Sea-blue histiocyte syndrome

Summary

Sea-blue histiocyte syndrome (MONDO:0010017) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sea-blue histiocyte syndrome
Mondo ID	MONDO:0010017
MeSH	D012618
OMIM	269600
Orphanet	158029
DOID	DOID:4423
NCIT	C85062
SNOMED CT	37821003
UMLS	C0036489
MedGen	19908
GARD	0008241
Is cancer (heuristic)	no

Also known as: inherited Lipemic splenomegaly

Data availability: 10 ClinVar variants · 2 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › lymphoid system disorder › lymphatic system disorder › histiocytosis › non-Langerhans cell histiocytosis › sea-blue histiocyte syndrome

Related subtypes (14): Niemann-Pick disease, sinus histiocytosis with massive lymphadenopathy, hereditary progressive mucinous histiocytosis, multicentric reticulohistiocytosis, generalized eruptive histiocytosis, benign cephalic histiocytosis, juvenile xanthogranuloma, xanthoma disseminatum, papular xanthoma, necrobiotic xanthogranuloma, indeterminate dendritic cell tumor, progressive nodular histiocytosis, Erdheim-Chester disease, xanthogranuloma

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

10 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
126456	NM_000041.4(APOE):c.497TCC[1] (p.Leu167del)	APOE	Pathogenic	criteria provided, multiple submitters, no conflicts
17880	NM_000041.4(APOE):c.127C>T (p.Arg43Cys)	APOE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17876	NM_000041.4(APOE):c.940A>C (p.Ser314Arg)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440842	NM_000041.4(APOE):c.91G>A (p.Glu31Lys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315806	NM_000041.4(APOE):c.688G>A (p.Glu230Lys)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478884	NM_000041.4(APOE):c.805C>G (p.Arg269Gly)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478904	NM_000041.4(APOE):c.434G>A (p.Gly145Asp)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1210034	NM_000041.4(APOE):c.69G>A (p.Ala23=)	APOE	Likely benign	criteria provided, multiple submitters, no conflicts
760030	NM_000041.4(APOE):c.249C>T (p.Asp83=)	APOE	Likely benign	criteria provided, multiple submitters, no conflicts
779286	NM_000041.4(APOE):c.651C>T (p.Ala217=)	APOE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 2 · 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
APOE	Supportive	Autosomal dominant	sea-blue histiocyte syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOE	P02649	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 1 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
Chylomicron clearance	1	2284.0×	0.007	APOE
Chylomicron assembly	1	1142.0×	0.007	APOE
Chylomicron remodeling	1	1142.0×	0.007	APOE
HDL remodeling	1	1142.0×	0.007	APOE
Plasma lipoprotein assembly	1	713.8×	0.007	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	634.4×	0.007	APOE
Scavenging by Class A Receptors	1	601.0×	0.007	APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	543.8×	0.007	APOE
Plasma lipoprotein remodeling	1	475.8×	0.007	APOE
Plasma lipoprotein clearance	1	475.8×	0.007	APOE
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.007	APOE
Metabolism of fat-soluble vitamins	1	380.7×	0.007	APOE
Nuclear signaling by ERBB4	1	346.1×	0.008	APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.008	APOE
Signaling by ERBB4	1	271.9×	0.008	APOE
Visual phototransduction	1	259.6×	0.008	APOE
Retinoid metabolism and transport	1	248.3×	0.008	APOE
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.008	APOE
Metabolism of vitamins and cofactors	1	116.5×	0.015	APOE
Amyloid fiber formation	1	102.9×	0.015	APOE
Signaling by Nuclear Receptors	1	102.0×	0.015	APOE
Post-translational protein phosphorylation	1	100.2×	0.015	APOE
Sensory Perception	1	95.2×	0.016	APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.016	APOE
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.026	APOE
Vesicle-mediated transport	1	34.8×	0.038	APOE
Transport of small molecules	1	25.1×	0.050	APOE
RNA Polymerase II Transcription	1	22.5×	0.054	APOE
Post-translational protein modification	1	19.2×	0.061	APOE
Gene expression (Transcription)	1	17.8×	0.064	APOE

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid transport involved in lipid storage	1	16852.0×	0.001	APOE
maintenance of location in cell	1	16852.0×	0.001	APOE
intermediate-density lipoprotein particle clearance	1	16852.0×	0.001	APOE
positive regulation of lipid transport across blood-brain barrier	1	16852.0×	0.001	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	16852.0×	0.001	APOE
triglyceride-rich lipoprotein particle clearance	1	8426.0×	0.001	APOE
regulation of amyloid-beta clearance	1	8426.0×	0.001	APOE
regulation of amyloid fibril formation	1	8426.0×	0.001	APOE
positive regulation of low-density lipoprotein particle receptor catabolic process	1	5617.3×	0.001	APOE
negative regulation of triglyceride metabolic process	1	4213.0×	0.001	APOE
positive regulation of phospholipid efflux	1	4213.0×	0.001	APOE
regulation of behavioral fear response	1	4213.0×	0.001	APOE
very-low-density lipoprotein particle clearance	1	3370.4×	0.001	APOE
acylglycerol homeostasis	1	3370.4×	0.001	APOE
cellular response to lipoprotein particle stimulus	1	3370.4×	0.001	APOE
AMPA glutamate receptor clustering	1	3370.4×	0.001	APOE
NMDA glutamate receptor clustering	1	3370.4×	0.001	APOE
positive regulation of lipoprotein transport	1	3370.4×	0.001	APOE
positive regulation of dendritic spine maintenance	1	3370.4×	0.001	APOE
regulation of amyloid precursor protein catabolic process	1	3370.4×	0.001	APOE
positive regulation of amyloid fibril formation	1	3370.4×	0.001	APOE
chylomicron remnant clearance	1	2808.7×	0.002	APOE
lipoprotein biosynthetic process	1	2808.7×	0.002	APOE
high-density lipoprotein particle clearance	1	2407.4×	0.002	APOE
lipoprotein catabolic process	1	2407.4×	0.002	APOE
negative regulation of cholesterol biosynthetic process	1	2407.4×	0.002	APOE
very-low-density lipoprotein particle remodeling	1	2106.5×	0.002	APOE
regulation of protein metabolic process	1	2106.5×	0.002	APOE
negative regulation of protein metabolic process	1	2106.5×	0.002	APOE
positive regulation of cholesterol metabolic process	1	2106.5×	0.002	APOE

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
APOE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	APOE

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)
APOE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.