Split hand-foot malformation 1

Summary

Split hand-foot malformation 1 (MONDO:0008464) is a disease caused by DLX5 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: DLX5 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	split hand-foot malformation 1
Mondo ID	MONDO:0008464
OMIM	183600
DOID	DOID:0090021
NCIT	C75045
UMLS	C2931019
MedGen	419314
GARD	0007685
Is cancer (heuristic)	no

Also known as: SHFD1 · SHFM1 · split hand-foot malformation type 1 · split hand/foot malformation 1 · split-hand/foot malformation 1 · split-hand/foot malformation type 1

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › split hand-foot malformation › split hand-foot malformation 1

Related subtypes (5): split hand-foot malformation 6, split hand-foot malformation 3, split hand-foot malformation 2, split hand-foot malformation 4, split hand-foot malformation 5

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

9 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
545583	GRCh37/hg19 7q21.2-22.1(chr7:92445452-99686985)x1	CYP3A4	Pathogenic	criteria provided, single submitter
156469	NM_005221.6(DLX5):c.115G>T (p.Glu39Ter)	DLX5	Pathogenic	no assertion criteria provided
91861	NM_005221.6(DLX5):c.558G>T (p.Gln186His)	LOC126860116	Pathogenic	no assertion criteria provided
218144	NM_016653.3(MAP3K20):c.1103T>G (p.Phe368Cys)	MAP3K20	Pathogenic	no assertion criteria provided
2502307	NM_005221.6(DLX5):c.509T>C (p.Leu170Pro)	DLX5	Likely pathogenic	criteria provided, single submitter
3381995	NM_005221.6(DLX5):c.481T>C (p.Tyr161His)	DLX5	Likely pathogenic	criteria provided, single submitter
3370334	NM_005221.6(DLX5):c.839del (p.Pro280fs)	DLX5	Uncertain significance	criteria provided, single submitter
3381862	NM_005221.6(DLX5):c.868T>G (p.Ter290Glu)	DLX5	Uncertain significance	criteria provided, single submitter
3382755	NM_005221.6(DLX5):c.569C>T (p.Ser190Phe)	DLX5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
DLX5	Strong	Autosomal dominant	split hand-foot malformation 1 with sensorineural hearing loss	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLX5	Orphanet:2440	Isolated split hand-split foot malformation
DLX5	Orphanet:71271	Split hand-split foot-deafness syndrome
MAP3K20	Orphanet:2020	Congenital fiber-type disproportion myopathy
MAP3K20	Orphanet:488232	Split-foot malformation-mesoaxial polydactyly syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLX5	HGNC:2918	ENSG00000105880	P56178	Homeobox protein DLX-5	gencc,clinvar
MAP3K20	HGNC:17797	ENSG00000091436	Q9NYL2	Mitogen-activated protein kinase kinase kinase 20	clinvar
CYP3A4	HGNC:2637	ENSG00000160868	P08684	Cytochrome P450 3A4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLX5	Homeobox protein DLX-5	Transcriptional factor involved in bone development.
MAP3K20	Mitogen-activated protein kinase kinase kinase 20	Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation.
CYP3A4	Cytochrome P450 3A4	A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Kinase	1	9.2×	0.313
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLX5	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
MAP3K20	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, SAM
CYP3A4	Enzyme (other)	yes	1.14.14.55	Cyt_P450, Cyt_P450_E_grp-II, Cyt_P450_E_CYP3A

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	1
skin of leg	1
tibia	1
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
ileal mucosa	1
jejunal mucosa	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLX5	158	broad	marker	tibia, primordial germ cell in gonad, skin of leg
MAP3K20	267	ubiquitous	marker	heart right ventricle, skeletal muscle tissue of rectus abdominis, biceps brachii
CYP3A4	194	tissue_specific	marker	jejunal mucosa, ileal mucosa, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLX5	1,886
MAP3K20	1,615
CYP3A4	46

