Gaucher disease type I

Summary

Gaucher disease type I (MONDO:0009265) is a disease caused by GBA1 (GenCC Strong), with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include eliglustat and imiglucerase.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: GBA1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 151
• Phenotypes (HPO): 49
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Prevalence at birth	1-9 / 100 000	2.48	Italy	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000823	Delayed puberty	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001971	Hypersplenism	Very frequent (80-99%)
HP:0002039	Anorexia	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0003656	Decreased beta-glucocerebrosidase level	Very frequent (80-99%)
HP:0010885	Avascular necrosis	Very frequent (80-99%)
HP:0000225	Gingival bleeding	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001876	Pancytopenia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0003281	Increased circulating ferritin concentration	Frequent (30-79%)
HP:0031830	Pinguecula	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000790	Hematuria	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001409	Portal hypertension	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002176	Spinal cord compression	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0002953	Vertebral compression fracture	Occasional (5-29%)
HP:0003233	Decreased HDL cholesterol concentration	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004975	Erlenmeyer flask deformity of the femurs	Occasional (5-29%)
HP:0005230	Biliary tract obstruction	Occasional (5-29%)
HP:0006530	Abnormal pulmonary interstitial morphology	Occasional (5-29%)
HP:0006775	Multiple myeloma	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0010702	Increased circulating antibody level	Occasional (5-29%)
HP:0032640	Elevated circulating CCL18 level	Occasional (5-29%)
HP:0034336	Splenic infarction	Occasional (5-29%)
HP:0001300	Parkinsonism	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0001399	Hepatic failure	Very rare (<1-4%)
HP:0012223	Splenic rupture	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gaucher disease type I
Mondo ID	MONDO:0009265
OMIM	230800
Orphanet	77259
DOID	DOID:0110957
SNOMED CT	62201009
UMLS	C1961835
MedGen	409531
GARD	0002441
Is cancer (heuristic)	no

Also known as: acid Beta-glucosidase deficiency · Gaucher disease type I · Gaucher disease, noncerebral juvenile · Gaucher’s disease type I · Gba deficiency · non-cerebral juvenile Gaucher disease

Data availability: 151 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › restrictive cardiomyopathy › familial restrictive cardiomyopathy › Gaucher disease type I

Related subtypes (9): cardiomyopathy, familial restrictive, 1, glycogen storage disease II, idiopathic hypereosinophilic syndrome, cardiomyopathy, familial restrictive, 2, cardiomyopathy, familial restrictive, 3, dilated cardiomyopathy 1KK, atrial standstill, ATTRV122I amyloidosis, cardiomyopathy, familial restrictive, 6

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:

34 likely pathogenic, 31 pathogenic/likely pathogenic, 29 pathogenic, 23 conflicting classifications of pathogenicity, 21 uncertain significance, 5 likely benign, 3 benign, 2 benign/likely benign, 1 conflicting classifications of pathogenicity; other, 1 conflicting classifications of pathogenicity; risk factor, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
4297	NM_001005741.2(GBA1):c.[1448T>C;1483G>C;1497G>C]		Pathogenic	criteria provided, multiple submitters, no conflicts
4299	NM_001005741.2(GBA1):c.[535G>C;c.1093G>A]		Pathogenic	no assertion criteria provided
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
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
2503944	NM_000157.4(GBA1):c.260G>A (p.Arg87Gln)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
4301	NM_000157.4(GBA1):c.754T>A (p.Phe252Ile)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4302	NM_000157.4(GBA1):c.84dup (p.Leu29fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4305	NM_000157.4(GBA1):c.983C>T (p.Pro328Leu)	GBA1	Pathogenic	no assertion criteria provided
4307	NM_000157.4(GBA1):c.73del (p.Leu25fs)	GBA1	Pathogenic	no assertion criteria provided
4311	NM_000157.4(GBA1):c.1604G>A (p.Arg535His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4314	NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4321	NM_000157.4(GBA1):c.259C>T (p.Arg87Trp)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4322	NM_000157.4(GBA1):c.533del (p.Pro178fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4326	NM_000157.4(GBA1):c.1192C>T (p.Arg398Ter)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4327	NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4328	NM_000157.4(GBA1):c.887G>A (p.Arg296Gln)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4330	NM_000157.4(GBA1):c.354G>C (p.Lys118Asn)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813820	NM_000157.4(GBA1):c.1505+2T>G	GBA1	Pathogenic	criteria provided, single submitter
632835	NM_000157.4(GBA1):c.595_596del (p.Leu199fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 8 · 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
MSH6	Orphanet:144	Lynch syndrome
MSH6	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

