mononuclear cell	1
adenohypophysis	1
granulocyte	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STX11	193	broad	marker	monocyte, mononuclear cell, leukocyte
SF3B5	286	ubiquitous	marker	adenohypophysis, mucosa of transverse colon, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SF3B5	3,038
STX11	2,409

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SF3B5	Q9BWJ5	67

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STX11	O75558	79.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA Splicing - Minor Pathway	1	223.9×	0.019	SF3B5
mRNA Splicing	1	109.8×	0.019	SF3B5
CHD1 and CHD2 subfamily	1	108.8×	0.019	SF3B5
mRNA Polyadenylation	1	87.8×	0.019	SF3B5
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.019	SF3B5
mRNA Splicing - Major Pathway	1	54.6×	0.024	SF3B5
Dengue Virus-Host Interactions	1	45.7×	0.024	SF3B5
Metabolism of RNA	1	41.7×	0.024	SF3B5

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
synaptic vesicle fusion to presynaptic active zone membrane	1	842.6×	0.008	STX11
obsolete vesicle docking	1	383.0×	0.008	STX11
membrane fusion	1	312.1×	0.008	STX11
U2-type prespliceosome assembly	1	312.1×	0.008	SF3B5
regulation of DNA repair	1	138.1×	0.014	SF3B5
regulation of RNA splicing	1	109.4×	0.015	SF3B5
exocytosis	1	75.9×	0.019	STX11
mRNA splicing, via spliceosome	1	45.8×	0.027	SF3B5
intracellular protein transport	1	32.4×	0.034	STX11
positive regulation of DNA-templated transcription	1	14.0×	0.070	SF3B5

Therapeutics

Drug target analysis

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

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
STX11	0	0
SF3B5	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
SF3B5	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	STX11, SF3B5

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)
STX11	0	—
SF3B5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.