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP3A4	P08684	122
MAP3K20	Q9NYL2	8
DLX5	P56178	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
Biosynthesis of maresin-like SPMs	1	951.7×	0.005	CYP3A4
Atorvastatin ADME	1	713.8×	0.005	CYP3A4
Prednisone ADME	1	634.4×	0.005	CYP3A4
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.005	DLX5
Aflatoxin activation and detoxification	1	317.2×	0.005	CYP3A4
Specification of the neural plate border	1	317.2×	0.005	DLX5
Xenobiotics	1	248.3×	0.006	CYP3A4
Aspirin ADME	1	158.6×	0.008	CYP3A4
Phase I - Functionalization of compounds	1	109.8×	0.010	CYP3A4
Regulation of RUNX2 expression and activity	1	90.6×	0.011	DLX5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of stress-activated protein kinase signaling cascade	1	5617.3×	0.004	MAP3K20
interneuron axon guidance	1	5617.3×	0.004	DLX5
positive regulation of mitotic DNA damage checkpoint	1	5617.3×	0.004	MAP3K20
alkaloid catabolic process	1	1872.4×	0.006	CYP3A4
olfactory pit development	1	1872.4×	0.006	DLX5
negative regulation of translation in response to endoplasmic reticulum stress	1	1872.4×	0.006	MAP3K20
vitamin D catabolic process	1	1404.3×	0.006	CYP3A4
GCN2-mediated signaling	1	1404.3×	0.006	MAP3K20
olfactory bulb interneuron differentiation	1	1123.5×	0.006	DLX5
monoterpenoid metabolic process	1	936.2×	0.006	CYP3A4
lipid hydroxylation	1	802.5×	0.006	CYP3A4
steroid catabolic process	1	802.5×	0.006	CYP3A4
stress-activated protein kinase signaling cascade	1	802.5×	0.006	MAP3K20
aflatoxin metabolic process	1	802.5×	0.006	CYP3A4
cell death	1	702.2×	0.006	MAP3K20
oxidative demethylation	1	702.2×	0.006	CYP3A4
anatomical structure formation involved in morphogenesis	1	624.1×	0.006	DLX5
vitamin D metabolic process	1	510.7×	0.007	CYP3A4
cellular response to UV-B	1	468.1×	0.007	MAP3K20
positive regulation of programmed cell death	1	374.5×	0.009	MAP3K20
androgen metabolic process	1	295.6×	0.010	CYP3A4
p38MAPK cascade	1	295.6×	0.010	MAP3K20
cell differentiation	2	19.4×	0.010	DLX5, MAP3K20
retinoic acid metabolic process	1	267.5×	0.010	CYP3A4
stress-activated MAPK cascade	1	234.1×	0.011	MAP3K20
estrogen metabolic process	1	208.1×	0.012	CYP3A4
cellular response to gamma radiation	1	200.6×	0.012	MAP3K20
xenobiotic catabolic process	1	187.2×	0.012	CYP3A4
endochondral ossification	1	181.2×	0.012	DLX5
pyroptotic inflammatory response	1	170.2×	0.012	MAP3K20

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
MAP3K20	PONATINIB
CYP3A4	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP3A4	695	4
MAP3K20	53	4
DLX5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	CYP3A4, MAP3K20
VEMURAFENIB	4	MAP3K20
FEDRATINIB	4	MAP3K20
AXITINIB	4	MAP3K20
SORAFENIB	4	MAP3K20
DASATINIB ANHYDROUS	4	MAP3K20
NERATINIB	4	MAP3K20
IBRUTINIB	4	CYP3A4, MAP3K20
REGORAFENIB	4	MAP3K20
DABRAFENIB	4	MAP3K20
PACRITINIB	4	MAP3K20
VANDETANIB	4	MAP3K20
NILOTINIB	4	CYP3A4, MAP3K20
BOSUTINIB	4	MAP3K20
ENCORAFENIB	4	MAP3K20
TOVORAFENIB	4	MAP3K20
DASATINIB	4	CYP3A4, MAP3K20
QUIZARTINIB	4	MAP3K20
IMATINIB	4	CYP3A4, MAP3K20
KETOCONAZOLE	4	CYP3A4
TELITHROMYCIN	4	CYP3A4
CYCLOSPORINE	4	CYP3A4
RITONAVIR	4	CYP3A4
TACROLIMUS ANHYDROUS	4	CYP3A4
CARFILZOMIB	4	CYP3A4
VORICONAZOLE	4	CYP3A4
BEPRIDIL	4	CYP3A4
PHENYLBUTAZONE	4	CYP3A4
CANDESARTAN CILEXETIL	4	CYP3A4
TELMISARTAN	4	CYP3A4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP3A4	5,927	ADMET:5828, Binding:97, Functional:1, Toxicity:1
MAP3K20	245	Binding:244, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP3A4	1.14.14.55, 1.14.14.73, 1.14.99.38	quinine 3-monooxygenase, albendazole monooxygenase (sulfoxide-forming), cholesterol 25-monooxygenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAP3K20	245
CYP3A4	5,927

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CYP3A4	1

Chemical tractability of cohort targets

30 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)
PONATINIB	4	CYP3A4, MAP3K20
VEMURAFENIB	4	MAP3K20
FEDRATINIB	4	MAP3K20
AXITINIB	4	MAP3K20
SORAFENIB	4	MAP3K20
DASATINIB ANHYDROUS	4	MAP3K20
NERATINIB	4	MAP3K20
IBRUTINIB	4	CYP3A4, MAP3K20
REGORAFENIB	4	MAP3K20
DABRAFENIB	4	MAP3K20
PACRITINIB	4	MAP3K20
VANDETANIB	4	MAP3K20
NILOTINIB	4	CYP3A4, MAP3K20
BOSUTINIB	4	MAP3K20
ENCORAFENIB	4	MAP3K20
TOVORAFENIB	4	MAP3K20
DASATINIB	4	CYP3A4, MAP3K20
QUIZARTINIB	4	MAP3K20
IMATINIB	4	CYP3A4, MAP3K20
KETOCONAZOLE	4	CYP3A4
TELITHROMYCIN	4	CYP3A4
CYCLOSPORINE	4	CYP3A4
RITONAVIR	4	CYP3A4
TACROLIMUS ANHYDROUS	4	CYP3A4
CARFILZOMIB	4	CYP3A4
VORICONAZOLE	4	CYP3A4
BEPRIDIL	4	CYP3A4
PHENYLBUTAZONE	4	CYP3A4
CANDESARTAN CILEXETIL	4	CYP3A4
TELMISARTAN	4	CYP3A4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MAP3K20, CYP3A4
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	DLX5

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)
DLX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.