Gaucher disease

Summary

Gaucher disease (MONDO:0018150) is a disease (an umbrella term covering 5 Mondo subtypes) caused by GBA1 (GenCC Definitive), with 8 cohort genes (3 GWAS associations across 1 studies) and 98 clinical trials. Top therapeutic interventions include eliglustat, taliglucerase alfa, and velaglucerase alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: GBA1 (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 8
• GWAS associations: 3
• ClinVar variants: 465
• Phenotypes (HPO): 93
• Clinical trials: 98

Clinical features

Epidemiology

Prevalence records

16 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.7	Europe	Validated
Point prevalence	1-9 / 100 000	1	Europe	Validated
Annual incidence	1-9 / 100 000	2.6	France	Validated
Point prevalence	1-9 / 1 000 000	0.67	Spain	Validated
Point prevalence	1-9 / 1 000 000	0.74	France	Validated
Point prevalence	1-9 / 1 000 000	0.224	China	Validated
Prevalence at birth	1-9 / 100 000	5.7	Austria	Validated
Prevalence at birth	1-9 / 100 000	2	France	Validated
Prevalence at birth	1-9 / 100 000	1.7	Australia	Validated
Prevalence at birth	1-9 / 100 000	1.13	Czech Republic	Validated
Prevalence at birth	1-9 / 100 000	1.35	Portugal	Validated
Prevalence at birth	1-9 / 100 000	1.16	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	7.5	Hungary	Validated
Prevalence at birth	1-9 / 1 000 000	0.45	Turkey	Validated
Prevalence at birth	1-9 / 100 000	2.11	Sweden	Validated
Prevalence at birth	1-9 / 100 000	1.3	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

93 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0003656	Decreased beta-glucocerebrosidase level	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001081	Cholelithiasis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001373	Joint dislocation	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003281	Increased circulating ferritin concentration	Frequent (30-79%)
HP:0003330	Abnormal bone structure	Frequent (30-79%)
HP:0004975	Erlenmeyer flask deformity of the femurs	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0010885	Avascular necrosis	Frequent (30-79%)
HP:0032640	Elevated circulating CCL18 level	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:6000213	Elevated circulating Angiotensin-converting enzyme concentration	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002179	Opisthotonus	Occasional (5-29%)
HP:0002206	Pulmonary fibrosis	Occasional (5-29%)
HP:0002754	Osteomyelitis	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0002797	Osteolysis	Occasional (5-29%)
HP:0002804	Arthrogryposis multiplex congenita	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0003233	Decreased HDL cholesterol concentration	Occasional (5-29%)
HP:0003459	Polyclonal elevation of IgM	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gaucher disease
Mondo ID	MONDO:0018150
MeSH	D005776
Orphanet	355
DOID	DOID:1926
ICD-10-CM	E75.22
ICD-11	1923566939
NCIT	C61268
SNOMED CT	190794006
UMLS	C0017205
MedGen	42164
GARD	0008233
MedDRA	10018048
NORD	1177
Is cancer (heuristic)	no

Also known as: acid beta-glucosidase deficiency · acute cerebral Gaucher disease · Gaucher disease · Gaucher syndrome · glucocerebrosidase deficiency · glucocerebrosidosis · glucosyl cerebroside lipidosis · glucosylceramidase deficiency · glucosylceramide beta-glucosidase deficiency · lipoid histiocytosis (kerasin type) · sphingolipidosis 1

Data availability: 465 ClinVar variants · 3 GWAS associations (1 study) · 1 GenCC gene-disease record · 81 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Gaucher disease

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (5): Gaucher disease type I, Gaucher disease type II, Gaucher disease type III, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease perinatal lethal

