Moyamoya disease with early-onset achalasia

Summary

Moyamoya disease with early-onset achalasia (MONDO:0014331) is a disease caused by GUCY1A1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GUCY1A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0001297	Stroke	Obligate (100%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0011834	Moyamoya phenomenon	Frequent (30-79%)
HP:0100659	Abnormality of the cerebral vasculature	Frequent (30-79%)
HP:0000965	Cutis marmorata	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0030402	Abnormal platelet aggregation	Occasional (5-29%)
HP:0030880	Raynaud phenomenon	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Moyamoya disease with early-onset achalasia
Mondo ID	MONDO:0014331
OMIM	615750
Orphanet	401945
SNOMED CT	718551002
UMLS	C3810403
MedGen	816733
GARD	0017664
Is cancer (heuristic)	no

Also known as: moyamoya 6 with achalasia · Moyamoya disease 6 with achalasia · MYMY6

Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › Moyamoya disease with early-onset achalasia

Related subtypes (30): benign digestive system neoplasm, autoimmune disorder of gastrointestinal tract, gastrointestinal mucositis, diarrheal disease, pancreas disorder, hepatobiliary disorder, digestive system cancer, peptic ulcer disease, stomach disorder, intestinal disorder, Meckel diverticulum, Cronkhite-Canada syndrome, diverticulosis, small-intestinal, diverticulosis of bowel, hernia, and retinal detachment, congenital enteropathy due to enteropeptidase deficiency, hereditary mixed polyposis syndrome, caudal duplication, hyperplastic polyposis syndrome, thoraco-abdominal enteric duplication, digestive duplication, juvenile polyposis syndrome, umbilical cord ulceration-intestinal atresia syndrome, growth retardation-mild developmental delay-chronic hepatitis syndrome, common mesentery, neoplasm of oropharynx, gastrointestinal polyp, digestive system neuroendocrine neoplasm, digestive system infectious disorder, upper digestive tract disorder, congenital peritoneal encapsulation

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

15 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
127094	NM_001130682.3(GUCY1A1):c.1086+1G>A	GUCY1A1	Pathogenic	no assertion criteria provided
127095	NM_001130682.3(GUCY1A1):c.1045C>T (p.Arg349Ter)	GUCY1A1	Pathogenic	criteria provided, single submitter
127096	NM_001130682.3(GUCY1A1):c.1170del (p.Glu391fs)	GUCY1A1	Pathogenic	no assertion criteria provided
1323042	NM_001130682.3(GUCY1A1):c.1086+1G>T	GUCY1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703698	NM_001130682.3(GUCY1A1):c.1422del (p.Lys475fs)	GUCY1A1	Pathogenic	criteria provided, single submitter
4686576	GUCY1A1, ARG593HIS (rs370478508)	GUCY1A1	Pathogenic	no assertion criteria provided
559596	NM_001130682.3(GUCY1A1):c.1258C>T (p.Arg420Ter)	GUCY1A1	Pathogenic	no assertion criteria provided
559597	NM_001130682.3(GUCY1A1):c.1550G>A (p.Cys517Tyr)	GUCY1A1	Pathogenic	no assertion criteria provided
559599	NM_001130682.3(GUCY1A1):c.1954G>T (p.Gly652Ter)	GUCY1A1	Pathogenic	no assertion criteria provided
3377733	NM_001130682.3(GUCY1A1):c.1886_1905del (p.Cys629fs)	GUCY1A1	Likely pathogenic	criteria provided, single submitter
1032479	NM_001130682.3(GUCY1A1):c.630C>T (p.Thr210=)	GUCY1A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
559598	NM_001130682.3(GUCY1A1):c.334_335del (p.Glu112fs)	GUCY1A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031673	NM_001130682.3(GUCY1A1):c.1535G>A (p.Arg512His)	GUCY1A1	Uncertain significance	criteria provided, single submitter
982720	NM_001130682.3(GUCY1A1):c.1687G>A (p.Val563Ile)	GUCY1A1	Uncertain significance	criteria provided, single submitter
1285312	NM_001130682.3(GUCY1A1):c.1074A>G (p.Lys358=)	GUCY1A1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
GUCY1A1	Strong	Autosomal recessive	Moyamoya disease with early-onset achalasia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GUCY1A1	Orphanet:401945	Moyamoya disease with early-onset achalasia

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
GUCY1A1	HGNC:4685	ENSG00000164116	Q02108	Guanylate cyclase soluble subunit alpha-1	gencc,clinvar

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUCY1A1	Enzyme (other)	yes	4.6.1.2	A/G_cyclase, HNOB_dom_associated, A/G_cyclase_CS

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
saphenous vein	1
urethra	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUCY1A1	289	broad	marker	urethra, vena cava, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GUCY1A1	1,383

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GUCY1A1	Q02108	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Nitric oxide stimulates guanylate cyclase	1	815.7×	0.002	GUCY1A1
Smooth Muscle Contraction	1	265.6×	0.004	GUCY1A1

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
retrograde trans-synaptic signaling by nitric oxide, modulating synaptic transmission	1	16852.0×	6e-04	GUCY1A1
obsolete positive regulation of nitric oxide mediated signal transduction	1	4213.0×	8e-04	GUCY1A1
response to oxygen levels	1	4213.0×	8e-04	GUCY1A1
relaxation of vascular associated smooth muscle	1	2808.7×	9e-04	GUCY1A1
nitric oxide-cGMP-mediated signaling	1	1532.0×	0.001	GUCY1A1
cGMP biosynthetic process	1	1404.3×	0.001	GUCY1A1
obsolete nitric oxide mediated signal transduction	1	1296.3×	0.001	GUCY1A1
obsolete cGMP-mediated signaling	1	802.5×	0.002	GUCY1A1
blood circulation	1	510.7×	0.002	GUCY1A1
regulation of blood pressure	1	221.7×	0.005	GUCY1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
GUCY1A1	BENZYDAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GUCY1A1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BENZYDAMINE	4	GUCY1A1
FRESPACIGUAT	2	GUCY1A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GUCY1A1	45	Binding:40, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY1A1	4.6.1.2	guanylate cyclase

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

2 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)
BENZYDAMINE	4	GUCY1A1
FRESPACIGUAT	2	GUCY1A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GUCY1A1
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	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: 0.