Hereditary progressive chorea without dementia

Summary

Hereditary progressive chorea without dementia (MONDO:0021011) is a disease caused by NKX2-1 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NKX2-1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary progressive chorea without dementia
Mondo ID	MONDO:0021011
OMIM	118700
UMLS	C0393584
MedGen	98278
GARD	0025275
Is cancer (heuristic)	no

Also known as: BCH · BHC · chorea, benign hereditary · chorea, hereditary benign · hereditary progressive chorea without dementia

Data availability: 56 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › choreatic disease › hereditary progressive chorea without dementia

Related subtypes (4): chorea gravidarum, choreoathetosis, familial inverted, chorea, benign familial, chorea, remitting, with nystagmus and cataract

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

56 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 13 pathogenic, 8 likely pathogenic, 7 benign, 7 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1417048	NM_001079668.3(NKX2-1):c.619G>T (p.Glu207Ter)	NKX2-1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685985	NM_001079668.3(NKX2-1):c.533del (p.Asp178fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2506944	NM_001079668.3(NKX2-1):c.456_457delinsACGG (p.Phe152fs)	NKX2-1	Pathogenic	criteria provided, single submitter
2584746	NM_001079668.3(NKX2-1):c.429G>A (p.Trp143Ter)	NKX2-1	Pathogenic	criteria provided, single submitter
3339885	NM_001079668.3(NKX2-1):c.43_64dup (p.Pro22fs)	NKX2-1	Pathogenic	criteria provided, single submitter
3576568	NM_001079668.3(NKX2-1):c.572G>T (p.Arg191Leu)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495058	NM_001079668.3(NKX2-1):c.1050del (p.Gln350fs)	NKX2-1	Pathogenic	criteria provided, single submitter
521085	NM_001079668.3(NKX2-1):c.646del (p.Leu216fs)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635557	NC_000014.9:g.(?36516072)(36520130_?)del	NKX2-1	Pathogenic	criteria provided, single submitter
8973	NM_001079668.3(NKX2-1):c.727C>A (p.Arg243Ser)	NKX2-1	Pathogenic	no assertion criteria provided
8974	NM_001079668.3(NKX2-1):c.713G>T (p.Trp238Leu)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8975	NM_001079668.3(NKX2-1):c.908del (p.Gly303fs)	NKX2-1	Pathogenic	no assertion criteria provided
8979	NM_001079668.3(NKX2-1):c.613G>T (p.Glu205Ter)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8980	NM_001079668.3(NKX2-1):c.745C>T (p.Gln249Ter)	NKX2-1	Pathogenic	criteria provided, single submitter
984956	NM_001079668.3(NKX2-1):c.1204dup (p.Ter402LeuextTer?)	NKX2-1	Pathogenic	no assertion criteria provided
8972	NC_000014.8:g.(36407609_36463186)_(37638963_37670256)del	NKX2-8	Pathogenic	no assertion criteria provided
3768284	NM_001079668.3(NKX2-1):c.521del (p.Gly174fs)	SFTA3	Pathogenic	criteria provided, single submitter
1685383	NM_001079668.3(NKX2-1):c.713G>C (p.Trp238Ser)	NKX2-1	Likely pathogenic	criteria provided, single submitter
2444325	NM_001079668.3(NKX2-1):c.535del (p.Asp178_Val179insTer)	NKX2-1	Likely pathogenic	criteria provided, single submitter
2506941	NM_001079668.3(NKX2-1):c.1025del (p.Gly342fs)	NKX2-1	Likely pathogenic	criteria provided, single submitter
3234068	NM_001079668.3(NKX2-1):c.246_276del (p.Met83fs)	NKX2-1	Likely pathogenic	criteria provided, single submitter
3897769	NM_001079668.3(NKX2-1):c.182del (p.Gly61fs)	NKX2-1	Likely pathogenic	criteria provided, single submitter
689773	NM_001079668.3(NKX2-1):c.872C>G (p.Pro291Arg)	NKX2-1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
807451	NM_001079668.3(NKX2-1):c.303_319del (p.Ala103fs)	NKX2-1	Likely pathogenic	criteria provided, single submitter
4538501	NM_001079668.3(NKX2-1):c.671T>C (p.Leu224Pro)	SFTA3	Likely pathogenic	criteria provided, single submitter
313138	NM_001079668.3(NKX2-1):c.1200C>T (p.Thr400=)	NKX2-1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313145	NM_001079668.3(NKX2-1):c.435C>G (p.Gly145=)	NKX2-1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695624	NM_001079668.3(NKX2-1):c.190C>A (p.Leu64Ile)	NKX2-1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8978	NM_001079668.3(NKX2-1):c.464-2A>T	NKX2-1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985595	NM_001079668.3(NKX2-1):c.623G>C (p.Arg208Pro)	NKX2-1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 6 · 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
NKX2-1	Strong	Autosomal dominant	hereditary progressive chorea without dementia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gencc,clinvar
NKX2-8	HGNC:16364	ENSG00000136327	O15522	Homeobox protein Nkx-2.8	clinvar
SFTA3	HGNC:18387	ENSG00000229415	P0C7M3	Surfactant-associated protein 3	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
SFTA3	Surfactant-associated protein 3	Putative surfactant protein.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 3 · 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
Transcription factor	2	4.1×	0.223
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
NKX2-8	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SFTA3	Other/Unknown	no
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	2
right lobe of thyroid gland	2
thyroid gland	2
C1 segment of cervical spinal cord	1
right testis	1
spinal cord	1
colonic epithelium	1
ventricular zone	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
NKX2-8	53	broad	yes	C1 segment of cervical spinal cord, spinal cord, right testis
SFTA3	107	tissue_specific	marker	right lobe of thyroid gland, thyroid gland, left lobe of thyroid gland
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
NKX2-1	2,403
NKX2-8	667
SFTA3	604

