Spondylocarpotarsal synostosis syndrome

Summary

Spondylocarpotarsal synostosis syndrome (MONDO:0010094) is a disease caused by FLNB (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FLNB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 94
• Phenotypes (HPO): 17
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0002945	Intervertebral space narrowing	Frequent (30-79%)
HP:0002948	Vertebral fusion	Frequent (30-79%)
HP:0003498	Disproportionate short stature	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0008368	Tarsal synostosis	Frequent (30-79%)
HP:0009702	Carpal synostosis	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0001216	Delayed ossification of carpal bones	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylocarpotarsal synostosis syndrome
Mondo ID	MONDO:0010094
MeSH	C535780
OMIM	272460
Orphanet	3275
DOID	DOID:0090116
SNOMED CT	702351004
UMLS	C1848934
MedGen	341339
GARD	0004974
Is cancer (heuristic)	no

Also known as: scoliosis, congenital with unilateral unsegmented bar · SCT · spondylocarpotarsal syndrome · spondylocarpotarsal synostosis · spondylocarpotarsal synostosis syndrome · Synspondylism · Synspondylism congenital · vertebral fusion with carpal coalition

Data availability: 94 ClinVar variants · 5 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 › spondylocarpotarsal synostosis syndrome

Related subtypes (8): developmental dysplasia of the hip, osteochondrodysplasia, brachydactyly-elbow wrist dysplasia 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

94 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 22 conflicting classifications of pathogenicity, 19 likely pathogenic, 18 pathogenic, 5 benign/likely benign, 3 likely benign, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332749	NM_001457.4(FLNB):c.1243C>T (p.Arg415Ter)	FLNB	Pathogenic	criteria provided, single submitter
1332815	NM_001457.4(FLNB):c.1204del (p.Val402fs)	FLNB	Pathogenic	criteria provided, single submitter
1332839	NM_001457.4(FLNB):c.1493del (p.Glu498fs)	FLNB	Pathogenic	criteria provided, single submitter
1332844	NM_001457.4(FLNB):c.1429delinsCT (p.Val477fs)	FLNB	Pathogenic	criteria provided, single submitter
1383728	NM_001457.4(FLNB):c.5842C>T (p.Arg1948Ter)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
21280	NM_001457.4(FLNB):c.1945C>T (p.Arg649Ter)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
38961	NM_001457.4(FLNB):c.502G>A (p.Gly168Ser)	FLNB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633651	NM_001457.4(FLNB):c.1592dup (p.His532fs)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
6395	NM_001457.4(FLNB):c.6408del (p.Ser2137fs)	FLNB	Pathogenic	no assertion criteria provided
6396	NM_001457.4(FLNB):c.2452C>T (p.Arg818Ter)	FLNB	Pathogenic	criteria provided, single submitter
6406	NM_001457.4(FLNB):c.5071G>A (p.Gly1691Ser)	FLNB	Pathogenic	criteria provided, multiple submitters, no conflicts
6407	NM_001457.4(FLNB):c.6010C>T (p.Arg2004Ter)	FLNB	Pathogenic	criteria provided, single submitter
6408	NM_001457.4(FLNB):c.5548G>T (p.Gly1850Ter)	FLNB	Pathogenic	no assertion criteria provided
807602	NM_001457.4(FLNB):c.5555-5_5561del	FLNB	Pathogenic	criteria provided, single submitter
998081	NM_001457.4(FLNB):c.3127-354_4223-1836del	FLNB	Pathogenic	criteria provided, single submitter
998082	NM_001457.4(FLNB):c.1346-1358_1941+403del	FLNB	Pathogenic	criteria provided, single submitter
587701	NM_002470.4(MYH3):c.4647+1G>A	MYH3	Pathogenic	criteria provided, single submitter
587702	NM_002470.4(MYH3):c.1581+1G>A	MYH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587703	NM_002470.4(MYH3):c.141T>G (p.Tyr47Ter)	MYH3	Pathogenic	criteria provided, single submitter
587704	NM_002470.4(MYH3):c.1411-391_1411-219del	MYH3	Pathogenic	criteria provided, single submitter
587706	NM_002470.4(MYH3):c.-9+1G>A	MYH3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705319	NM_001457.4(FLNB):c.698del (p.Tyr233fs)	FLNB	Likely pathogenic	criteria provided, single submitter
2502318	NM_001457.4(FLNB):c.2772del (p.Thr923_Tyr924insTer)	FLNB	Likely pathogenic	criteria provided, single submitter
2505550	NM_001457.4(FLNB):c.219_222dup (p.Met75fs)	FLNB	Likely pathogenic	criteria provided, single submitter
2585626	NM_001457.4(FLNB):c.3535G>T (p.Glu1179Ter)	FLNB	Likely pathogenic	criteria provided, single submitter
3065036	NM_001457.4(FLNB):c.5025del (p.Tyr1676fs)	FLNB	Likely pathogenic	criteria provided, single submitter
3366935	NM_001457.4(FLNB):c.3282_3283insAGCA (p.Cys1095fs)	FLNB	Likely pathogenic	criteria provided, single submitter
3391439	NM_001457.4(FLNB):c.7417+2T>A	FLNB	Likely pathogenic	criteria provided, single submitter
3393047	NM_001457.4(FLNB):c.6889-2A>G	FLNB	Likely pathogenic	criteria provided, single submitter
3909973	NM_001457.4(FLNB):c.28G>T (p.Glu10Ter)	FLNB	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 11 · 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
FLNB	Definitive	Autosomal recessive	spondylocarpotarsal synostosis syndrome	13
MYH3	Supportive	Autosomal recessive	spondylocarpotarsal synostosis syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNB	Orphanet:1190	Atelosteogenesis type I
FLNB	Orphanet:1263	Boomerang dysplasia
FLNB	Orphanet:3275	Spondylocarpotarsal synostosis
FLNB	Orphanet:503	Larsen syndrome
FLNB	Orphanet:56305	Atelosteogenesis type III
MYH3	Orphanet:1146	Distal arthrogryposis type 1
MYH3	Orphanet:1147	Sheldon-Hall syndrome
MYH3	Orphanet:2053	Freeman-Sheldon syndrome
MYH3	Orphanet:2990	Autosomal recessive multiple pterygium syndrome
MYH3	Orphanet:3275	Spondylocarpotarsal synostosis
MYH3	Orphanet:65743	Autosomal dominant multiple pterygium syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNB	HGNC:3755	ENSG00000136068	O75369	Filamin-B	gencc,clinvar
MYH3	HGNC:7573	ENSG00000109063	P11055	Myosin-3	gencc,clinvar
FLNB-AS1	HGNC:40239	ENSG00000244161		FLNB antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNB	Filamin-B	Connects cell membrane constituents to the actin cytoskeleton.
MYH3	Myosin-3	Muscle contraction.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNB	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
MYH3	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
FLNB-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
transverse colon	2
mucosa of transverse colon	1
tibial nerve	1
left testis	1
right testis	1
testis	1
body of uterus	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNB	290	ubiquitous	marker	mucosa of transverse colon, tibial nerve, transverse colon
MYH3	203	tissue_specific	yes	left testis, right testis, testis
FLNB-AS1	153	tissue_specific	yes	transverse colon, mucosa of stomach, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNB	2,927
MYH3	1,795
FLNB-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNB	O75369	23

