Glycogen storage disorder due to hepatic glycogen synthase deficiency

Summary

Glycogen storage disorder due to hepatic glycogen synthase deficiency (MONDO:0009414) is a disease caused by GYS2 (GenCC Strong), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GYS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 230
• Phenotypes (HPO): 14
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000737	Irritability	Frequent (30-79%)
HP:0001946	Ketosis	Frequent (30-79%)
HP:0002919	Ketonuria	Frequent (30-79%)
HP:0003076	Glycosuria	Frequent (30-79%)
HP:0011998	Postprandial hyperglycemia	Frequent (30-79%)
HP:0012734	Ketotic hypoglycemia	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003077	Hyperlipidemia	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0011024	Abnormality of the gastrointestinal tract	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disorder due to hepatic glycogen synthase deficiency
Mondo ID	MONDO:0009414
MeSH	C565485
OMIM	240600
Orphanet	2089
SNOMED CT	237964009
UMLS	C1855861
MedGen	343430
GARD	0002513
Is cancer (heuristic)	no

Also known as: glycogen storage disease 0, liver · glycogen storage disease due to glycogen synthase deficiency of liver · glycogen storage disease due to hepatic glycogen synthase deficiency · glycogen storage disease due to liver glycogen synthase deficiency · glycogen storage disease type 0, liver · glycogen storage disease type 0a · glycogen synthase deficiency · glycogenosis type 0a · GSD due to hepatic glycogen synthase deficiency · GSD type 0a · GSD0A · hepatic glycogen synthase deficiency · hypoglycemia with deficiency of glycogen synthetase in the liver · liver glycogen storage disease due to glycogen synthase deficiency · liver GSD 0

Data availability: 230 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disorder due to hepatic glycogen synthase deficiency

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

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

230 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 59 likely benign, 24 benign, 17 likely pathogenic, 17 conflicting classifications of pathogenicity, 15 pathogenic, 11 benign/likely benign, 11 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323047	NM_021957.4(GYS2):c.1094_1098del (p.Phe365fs)	GYS2	Pathogenic	criteria provided, single submitter
16049	NM_021957.4(GYS2):c.736C>T (p.Arg246Ter)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16050	NM_021957.4(GYS2):c.941+1G>C	GYS2	Pathogenic	criteria provided, single submitter
16051	NM_021957.4(GYS2):c.1436C>A (p.Pro479Gln)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16052	NM_021957.4(GYS2):c.1015G>C (p.Ala339Pro)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16054	NM_021957.4(GYS2):c.116A>G (p.Asn39Ser)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16055	NM_021957.4(GYS2):c.1447T>C (p.Ser483Pro)	GYS2	Pathogenic	no assertion criteria provided
1806174	NM_021957.4(GYS2):c.522T>G (p.Tyr174Ter)	GYS2	Pathogenic	criteria provided, single submitter
2093847	NM_021957.4(GYS2):c.376_377del (p.Asn126fs)	GYS2	Pathogenic	criteria provided, single submitter
214529	NM_021957.4(GYS2):c.547C>T (p.Gln183Ter)	GYS2	Pathogenic	criteria provided, multiple submitters, no conflicts
214530	NM_021957.4(GYS2):c.574C>T (p.Arg192Ter)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2153549	NM_021957.4(GYS2):c.1413_1416del (p.Asp471fs)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2634940	NM_021957.4(GYS2):c.1557_1579del (p.Thr520fs)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3244318	NC_000012.11:g.(?21733256)(21757526_?)del	GYS2	Pathogenic	criteria provided, single submitter
3244319	NC_000012.11:g.(?21689888)(21711267_?)del	GYS2	Pathogenic	criteria provided, single submitter
3339273	NM_021957.4(GYS2):c.50dup (p.Trp18fs)	GYS2	Pathogenic	criteria provided, single submitter
3768522	NM_021957.4(GYS2):c.13C>T (p.Arg5Ter)	GYS2	Pathogenic	criteria provided, single submitter
3779719	NM_021957.4(GYS2):c.176G>A (p.Trp59Ter)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4529507	NG_016167.1:g.21559097_21559098ins[PP887427.1:g.1_1518]	GYS2	Pathogenic	criteria provided, single submitter
4702468	NM_021957.4(GYS2):c.1264C>T (p.Arg422Ter)	GYS2	Pathogenic	criteria provided, single submitter
4807181	NM_021957.4(GYS2):c.1209dup (p.Leu404fs)	GYS2	Pathogenic	criteria provided, single submitter
498897	NM_021957.4(GYS2):c.457del (p.Met152_Leu153insTer)	GYS2	Pathogenic	criteria provided, multiple submitters, no conflicts
566739	NM_021957.4(GYS2):c.1062+1G>T	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
569452	NM_021957.4(GYS2):c.1156C>T (p.Arg386Ter)	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
665082	NM_021957.4(GYS2):c.495+1G>T	GYS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
937499	NM_021957.4(GYS2):c.465del (p.Phe155fs)	GYS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3897898	NM_021957.4:c.[736C>T];[1170-1G>A]		Likely pathogenic	criteria provided, single submitter
1223503	NM_021957.4(GYS2):c.122-8_186delinsATCAGA	GYS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
16053	NM_021957.4(GYS2):c.1472T>G (p.Met491Arg)	GYS2	Likely pathogenic	criteria provided, single submitter
2161127	NM_021957.4(GYS2):c.942-2A>G	GYS2	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
GYS2	Strong	Autosomal recessive	glycogen storage disorder due to hepatic glycogen synthase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GYS2	Orphanet:2089	Glycogen storage disease due to hepatic glycogen synthase deficiency

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
GYS2	HGNC:4707	ENSG00000111713	P54840	Glycogen [starch] synthase, liver	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GYS2	Glycogen [starch] synthase, liver	Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.

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)
GYS2	Other/Unknown	no		Glycogen_synth

Expression context

Cohort genes with no expression data: 0.

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
liver	1
primordial germ cell in gonad	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GYS2	51	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GYS2	2,307

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GYS2	P54840	87.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Glycogen storage disease type 0 (liver GYS2)	1	5710.0×	4e-04	GYS2
Glycogen storage disease type IV (GBE1)	1	3806.7×	4e-04	GYS2
Glycogen synthesis	1	815.7×	0.001	GYS2

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
glycogen biosynthetic process	1	936.2×	0.002	GYS2
response to glucose	1	255.3×	0.004	GYS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GYS2	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
GYS2	2	Binding:2

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	GYS2

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)
GYS2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy