Cardiospondylocarpofacial syndrome

Summary

Cardiospondylocarpofacial syndrome (MONDO:0008005) is a disease caused by MAP3K7 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAP3K7 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	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:0000405	Conductive hearing impairment	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001634	Mitral valve prolapse	Very frequent (80-99%)
HP:0001653	Mitral regurgitation	Very frequent (80-99%)
HP:0002705	High, narrow palate	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0005048	Synostosis of carpal bones	Very frequent (80-99%)
HP:0000692	Tooth malposition	Frequent (30-79%)
HP:0006352	Failure of eruption of permanent teeth	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiospondylocarpofacial syndrome
Mondo ID	MONDO:0008005
MeSH	C563572
OMIM	157800
Orphanet	3238
NCIT	C188216
SNOMED CT	720612000
UMLS	C2931461
MedGen	444060
GARD	0002362
Is cancer (heuristic)	no

Also known as: cardiospondylocarpofacial syndrome · congenital heart disease, deafness, and skeletal malformations · CSCF · Forney Robinson Pascoe syndrome · Forney syndrome · Forney-Robinson-Pascoe syndrome · mitral regurgitation-deafness-skeletal anomalies syndrome

Data availability: 22 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › filamin-related bone disorder › cardiospondylocarpofacial syndrome

Related subtypes (5): Frank-Ter Haar syndrome, spondylocarpotarsal synostosis syndrome, terminal osseous dysplasia-pigmentary defects syndrome, otopalatodigital syndrome spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder

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

22 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 5 pathogenic, 4 likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1341502	NM_145331.3(MAP3K7):c.616T>G (p.Tyr206Asp)	MAP3K7	Pathogenic	criteria provided, single submitter
264702	NM_145331.3(MAP3K7):c.130_135del (p.Arg44_Gly45del)	MAP3K7	Pathogenic	no assertion criteria provided
264704	NM_145331.3(MAP3K7):c.145GTT[1] (p.Val50del)	MAP3K7	Pathogenic	criteria provided, multiple submitters, no conflicts
264705	NM_145331.3(MAP3K7):c.721T>A (p.Trp241Arg)	MAP3K7	Pathogenic	criteria provided, single submitter
974910	NM_145331.3(MAP3K7):c.737-7A>G	MAP3K7	Pathogenic	criteria provided, multiple submitters, no conflicts
1173089	NM_145331.3(MAP3K7):c.815C>A (p.Ser272Tyr)	MAP3K7	Likely pathogenic	criteria provided, single submitter
264703	NM_145331.3(MAP3K7):c.328G>T (p.Gly110Cys)	MAP3K7	Likely pathogenic	criteria provided, single submitter
4819273	NM_145331.3(MAP3K7):c.575G>A (p.Ser192Asn)	MAP3K7	Likely pathogenic	criteria provided, single submitter
684731	NM_145331.3(MAP3K7):c.122TTG[1] (p.Val42del)	MAP3K7	Likely pathogenic	criteria provided, single submitter
1806063	NM_145331.3(MAP3K7):c.631G>A (p.Asp211Asn)	MAP3K7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
689611	NM_145331.3(MAP3K7):c.248G>A (p.Arg83His)	MAP3K7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
929459	NM_145331.3(MAP3K7):c.143G>A (p.Gly48Glu)	MAP3K7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031196	NM_145331.3(MAP3K7):c.868-17T>A	MAP3K7	Uncertain significance	criteria provided, single submitter
1701696	NM_145331.3(MAP3K7):c.795TTG[1] (p.Cys266del)	MAP3K7	Uncertain significance	criteria provided, single submitter
3065948	NM_145331.3(MAP3K7):c.124G>T (p.Val42Phe)	MAP3K7	Uncertain significance	criteria provided, single submitter
3381881	NM_145331.3(MAP3K7):c.742C>G (p.Arg248Gly)	MAP3K7	Uncertain significance	criteria provided, single submitter
3382947	NM_145331.3(MAP3K7):c.793C>T (p.Arg265Cys)	MAP3K7	Uncertain significance	criteria provided, single submitter
3393073	NM_145331.3(MAP3K7):c.512T>C (p.Leu171Pro)	MAP3K7	Uncertain significance	criteria provided, single submitter
4279825	NM_145331.3(MAP3K7):c.1162A>G (p.Met388Val)	MAP3K7	Uncertain significance	criteria provided, single submitter
4526449	NM_145331.3(MAP3K7):c.713G>A (p.Arg238Gln)	MAP3K7	Uncertain significance	no assertion criteria provided
4819633	NM_145331.3(MAP3K7):c.197_200del (p.Glu66fs)	MAP3K7	Uncertain significance	criteria provided, single submitter
992915	NM_145331.3(MAP3K7):c.632A>G (p.Asp211Gly)	MAP3K7	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
MAP3K7	Strong	Autosomal dominant	cardiospondylocarpofacial syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP3K7	Orphanet:1826	Frontometaphyseal dysplasia
MAP3K7	Orphanet:3238	Cardiospondylocarpofacial syndrome