Genetics & variants

GWAS landscape

3 GWAS associations across 1 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs11986414	1e-06	CLN8, KBTBD11-OT1	A	3.72
rs82625	2e-06	NHLRC2 - ADRB1	?
rs9806762	7e-06	NTRK3	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST001380	Zhang CK	2012	139	0	Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	2
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs11986414	8	1798784	A>C,G,T	0.05	intron_variant	CLN8, KBTBD11-OT1	1e-06	Tier 4: intronic/intergenic
rs82625	10	113996371	T>A,C,G	0.05	intergenic_variant	NHLRC2 - ADRB1	2e-06	Tier 4: intronic/intergenic
rs9806762	15	88118508	A>C,G	0.05	intron_variant	NTRK3	7e-06	Tier 4: intronic/intergenic

ClinVar germline variants

465 retrieved; paginated sample, class counts are floors:

189 likely pathogenic, 103 uncertain significance, 69 pathogenic, 46 conflicting classifications of pathogenicity, 45 pathogenic/likely pathogenic, 4 benign, 3 likely benign, 2 conflicting classifications of pathogenicity; risk factor, 1 conflicting classifications of pathogenicity; other, 1 not provided, 1 pathogenic/likely pathogenic; risk factor, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119997	NM_000157.4(GBA1):c.604C>T (p.Arg202Ter)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184271	NM_000157.4(GBA1):c.1255G>A (p.Asp419Asn)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1211295	NM_000157.4(GBA1):c.1249T>G (p.Trp417Gly)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321421	NM_000157.4(GBA1):c.256C>T (p.Arg86Ter)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1321450	NM_000157.4(GBA1):c.203del (p.Pro68fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322984	NM_000157.4(GBA1):c.1388+1G>A	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322986	NM_000157.4(GBA1):c.408_412del (p.Pro137fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677224	NM_000157.4(GBA1):c.1439_1445del (p.Lys480fs)	GBA1	Pathogenic	criteria provided, single submitter
1698486	NM_000157.4(GBA1):c.898del (p.Ala300fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698566	NM_000157.4(GBA1):c.1505+2T>A	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193611	NM_000157.4(GBA1):c.1265_1319del (p.Leu422fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
21070	NM_000157.4(GBA1):c.1505G>A (p.Arg502His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21072	NM_000157.4(GBA1):c.703T>C (p.Ser235Pro)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242383	NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2436490	NM_000157.4(GBA1):c.1260G>A (p.Trp420Ter)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501093	NM_000157.4(GBA1):c.847T>C (p.Tyr283His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2503944	NM_000157.4(GBA1):c.260G>A (p.Arg87Gln)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2581173	NM_000157.4(GBA1):c.1054T>C (p.Tyr352His)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2682534	NM_000157.4(GBA1):c.1193G>A (p.Arg398Gln)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3251365	NM_000157.4(GBA1):c.680A>T (p.Asn227Ile)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3385311	NM_000157.4(GBA1):c.1193G>C (p.Arg398Pro)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769123	NM_000157.4(GBA1):c.1165C>T (p.Gln389Ter)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769167	NM_000157.4(GBA1):c.702dup (p.Ser235fs)	GBA1	Pathogenic	criteria provided, single submitter
4068448	NM_000157.4(GBA1):c.762-1G>T	GBA1	Pathogenic	criteria provided, single submitter
4290	NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)	GBA1	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
4291	NM_000157.4(GBA1):c.476G>A (p.Arg159Gln)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292	NM_000157.4(GBA1):c.1297G>T (p.Val433Leu)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293	NM_000157.4(GBA1):c.1342G>C (p.Asp448His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4295	NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4298	NM_000157.4(GBA1):c.764T>A (p.Phe255Tyr)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 16 · 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
GBA1	Definitive	Autosomal recessive	Gaucher disease perinatal lethal	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GBA1	Orphanet:2072	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
GBA1	Orphanet:411602	Hereditary late-onset Parkinson disease
GBA1	Orphanet:77259	Gaucher disease type 1
GBA1	Orphanet:77260	Gaucher disease type 2
GBA1	Orphanet:77261	Gaucher disease type 3
GBA1	Orphanet:85212	Fetal Gaucher disease
SMPD1	Orphanet:77292	Infantile neurovisceral acid sphingomyelinase deficiency
SMPD1	Orphanet:77293	Chronic visceral acid sphingomyelinase deficiency
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F
CLN8	Orphanet:1947	Northern epilepsy
CLN8	Orphanet:700484	Late infantile CLN8 disease
ELP1	Orphanet:1764	Familial dysautonomia
NTRK3	Orphanet:146	Differentiated thyroid carcinoma
NTRK3	Orphanet:2030	Fibrosarcoma
NTRK3	Orphanet:2665	Congenital mesoblastic nephroma

