Split hand-foot malformation 3

Summary

Split hand-foot malformation 3 (MONDO:0009525) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 42
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000308	Microretrognathia	Very frequent (80-99%)
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0002916	Abnormality of chromosome segregation	Very frequent (80-99%)
HP:0003028	Abnormality of the ankles	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0012165	Oligodactyly	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000089	Renal hypoplasia	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0003019	Abnormality of the wrist	Frequent (30-79%)
HP:0006501	Aplasia/Hypoplasia of the radius	Frequent (30-79%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Frequent (30-79%)
HP:0000171	Microglossia	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0001839	Split foot	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0008368	Tarsal synostosis	Occasional (5-29%)
HP:0040071	Abnormal morphology of ulna	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	split hand-foot malformation 3
Mondo ID	MONDO:0009525
MeSH	C565437
OMIM	246560
Orphanet	1307
DOID	DOID:0090025
NCIT	C75121
SNOMED CT	722429003
UMLS	C1838652
MedGen	325070
GARD	0003252
Is cancer (heuristic)	no

Also known as: 10q24 microduplication syndrome · Buttiens Fryns syndrome · Buttiens-Fryns syndrome · chromosome 10q24 duplication syndrome · limb deficiencies distal with micrognathia · SHFM3 · split hand-foot malformation 3 · split hand-foot malformation type 3 · split-hand/foot malformation 3 · split-hand/foot malformation 3, gene duplication syndrome · split-hand/foot malformation type 3

Data availability: 42 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome › split hand-foot malformation 3

Related subtypes (68): acromegaloid facial appearance syndrome, Hypoglossia-hypodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, campomelic dysplasia, cerebrocostomandibular syndrome, autosomal dominant popliteal pterygium syndrome, Pallister-Hall syndrome, autosomal dominant primary microcephaly, microgastria-limb reduction defect syndrome, Mobius syndrome, oculodentodigital dysplasia, Char syndrome, Prader-Willi syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, short stature-wormian bones-dextrocardia syndrome, ablepharon macrostomia syndrome, Goodman syndrome, anophthalmia/microphthalmia-esophageal atresia syndrome, microphthalmia with limb anomalies, Antley-Bixler syndrome, campomelia, Cumming type, CHARGE syndrome, Toriello-Carey syndrome, Donnai-Barrow syndrome, lethal faciocardiomelic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, hypomandibular faciocranial dysostosis, isotretinoin-like syndrome, oculotrichoanal syndrome, Hennekam-Beemer syndrome, Mietens syndrome, Schinzel-Giedion syndrome, SHORT syndrome, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, occipital horn syndrome, hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome, Potocki-Shaffer syndrome, Marshall-Smith syndrome, PHACE syndrome, Noonan syndrome-like disorder with loose anagen hair, branchiogenic deafness syndrome, combined immunodeficiency with faciooculoskeletal anomalies, chromosome 1p32-p31 deletion syndrome, Malan overgrowth syndrome, dysmorphism-conductive hearing loss-heart defect syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, short stature-heart defect-craniofacial anomalies syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, polyvalvular heart disease syndrome, Kallmann syndrome-heart disease syndrome, Meier-Gorlin syndrome, symptomatic form of Coffin-Lowry syndrome in female carriers, Prader-Willi-like syndrome, contractures-developmental delay-Pierre Robin syndrome, 22q11.2 deletion syndrome, Noonan syndrome, Carpenter syndrome, Bosley-Salih-Alorainy syndrome, Sotos syndrome, Robinow syndrome, King-Denborough syndrome, Weiss-Kruszka syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, 4q25 proximal deletion syndrome, restrictive dermopathy 1, mosaic SMO syndrome

