Brachydactyly-elbow wrist dysplasia syndrome

Summary

Brachydactyly-elbow wrist dysplasia syndrome (MONDO:0008520) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 3
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0031095	Abnormal humerus morphology	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001231	Abnormal fingernail morphology	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0003042	Elbow dislocation	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0006501	Aplasia/Hypoplasia of the radius	Very frequent (80-99%)
HP:0009832	Abnormal distal phalanx morphology of finger	Very frequent (80-99%)
HP:0040071	Abnormal morphology of ulna	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly-elbow wrist dysplasia syndrome
Mondo ID	MONDO:0008520
MeSH	C566090
OMIM	186550
Orphanet	1275
SNOMED CT	764437006
UMLS	C1861313
MedGen	396103
GARD	0000966
Is cancer (heuristic)	no

Also known as: brachydactyly elbow wrist dysplasia · brachydactyly with joint dysplasia · brachydactyly-joint dysplasia syndrome · carpal synostosis with dysplastic elbow joints and brachydactyly · LBNBG · Liebenberg syndrome

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

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › brachydactyly-elbow wrist dysplasia syndrome

Related subtypes (8): developmental dysplasia of the hip, osteochondrodysplasia, spondylocarpotarsal synostosis syndrome, odontoid hypoplasia, dysostosis, segmental odontomaxillary dysplasia, angioosteohypotrophic syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type

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

3 retrieved; paginated sample, class counts are floors:

2 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1806125	NM_002653.5(PITX1):c.934T>C (p.Tyr312His)	PITX1	Uncertain significance	criteria provided, single submitter
1294420	NM_002653.5(PITX1):c.793G>A (p.Gly265Ser)	PITX1	Benign	criteria provided, single submitter
286868	NM_002653.5(PITX1):c.896G>C (p.Gly299Ala)	PITX1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
MACROH2A1	Supportive	Autosomal dominant	brachydactyly-elbow wrist dysplasia syndrome
PITX1	Supportive	Autosomal dominant	brachydactyly-elbow wrist dysplasia syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PITX1	Orphanet:1275	Brachydactyly-elbow wrist dysplasia syndrome
PITX1	Orphanet:293144	Familial clubfoot due to 5q31 microdeletion
PITX1	Orphanet:293150	Familial clubfoot due to PITX1 point mutation
PITX1	Orphanet:498494	Mirror-image polydactyly
MACROH2A1	Orphanet:1275	Brachydactyly-elbow wrist dysplasia 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
PITX1	HGNC:9004	ENSG00000069011	P78337	Pituitary homeobox 1	gencc,clinvar
MACROH2A1	HGNC:4740	ENSG00000113648	O75367	Core histone macro-H2A.1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PITX1	Pituitary homeobox 1	Sequence-specific transcription factor that binds gene promoters and activates their transcription.
MACROH2A1	Core histone macro-H2A.1	Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PITX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
MACROH2A1	Other/Unknown	no		Histone_H2A, Macro_dom, H2A/H2B/H3

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
esophagus mucosa	1
lower esophagus mucosa	1
pharyngeal mucosa	1
epithelium of nasopharynx	1
monocyte	1
tongue squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PITX1	180	broad	marker	lower esophagus mucosa, esophagus mucosa, pharyngeal mucosa
MACROH2A1	302	ubiquitous	marker	epithelium of nasopharynx, tongue squamous epithelium, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MACROH2A1	3,047
PITX1	1,884

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MACROH2A1	O75367	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PITX1	P78337	62.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
regulation of NAD metabolic process	1	8426.0×	0.001	MACROH2A1
negative regulation of protein localization to chromosome, telomeric region	1	8426.0×	0.001	MACROH2A1
negative regulation of cell cycle G2/M phase transition	1	4213.0×	0.001	MACROH2A1
regulation of response to oxidative stress	1	4213.0×	0.001	MACROH2A1
positive regulation of response to oxidative stress	1	4213.0×	0.001	MACROH2A1
branchiomeric skeletal muscle development	1	2808.7×	0.002	PITX1
positive regulation of endodermal cell differentiation	1	2808.7×	0.002	MACROH2A1
negative regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	2106.5×	0.002	MACROH2A1
positive regulation of maintenance of mitotic sister chromatid cohesion	1	1685.2×	0.002	MACROH2A1
myoblast fate commitment	1	1685.2×	0.002	PITX1
negative regulation of response to oxidative stress	1	1203.7×	0.002	MACROH2A1
protein poly-ADP-ribosylation	1	1053.2×	0.002	MACROH2A1
establishment of protein localization to chromatin	1	936.2×	0.003	MACROH2A1
dosage compensation by inactivation of X chromosome	1	766.0×	0.003	MACROH2A1
regulation of oxidative phosphorylation	1	601.9×	0.003	MACROH2A1
positive regulation of keratinocyte differentiation	1	401.2×	0.005	MACROH2A1
pituitary gland development	1	324.1×	0.006	PITX1
embryonic hindlimb morphogenesis	1	290.6×	0.006	PITX1
regulation of lipid metabolic process	1	216.1×	0.007	MACROH2A1
negative regulation of gene expression, epigenetic	1	200.6×	0.007	MACROH2A1
epigenetic regulation of gene expression	1	191.5×	0.007	MACROH2A1
transcription initiation-coupled chromatin remodeling	1	191.5×	0.007	MACROH2A1
heterochromatin formation	1	127.7×	0.010	MACROH2A1
cartilage development	1	125.8×	0.010	PITX1
nucleosome assembly	1	70.2×	0.017	MACROH2A1
anatomical structure morphogenesis	1	69.6×	0.017	PITX1
skeletal system development	1	62.9×	0.018	PITX1
DNA repair	1	31.9×	0.034	MACROH2A1
negative regulation of DNA-templated transcription	1	15.8×	0.067	PITX1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.113	MACROH2A1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PITX1	0	0
MACROH2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	PITX1, MACROH2A1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PITX1	0	—
MACROH2A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.