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	gencc,clinvar
SMPD1	HGNC:11120	ENSG00000166311	P17405	Sphingomyelin phosphodiesterase	clinvar
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	clinvar
CLN8	HGNC:2079	ENSG00000182372	Q9UBY8	Protein CLN8	gwas
ADRB1	HGNC:285	ENSG00000043591	P08588	Beta-1 adrenergic receptor	gwas
ELP1	HGNC:5959	ENSG00000070061	O95163	Elongator complex protein 1	clinvar
NTRK3	HGNC:8033	ENSG00000140538	Q16288	NT-3 growth factor receptor	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.
SMPD1	Sphingomyelin phosphodiesterase	Converts sphingomyelin to ceramide.
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
CLN8	Protein CLN8	Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.
ADRB1	Beta-1 adrenergic receptor	G protein-coupled receptor for catecholamines that couples to G(s) proteins to activate adenylate cyclase and cAMP-dependent pathway.
ELP1	Elongator complex protein 1	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
NTRK3	NT-3 growth factor receptor	Receptor tyrosine kinase involved in nervous system and probably heart development.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.62

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
Enzyme (other)	3	4.5×	0.118
Scaffold/PPI	2	4.3×	0.185
Kinase	1	3.5×	0.362
GPCR	1	3.0×	0.362
Other/Unknown	1	0.2×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C
SMPD1	Enzyme (other)	yes	3.1.4.12	Calcineurin-like_PHP, SaposinB_dom, Saposin-like
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
CLN8	Other/Unknown	no		TLC-dom, TLCD
ADRB1	GPCR	yes		GPCR_Rhodpsn, ADRB1_rcpt, ADR_fam
ELP1	Scaffold/PPI	no		Elp1, WD40/YVTN_repeat-like_dom_sf, Beta-prop_ELP1_1st
NTRK3	Kinase	yes	2.7.10.1	LRRNT, Cys-rich_flank_reg_C, Prot_kinase_dom

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	3
islet of Langerhans	2
placenta	1
type B pancreatic cell	1
olfactory bulb	1
sural nerve	1
trigeminal ganglion	1
corpus epididymis	1
gastrocnemius	1
mucosa of stomach	1
C1 segment of cervical spinal cord	1
corpus callosum	1
bronchial epithelial cell	1
heart right ventricle	1
parotid gland	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
Brodmann (1909) area 10	1
Brodmann (1909) area 23	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBA1	134	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, placenta
SMPD1	262	ubiquitous	marker	type B pancreatic cell, stromal cell of endometrium, islet of Langerhans
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach
CLN8	134	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, stromal cell of endometrium
ADRB1	205	broad	marker	heart right ventricle, parotid gland, bronchial epithelial cell
ELP1	291	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
NTRK3	242	broad	marker	Brodmann (1909) area 10, Brodmann (1909) area 23, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTRK3	4,147
PRDX6	4,106
ELP1	2,733
GBA1	2,568
SMPD1	1,729
ADRB1	1,702
PRX	1,569
CLN8	1,122