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
MAP3K7	HGNC:6859	ENSG00000135341	O43318	Mitogen-activated protein kinase kinase kinase 7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP3K7	Mitogen-activated protein kinase kinase kinase 7	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP3K7	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ser/Thr_kinase_AS

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
corpus epididymis	1
tendon	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP3K7	290	ubiquitous	marker	tendon of biceps brachii, tendon, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP3K7	5,457

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP3K7	O43318	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. 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
IRAK2 mediated activation of TAK1 complex	1	1142.0×	0.010	MAP3K7
TICAM1,TRAF6-dependent induction of TAK1 complex	1	1038.2×	0.010	MAP3K7
Alpha-protein kinase 1 signaling pathway	1	1038.2×	0.010	MAP3K7
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.010	MAP3K7
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	761.3×	0.010	MAP3K7
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	713.8×	0.010	MAP3K7
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	519.1×	0.010	MAP3K7
TCR signaling	1	496.5×	0.010	MAP3K7
activated TAK1 mediates p38 MAPK activation	1	496.5×	0.010	MAP3K7
TNF signaling	1	423.0×	0.010	MAP3K7
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	356.9×	0.010	MAP3K7
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.010	MAP3K7
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.010	MAP3K7
NOD1/2 Signaling Pathway	1	317.2×	0.010	MAP3K7
MAP kinase activation	1	308.6×	0.010	MAP3K7
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.010	MAP3K7
Beta-catenin independent WNT signaling	1	292.8×	0.010	MAP3K7
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.010	MAP3K7
Interleukin-1 family signaling	1	271.9×	0.010	MAP3K7
Interleukin-17 signaling	1	253.8×	0.010	MAP3K7
C-type lectin receptors (CLRs)	1	237.9×	0.010	MAP3K7
Toll Like Receptor 10 (TLR10) Cascade	1	215.5×	0.010	MAP3K7
Toll Like Receptor 5 (TLR5) Cascade	1	215.5×	0.010	MAP3K7
MyD88 cascade initiated on plasma membrane	1	203.9×	0.010	MAP3K7
Activation of NF-kappaB in B cells	1	196.9×	0.010	MAP3K7
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.010	MAP3K7
TRIF (TICAM1)-mediated TLR4 signaling	1	190.3×	0.010	MAP3K7
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	190.3×	0.010	MAP3K7
MyD88 dependent cascade initiated on endosome	1	190.3×	0.010	MAP3K7
MyD88-independent TLR4 cascade	1	184.2×	0.010	MAP3K7