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

42 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 11 likely benign, 7 benign, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
625658	GRCh37/hg19 10q24.31-24.32(chr10:102822575-103558868)	FBXW4	Pathogenic	criteria provided, single submitter
298537	NM_022039.4(FBXW4):c.726-12G>T	FBXW4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877576	NM_022039.4(FBXW4):c.755T>C (p.Val252Ala)	FBXW4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298522	NM_022039.4(FBXW4):c.*606A>C	FBXW4	Uncertain significance	criteria provided, single submitter
298528	NM_022039.4(FBXW4):c.1657G>A (p.Ala553Thr)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
298529	NM_022039.4(FBXW4):c.1473C>T (p.His491=)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
298530	NM_022039.4(FBXW4):c.1465G>A (p.Glu489Lys)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
298532	NM_022039.4(FBXW4):c.1302-9C>T	FBXW4	Uncertain significance	criteria provided, single submitter
298535	NM_022039.4(FBXW4):c.1181A>G (p.His394Arg)	FBXW4	Uncertain significance	criteria provided, single submitter
298536	NM_022039.4(FBXW4):c.923G>A (p.Arg308His)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
298538	NM_022039.4(FBXW4):c.710G>A (p.Arg237Gln)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
298544	NM_022039.4(FBXW4):c.409A>G (p.Arg137Gly)	FBXW4	Uncertain significance	criteria provided, single submitter
298548	NM_022039.4(FBXW4):c.192G>A (p.Thr64=)	FBXW4	Uncertain significance	criteria provided, single submitter
877573	NM_022039.4(FBXW4):c.1170G>T (p.Gly390=)	FBXW4	Uncertain significance	criteria provided, single submitter
879142	NM_022039.4(FBXW4):c.*600G>A	FBXW4	Uncertain significance	criteria provided, single submitter
879143	NM_022039.4(FBXW4):c.*381C>G	FBXW4	Uncertain significance	criteria provided, single submitter
879193	NM_022039.4(FBXW4):c.316G>T (p.Ala106Ser)	FBXW4	Uncertain significance	criteria provided, multiple submitters, no conflicts
880346	NM_022039.4(FBXW4):c.1549C>T (p.Arg517Trp)	FBXW4	Uncertain significance	criteria provided, single submitter
298541	NM_022039.4(FBXW4):c.493G>A (p.Glu165Lys)	LOC130004563	Uncertain significance	criteria provided, single submitter
298543	NM_022039.4(FBXW4):c.437G>A (p.Trp146Ter)	LOC130004563	Uncertain significance	criteria provided, single submitter
878594	NM_022039.4(FBXW4):c.715G>A (p.Gly239Ser)	LOC130004563	Uncertain significance	criteria provided, single submitter
878595	NM_022039.4(FBXW4):c.507G>A (p.Ala169=)	LOC130004563	Uncertain significance	criteria provided, single submitter
193449	NM_022039.4(FBXW4):c.461T>A (p.Val154Glu)	FBXW4	Benign	criteria provided, multiple submitters, no conflicts
281768	NM_022039.4(FBXW4):c.1410T>C (p.Tyr470=)	FBXW4	Benign	criteria provided, multiple submitters, no conflicts
298523	NM_022039.4(FBXW4):c.*453C>T	FBXW4	Likely benign	criteria provided, single submitter
298525	NM_022039.4(FBXW4):c.*259C>T	FBXW4	Benign	criteria provided, single submitter
298526	NM_022039.4(FBXW4):c.*233G>T	FBXW4	Likely benign	criteria provided, single submitter
298527	NM_022039.4(FBXW4):c.*7G>C	FBXW4	Benign	criteria provided, multiple submitters, no conflicts
298531	NM_022039.4(FBXW4):c.1437C>T (p.Ser479=)	FBXW4	Likely benign	criteria provided, single submitter
298533	NM_022039.4(FBXW4):c.1254G>A (p.Thr418=)	FBXW4	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
FBXW4	Limited	Autosomal dominant	split hand-foot malformation 3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXW4	Orphanet:2440	Isolated split hand-split foot malformation

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
FBXW4	HGNC:10847	ENSG00000107829	P57775	F-box/WD repeat-containing protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXW4	F-box/WD repeat-containing protein 4	Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBXW4	Scaffold/PPI	no		WD40_rpt, F-box_dom, WD40/YVTN_repeat-like_dom_sf

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
C1 segment of cervical spinal cord	1
apex of heart	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXW4	281	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBXW4	789

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXW4	P57775	90.91

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
Association of TriC/CCT with target proteins during biosynthesis	1	292.8×	0.010	FBXW4
Neddylation	1	47.4×	0.027	FBXW4
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	FBXW4

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
embryonic limb morphogenesis	1	401.2×	0.005	FBXW4
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	374.5×	0.005	FBXW4
Wnt signaling pathway	1	99.7×	0.013	FBXW4
ubiquitin-dependent protein catabolic process	1	74.2×	0.013	FBXW4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
FBXW4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	FBXW4

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)
FBXW4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.