Intra-cohort edges

A	B	Sources
GBA1	SMPD1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GBA1	P04062	58
ADRB1	P08588	7
ELP1	O95163	5
NTRK3	Q16288	5
SMPD1	P17405	4
PRDX6	P30041	3
PRX	Q9BXM0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLN8	Q9UBY8	90.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 8 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid catabolism	2	83.7×	0.007	GBA1, SMPD1
NTF3 activates NTRK3 signaling	1	815.7×	0.013	NTRK3
Activated NTRK3 signals through PLCG1	1	543.8×	0.013	NTRK3
NTRK3 as a dependence receptor	1	543.8×	0.013	NTRK3
Activated NTRK3 signals through PI3K	1	271.9×	0.021	NTRK3
Adrenoceptors	1	181.3×	0.022	ADRB1
Activated NTRK3 signals through RAS	1	181.3×	0.022	NTRK3
Signaling by NTRK3 (TRKC)	1	163.1×	0.022	NTRK3
Receptor-type tyrosine-protein phosphatases	1	81.6×	0.039	NTRK3
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	52.6×	0.049	PRX
Amine ligand-binding receptors	1	49.4×	0.049	ADRB1
Glycosphingolipid metabolism	1	42.9×	0.049	SMPD1
Detoxification of Reactive Oxygen Species	1	42.9×	0.049	PRDX6
Association of TriC/CCT with target proteins during biosynthesis	1	41.8×	0.049	GBA1
Regulation of clotting cascade	1	33.3×	0.057	SMPD1
Sphingolipid metabolism	1	24.0×	0.074	SMPD1
Constitutive Signaling by Aberrant PI3K in Cancer	1	18.1×	0.092	NTRK3
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	13.8×	0.113	NTRK3
HATs acetylate histones	1	11.3×	0.127	ELP1
Class A/1 (Rhodopsin-like receptors)	1	10.6×	0.127	ADRB1
G alpha (s) signalling events	1	10.5×	0.127	ADRB1
PIP3 activates AKT signaling	1	9.5×	0.131	NTRK3
GPCR ligand binding	1	9.2×	0.131	ADRB1
GPCR downstream signalling	1	6.2×	0.182	ADRB1
Signaling by GPCR	1	5.7×	0.188	ADRB1
Metabolism of lipids	1	4.5×	0.225	SMPD1
Neutrophil degranulation	1	3.3×	0.287	PRDX6
Metabolism	1	1.7×	0.484	SMPD1
Signal Transduction	1	1.4×	0.516	ADRB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
termination of signal transduction	2	1404.3×	5e-05	GBA1, SMPD1
ceramide biosynthetic process	3	158.0×	5e-05	GBA1, SMPD1, CLN8
cholesterol metabolic process	3	73.5×	3e-04	GBA1, SMPD1, CLN8
lysosome organization	2	76.6×	0.009	GBA1, CLN8
negative regulation of MAPK cascade	2	75.2×	0.009	GBA1, SMPD1
positive regulation of axon extension involved in regeneration	1	2106.5×	0.010	NTRK3
positive regulation of neuronal action potential	1	2106.5×	0.010	GBA1
positive regulation of heart rate by epinephrine-norepinephrine	1	1053.2×	0.011	ADRB1
positive regulation of the force of heart contraction by epinephrine-norepinephrine	1	1053.2×	0.011	ADRB1
cerebellar Purkinje cell layer formation	1	1053.2×	0.011	GBA1
glutamate reuptake	1	1053.2×	0.011	CLN8
retinal rod cell apoptotic process	1	1053.2×	0.011	CLN8
beta-glucoside catabolic process	1	1053.2×	0.011	GBA1
norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure	1	702.2×	0.011	ADRB1
tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation	1	702.2×	0.011	ELP1
glucosylceramide catabolic process	1	702.2×	0.011	GBA1
somatic motor neuron differentiation	1	702.2×	0.011	CLN8
axon extension involved in regeneration	1	702.2×	0.011	NTRK3
regulation of lysosomal protein catabolic process	1	702.2×	0.011	GBA1
heat generation	1	526.6×	0.014	ADRB1
sphingomyelin metabolic process	1	421.3×	0.014	SMPD1
sphingomyelin catabolic process	1	421.3×	0.014	SMPD1
pyramidal neuron differentiation	1	421.3×	0.014	GBA1
mechanoreceptor differentiation	1	421.3×	0.014	NTRK3
autophagosome organization	1	421.3×	0.014	GBA1
negative regulation of neuron apoptotic process	2	27.7×	0.014	GBA1, CLN8
axon ensheathment	1	351.1×	0.014	PRX
response to pH	1	351.1×	0.014	GBA1
fear response	1	351.1×	0.014	ADRB1
musculoskeletal movement	1	351.1×	0.014	CLN8