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
I-kappaB phosphorylation	1	5617.3×	0.003	MAP3K7
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	2808.7×	0.003	MAP3K7
interleukin-17A-mediated signaling pathway	1	2808.7×	0.003	MAP3K7
interleukin-33-mediated signaling pathway	1	2106.5×	0.003	MAP3K7
positive regulation of cGAS/STING signaling pathway	1	2106.5×	0.003	MAP3K7
TRIF-dependent toll-like receptor signaling pathway	1	1532.0×	0.003	MAP3K7
positive regulation of T cell cytokine production	1	1296.3×	0.003	MAP3K7
anoikis	1	1296.3×	0.003	MAP3K7
positive regulation of JUN kinase activity	1	1296.3×	0.003	MAP3K7
positive regulation of cell size	1	1296.3×	0.003	MAP3K7
toll-like receptor 3 signaling pathway	1	1123.5×	0.003	MAP3K7
positive regulation of vascular associated smooth muscle cell migration	1	991.3×	0.003	MAP3K7
MyD88-dependent toll-like receptor signaling pathway	1	936.2×	0.003	MAP3K7
cellular response to angiotensin	1	936.2×	0.003	MAP3K7
cytoplasmic pattern recognition receptor signaling pathway	1	887.0×	0.003	MAP3K7
p38MAPK cascade	1	887.0×	0.003	MAP3K7
signal transduction in response to DNA damage	1	802.5×	0.003	MAP3K7
interleukin-1-mediated signaling pathway	1	802.5×	0.003	MAP3K7
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.003	MAP3K7
Fc-epsilon receptor signaling pathway	1	732.7×	0.003	MAP3K7
stress-activated MAPK cascade	1	702.2×	0.003	MAP3K7
positive regulation of macroautophagy	1	526.6×	0.003	MAP3K7
toll-like receptor 4 signaling pathway	1	526.6×	0.003	MAP3K7
positive regulation of interleukin-2 production	1	468.1×	0.003	MAP3K7
positive regulation of cell cycle	1	443.5×	0.003	MAP3K7
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.003	MAP3K7
canonical NF-kappaB signal transduction	1	366.4×	0.004	MAP3K7
JNK cascade	1	271.8×	0.005	MAP3K7
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.005	MAP3K7
cellular response to tumor necrosis factor	1	163.6×	0.008	MAP3K7

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
MAP3K7	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K7	29	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MAP3K7
SORAFENIB	4	MAP3K7
RUXOLITINIB	4	MAP3K7
BOSUTINIB	4	MAP3K7
ADENOSINE	4	MAP3K7
NINTEDANIB	4	MAP3K7
SUNITINIB	4	MAP3K7
DASATINIB	4	MAP3K7
QUIZARTINIB	4	MAP3K7
CRIZOTINIB	4	MAP3K7
MIDOSTAURIN	4	MAP3K7
CANERTINIB	3	MAP3K7
ALVOCIDIB	3	MAP3K7
DOVITINIB	3	MAP3K7
MOTESANIB	3	MAP3K7
LESTAURTINIB	3	MAP3K7
DORAMAPIMOD	2	MAP3K7
FORETINIB	2	MAP3K7
ADENOSINE TRIPHOSPHATE	2	MAP3K7
SU-014813	2	MAP3K7
REBASTINIB	2	MAP3K7
DEFOSBARASERTIB	2	MAP3K7
TG100-115	2	MAP3K7
R-406	2	MAP3K7
RAF-265	2	MAP3K7
TOZASERTIB	2	MAP3K7
KW-2449	1	MAP3K7
BMS-387032	1	MAP3K7
AST-487	1	MAP3K7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MAP3K7	375	Binding:374, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP3K7	375

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

29 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)
FEDRATINIB	4	MAP3K7
SORAFENIB	4	MAP3K7
RUXOLITINIB	4	MAP3K7
BOSUTINIB	4	MAP3K7
ADENOSINE	4	MAP3K7
NINTEDANIB	4	MAP3K7
SUNITINIB	4	MAP3K7
DASATINIB	4	MAP3K7
QUIZARTINIB	4	MAP3K7
CRIZOTINIB	4	MAP3K7
MIDOSTAURIN	4	MAP3K7
CANERTINIB	3	MAP3K7
ALVOCIDIB	3	MAP3K7
DOVITINIB	3	MAP3K7
MOTESANIB	3	MAP3K7
LESTAURTINIB	3	MAP3K7
DORAMAPIMOD	2	MAP3K7
FORETINIB	2	MAP3K7
ADENOSINE TRIPHOSPHATE	2	MAP3K7
SU-014813	2	MAP3K7
REBASTINIB	2	MAP3K7
DEFOSBARASERTIB	2	MAP3K7
TG100-115	2	MAP3K7
R-406	2	MAP3K7
RAF-265	2	MAP3K7
TOZASERTIB	2	MAP3K7
KW-2449	1	MAP3K7
BMS-387032	1	MAP3K7
AST-487	1	MAP3K7

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP3K7
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.