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
NKX2-1	P43699	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NKX2-8	O15522	68.38
SFTA3	P0C7M3	61.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 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
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	1142.0×	0.005	NOTCH1
Defective LFNG causes SCDO3	1	1142.0×	0.005	NOTCH1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.005	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	815.7×	0.005	NOTCH1
Defective CSF2RB causes SMDP5	1	815.7×	0.005	SFTA3
Defective CSF2RA causes SMDP4	1	815.7×	0.005	SFTA3
Regulation of NFE2L2 gene expression	1	713.8×	0.005	NOTCH1
NFE2L2 regulating tumorigenic genes	1	475.8×	0.006	NOTCH1
RUNX3 regulates NOTCH signaling	1	407.9×	0.006	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	380.7×	0.006	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.006	NOTCH1
Pre-NOTCH Processing in Golgi	1	317.2×	0.006	NOTCH1
MECP2 regulates neuronal receptors and channels	1	300.5×	0.006	NOTCH1
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.006	NOTCH1
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.007	NOTCH1
Notch-HLH transcription pathway	1	203.9×	0.007	NOTCH1
Formation of paraxial mesoderm	1	203.9×	0.007	NOTCH1
Surfactant metabolism	1	184.2×	0.008	SFTA3
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.008	NOTCH1
Nuclear events stimulated by ALK signaling in cancer	1	163.1×	0.008	NOTCH1
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.010	NOTCH1
Somitogenesis	1	116.5×	0.010	NOTCH1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.011	NOTCH1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.011	NOTCH1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.014	NOTCH1
Pre-NOTCH Transcription and Translation	1	61.4×	0.016	NOTCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lung development	3	148.7×	1e-04	NKX2-1, NKX2-8, NOTCH1
endoderm development	2	312.1×	0.001	NKX2-1, NOTCH1
oligodendrocyte differentiation	2	210.7×	0.002	NKX2-1, NOTCH1
forebrain development	2	175.5×	0.002	NKX2-1, NOTCH1
epithelial cell proliferation	2	156.0×	0.002	NKX2-8, NOTCH1
negative regulation of epithelial cell proliferation	2	145.3×	0.002	NKX2-8, NOTCH1
liver development	2	110.9×	0.003	NKX2-8, NOTCH1
coronary sinus valve morphogenesis	1	4213.0×	0.004	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	4213.0×	0.004	NOTCH1
foregut morphogenesis	1	4213.0×	0.004	NOTCH1
regulation of epithelial cell proliferation involved in prostate gland development	1	4213.0×	0.004	NOTCH1
venous endothelial cell differentiation	1	4213.0×	0.004	NOTCH1
endocardium morphogenesis	1	2106.5×	0.004	NOTCH1
coronary vein morphogenesis	1	2106.5×	0.004	NOTCH1
cardiac right atrium morphogenesis	1	2106.5×	0.004	NOTCH1
growth involved in heart morphogenesis	1	2106.5×	0.004	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	2106.5×	0.004	NOTCH1
cell differentiation in spinal cord	1	2106.5×	0.004	NOTCH1
developmental induction	1	2106.5×	0.004	NKX2-1
positive regulation of aorta morphogenesis	1	2106.5×	0.004	NOTCH1
mitral valve formation	1	1404.3×	0.004	NOTCH1
cardiac chamber formation	1	1404.3×	0.004	NOTCH1
auditory receptor cell fate commitment	1	1404.3×	0.004	NOTCH1
cerebral cortex GABAergic interneuron differentiation	1	1404.3×	0.004	NKX2-1
retinal cone cell differentiation	1	1404.3×	0.004	NOTCH1
secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development	1	1404.3×	0.004	NOTCH1
cardiac vascular smooth muscle cell development	1	1404.3×	0.004	NOTCH1
vasculogenesis involved in coronary vascular morphogenesis	1	1404.3×	0.004	NOTCH1
regulation of cell adhesion involved in heart morphogenesis	1	1404.3×	0.004	NOTCH1
distal tubule development	1	1404.3×	0.004	NOTCH1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH1	1	2
NKX2-1	0	0
NKX2-8	0	0
SFTA3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
VAREGACESTAT	2	NOTCH1

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	1	NOTCH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	NKX2-1, NKX2-8, SFTA3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-1	0	—
NKX2-8	0	—
SFTA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.