Therapeutics

Drugs indicated or in trials for this disease

5 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Eliglustat	Approved (phase 4)
Imiglucerase	Approved (phase 4)
Miglustat	Approved (phase 4)
Taliglucerase Alfa	Approved (phase 4)
Velaglucerase Alfa	Approved (phase 4)

6 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Venglustat	Phase 3
Vitamin E	Phase 3
Acetylcysteine	Phase 2
Ambroxol	Phase 2
Arimoclomol	Phase 2
Busulfan	Phase 2

Drug target analysis

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

Druggability breadth: 6 of 8 evidence-associated genes (75%) 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
GBA1	MIGALASTAT
SMPD1	IMIPRAMINE
ADRB1	LABETALOL HYDROCHLORIDE
NTRK3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADRB1	154	4
NTRK3	41	4
GBA1	12	4
SMPD1	3	4
PRX	0	0
PRDX6	0	0
CLN8	0	0
ELP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	ADRB1, GBA1
TAMOXIFEN	4	ADRB1, GBA1
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
LABETALOL HYDROCHLORIDE	4	ADRB1
PHENYLEPHRINE	4	ADRB1
NOREPINEPHRINE	4	ADRB1
PROPRANOLOL HYDROCHLORIDE	4	ADRB1
SOTALOL HYDROCHLORIDE	4	ADRB1
PROPRANOLOL	4	ADRB1
ISOPROTERENOL	4	ADRB1
SOTALOL	4	ADRB1
PRACTOLOL	4	ADRB1
BEPRIDIL	4	ADRB1
CANDESARTAN CILEXETIL	4	ADRB1
CLOTRIMAZOLE	4	ADRB1
INDACATEROL	4	ADRB1
ARIPIPRAZOLE	4	ADRB1
RUCAPARIB	4	ADRB1
DULOXETINE	4	ADRB1
VILANTEROL	4	ADRB1
TIOCONAZOLE	4	ADRB1
DECITABINE	4	ADRB1
LEVOBUNOLOL	4	ADRB1
CINACALCET	4	ADRB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
ADRB1	809	Binding:509, Functional:290, ADMET:10
GBA1	436	Binding:403, Functional:33
NTRK3	408	Binding:400, Functional:4, ADMET:4
SMPD1	42	Binding:40, Functional:2
PRDX6	15	Binding:15
ELP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA1	3.2.1.45	glucosylceramidase
SMPD1	3.1.4.12	sphingomyelin phosphodiesterase
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2
NTRK3	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
GBA1	436
ADRB1	809
NTRK3	408