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
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	gencc,clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar

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.
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

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
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N

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
islet of Langerhans	1
placenta	1
stromal cell of endometrium	1
embryo	1
ganglionic eminence	1
ventricular zone	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
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSH6	4,091
GBA1	2,568

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GBA1	P04062	58
MSH6	P52701	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective Mismatch Repair Associated With MSH6	1	2855.0×	0.002	MSH6
Defective Mismatch Repair Associated With MSH2	1	1903.3×	0.002	MSH6
Mismatch Repair	1	1427.5×	0.002	MSH6
Diseases of Mismatch Repair (MMR)	1	1427.5×	0.002	MSH6
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	407.9×	0.005	MSH6
Diseases of DNA repair	1	285.5×	0.006	MSH6
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.009	GBA1
Glycosphingolipid catabolism	1	146.4×	0.009	GBA1
DNA Repair	1	49.2×	0.022	MSH6
Disease	1	6.5×	0.147	MSH6

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
determination of adult lifespan	2	432.1×	3e-04	GBA1, MSH6
meiotic mismatch repair	1	8426.0×	0.002	MSH6
positive regulation of neuronal action potential	1	8426.0×	0.002	GBA1
cerebellar Purkinje cell layer formation	1	4213.0×	0.003	GBA1
beta-glucoside catabolic process	1	4213.0×	0.003	GBA1
glucosylceramide catabolic process	1	2808.7×	0.003	GBA1
termination of signal transduction	1	2808.7×	0.003	GBA1
regulation of lysosomal protein catabolic process	1	2808.7×	0.003	GBA1
somatic recombination of immunoglobulin gene segments	1	2106.5×	0.003	MSH6
pyramidal neuron differentiation	1	1685.2×	0.003	GBA1
autophagosome organization	1	1685.2×	0.003	GBA1
response to pH	1	1404.3×	0.004	GBA1
lymphocyte migration	1	1203.7×	0.004	GBA1
negative regulation of protein metabolic process	1	1053.2×	0.004	GBA1
response to thyroid hormone	1	1053.2×	0.004	GBA1
microglial cell proliferation	1	936.2×	0.004	GBA1
microglia differentiation	1	766.0×	0.005	GBA1
positive regulation of type 2 mitophagy	1	766.0×	0.005	GBA1
glycolipid biosynthetic process	1	702.2×	0.005	GBA1
response to dexamethasone	1	601.9×	0.005	GBA1
negative regulation of DNA recombination	1	561.7×	0.005	MSH6
somatic hypermutation of immunoglobulin genes	1	526.6×	0.005	MSH6
sphingosine biosynthetic process	1	526.6×	0.005	GBA1
lysosomal protein catabolic process	1	526.6×	0.005	GBA1
regulation of TOR signaling	1	468.1×	0.005	GBA1
respiratory electron transport chain	1	421.3×	0.006	GBA1
isotype switching	1	421.3×	0.006	MSH6
brain morphogenesis	1	366.4×	0.006	GBA1
antigen processing and presentation	1	351.1×	0.006	GBA1
homeostasis of number of cells	1	337.0×	0.006	GBA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
GBA1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GBA1	12	4
MSH6	1	2

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	GBA1
TAMOXIFEN	4	GBA1
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1
MOLIBRESIB	2	MSH6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GBA1	436	Binding:403, Functional:33
MSH6	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA1	3.2.1.45	glucosylceramidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GBA1	436

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

13 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	GBA1
TAMOXIFEN	4	GBA1
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1
MOLIBRESIB	2	MSH6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GBA1
B	Phased (≥1) drug, not yet approved	1	MSH6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00365131	PHASE4	COMPLETED	A Multicenter Study of the Efficacy of Cerezyme in Testing Skeletal Disease in Patients With Type I Gaucher Disease.
NCT03485677	PHASE3	COMPLETED	Safety and Efficacy of Eliglustat With or Without Imiglucerase in Pediatric Patients With Gaucher Disease (GD) Type 1 and Type 3
NCT06143904	PHASE1	COMPLETED	A Study to Evaluate Absolute Bioavailability, Absorption, Metabolism, and Excretion of Genz-112638 in Healthy Male Participants
NCT02437396	Not specified	RECRUITING	Oxidative Stress and Inflammatory Biomarkers in Gaucher Disease
NCT06162338	Not specified	RECRUITING	A Study of the Safety and Preliminary Efficacy of LY-M001 Injection in the Treatment of Adult Patients With Gaucher Disease Type I

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELIGLUSTAT	4	2
IMIGLUCERASE	4	1