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
ADRB1	1

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)
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	ADRB1, GBA1
TAMOXIFEN	4	ADRB1, GBA1
IMIPRAMINE	4	SMPD1
CHLORPROMAZINE	4	SMPD1
LABETALOL HYDROCHLORIDE	4	ADRB1
PHENYLEPHRINE	4	ADRB1
NOREPINEPHRINE	4	ADRB1
PROPRANOLOL HYDROCHLORIDE	4	ADRB1
SOTALOL HYDROCHLORIDE	4	ADRB1
PROPRANOLOL	4	ADRB1
ISOPROTERENOL	4	ADRB1
SOTALOL	4	ADRB1
PRACTOLOL	4	ADRB1
BEPRIDIL	4	ADRB1
CANDESARTAN CILEXETIL	4	ADRB1
CLOTRIMAZOLE	4	ADRB1
INDACATEROL	4	ADRB1
ARIPIPRAZOLE	4	ADRB1
RUCAPARIB	4	ADRB1
DULOXETINE	4	ADRB1
VILANTEROL	4	ADRB1
TIOCONAZOLE	4	ADRB1
DECITABINE	4	ADRB1
LEVOBUNOLOL	4	ADRB1
CINACALCET	4	ADRB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	GBA1, SMPD1, ADRB1, NTRK3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PRDX6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PRX, CLN8, ELP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRX	0	—
PRDX6	15	—
CLN8	0	—
ELP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 98.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	56
PHASE3	14
PHASE2	10
PHASE1	7
PHASE4	5
PHASE1/PHASE2	4
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01132690	PHASE4	COMPLETED	A Safety and Efficacy Study of Two Dose Levels of Taliglucerase Alfa in Pediatric Subjects With Gaucher Disease
NCT02528617	PHASE4	WITHDRAWN	The Effect of Velaglucerase Alfa (Vpriv) on Skeletal Development in Pediatric Gaucher Disease
NCT02574286	PHASE4	COMPLETED	Study of the Effect of Velaglucerase Alfa (VPRIV®) on Bone-related Pathology in Treatment-naïve Participants With Type 1 Gaucher Disease
NCT03721627	PHASE4	UNKNOWN	Chronic Hepatitis C Treatment in Egyptian Children With Gaucher Disease.
NCT04718779	PHASE4	COMPLETED	A Study of Enzyme Replacement Therapy (VPRIV) in People With Type 1 Gaucher Disease Who Were Previously Treated With Substrate Reduction Therapy
NCT07223944	PHASE3	RECRUITING	A Gaucher Disease Gene Therapy Trial With FLT201
NCT00319046	PHASE3	COMPLETED	Clinical Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Miglustat in Patients With Stable Type 1 Gaucher Disease
NCT00376168	PHASE3	COMPLETED	A Phase III Trial to Assess the Safety and Efficacy of Plant Cell Expressed GCD in Patients With Gaucher Disease
NCT00478647	PHASE2/PHASE3	COMPLETED	Study of GA-GCB Enzyme Replacement Therapy in Type 1 Gaucher Disease Patients Previously Treated With Imiglucerase
NCT00705939	PHASE3	COMPLETED	Plant Cell Expressed Recombinant Human Glucocerebrosidase Extension Trial
NCT00712348	PHASE3	COMPLETED	Switchover Trial From Imiglucerase to Plant Cell Expressed Recombinant Human Glucocerebrosidase
NCT01074944	PHASE3	COMPLETED	A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease to Evaluate Once Daily Versus Twice Daily Dosing (EDGE)
NCT01161914	PHASE3	WITHDRAWN	The Safety and Efficacy Study of ISU302 in Patient With Type I Gaucher Disease
NCT01411228	PHASE3	COMPLETED	A Multicenter Extension Study of Taliglucerase Alfa in Pediatric Subjects With Gaucher Disease
NCT01422187	PHASE3	COMPLETED	A Multicenter Extension Study of Taliglucerase Alfa in Adult Subjects With Gaucher Disease
NCT01614574	PHASE3	COMPLETED	Study of Velaglucerase Alfa Enzyme Replacement Therapy in Japanese Patients With Gaucher Disease
NCT01842841	PHASE3	COMPLETED	Multicenter Extension Study of Velaglucerase Alfa in Japanese Patients With Gaucher Disease
NCT02536755	PHASE3	COMPLETED	Phase 3b Study to Evaluate Skeletal Response to Eliglustat in Adult Patients Who Completed Phase 2 or Phase 3 Studies
NCT05529992	PHASE3	COMPLETED	A Study of Velaglucerase Alfa (VPRIV) in Chinese Children, Teenagers, and Adults With Type 1 Gaucher Disease
NCT06211478	PHASE3	COMPLETED	Role of Vitamin E in Gaucher Disease Patients
NCT02843035	PHASE2	ACTIVE_NOT_RECRUITING	Venglustat in Combination With Cerezyme in Adult Patients With Gaucher Disease Type 3 With Venglustat Monotherapy Extension
NCT05487599	PHASE1/PHASE2	RECRUITING	A Clinical Trial of PR001 (LY3884961) in Patients With Peripheral Manifestations of Gaucher Disease (PROCEED)
NCT06523517	PHASE2	NOT_YET_RECRUITING	Efficacy and Safety of Eliglustat in Chinese Pediatric Patients With Gaucher Disease Type 1 and Type 3
NCT06818838	PHASE1/PHASE2	RECRUITING	A Clinical Study Evaluating LY-M001 Injection in the Treatment of Adult Patients With Type I Gaucher Disease
NCT00041535	PHASE2	COMPLETED	OGT 918-006: A Phase I/II Randomized, Controlled Study of OGT 918 in Patients With Neuronopathic Gaucher Disease
NCT00391625	PHASE1/PHASE2	COMPLETED	Open-Label Extension Study Evaluating Long Term Safety in Patients With Type 1 Gaucher Disease Receiving DRX008A (ERT)
NCT00433147	PHASE2	COMPLETED	A Study of AT2101 (Afegostat Tartrate) in Adult Patients With Type 1 Gaucher Disease Currently Receiving Enzyme Replacement Therapy
NCT00446550	PHASE2	COMPLETED	A Study of Oral AT2101 (Afegostat Tartrate) in Treatment-naive Patients With Gaucher Disease
NCT00813865	PHASE2	COMPLETED	A Long-Term Extension Study of AT2101 (Afegostat Tartrate) in Type 1 Gaucher Patients
NCT01951989	PHASE2	UNKNOWN	Intra-monocyte Imiglucerase Kinetics in Gaucher Disease
NCT02107846	PHASE2	COMPLETED	An Open-Label, Dose Escalation Study to Evaluate the Safety and the Pharmacokinetics of Oral PRX-112
NCT02583672	PHASE2	COMPLETED	Role of Oxidative Stress and Inflammation in Type 1 Gaucher Disease (GD1)
NCT04145037	PHASE1/PHASE2	TERMINATED	Lentiviral Vector Gene Therapy - The Guard1 Trial of AVR-RD-02 for Subjects With Type 1 Gaucher Disease
NCT06050967	PHASE2	COMPLETED	A Second-generation AI Based Therapeutic Regimen in Patients With Gaucher Disease Treated With Enzyme Replacement Therapy.
NCT00258778	PHASE1	COMPLETED	Phase I Single Dose-Escalation Safety Study of Human Glucocerebrosidase (prGCD)
NCT01747980	PHASE1	COMPLETED	Safety and Pharmacokinetics of Oral PRX-112 in Gaucher Disease Patients
NCT01881633	PHASE1	COMPLETED	A Study of the Tolerability, Safety, and Pharmacokinetics of ISU302 in Healthy Volunteers
NCT02422654	PHASE1	COMPLETED	Taste Evaluation of Different Liquid Formulations With Eliglustat
NCT02536911	PHASE1	COMPLETED	A Study of the Effects of Hepatic Impairment on the Pharmacokinetics and Tolerability of Eliglustat Tartrate
NCT02536937	PHASE1	COMPLETED	A Study of the Effects of Renal Impairment on the Pharmacokinetics and Tolerability of Eliglustat Tartrate

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELIGLUSTAT	4	10
TALIGLUCERASE ALFA	4	7
VELAGLUCERASE ALFA	4	6
IMIGLUCERASE	4	3
MIGLUSTAT	4	3
CHOLECALCIFEROL	4	1
ERGOCALCIFEROL	4	1
LEDIPASVIR	4	1
SOFOSBUVIR	4	1
VITAMIN E	4	1
VENGLUSTAT	3	1
AFEGOSTAT TARTRATE	2	3
CHEMBL1258950	0	1
CHEMBL1259058	0	1
CHEMBL4634610	0	1
ALPHA-TOCOPHEROL	0	1