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYH3	P11055	74.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Striated Muscle Contraction	1	154.3×	0.019	MYH3
ISG15 antiviral mechanism	1	75.1×	0.020	FLNB
Muscle contraction	1	38.6×	0.026	MYH3

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
keratinocyte development	1	766.0×	0.009	FLNB
muscle filament sliding	1	526.6×	0.009	MYH3
epithelial cell morphogenesis	1	468.1×	0.009	FLNB
actin filament-based movement	1	401.2×	0.009	MYH3
skeletal muscle contraction	1	255.3×	0.009	MYH3
face morphogenesis	1	247.8×	0.009	MYH3
ATP metabolic process	1	234.1×	0.009	MYH3
embryonic limb morphogenesis	1	200.6×	0.009	MYH3
sarcomere organization	1	191.5×	0.009	MYH3
skeletal muscle tissue development	1	145.3×	0.010	FLNB
muscle contraction	1	104.0×	0.012	MYH3
cellular response to type II interferon	1	104.0×	0.012	FLNB
muscle organ development	1	83.4×	0.014	MYH3
actin cytoskeleton organization	1	39.6×	0.027	FLNB
signal transduction	1	8.0×	0.121	FLNB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNB	0	0
MYH3	0	0
FLNB-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FLNB	2	Binding:2

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	1	FLNB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MYH3, FLNB-AS1

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)
FLNB	2	—
MYH3	0	—
FLNB-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02872662	Not specified	COMPLETED	Individual Molecular MRD Monitoring for MDS Patients After Allo-SCT
NCT03821727	Not specified	COMPLETED	SCT in Ph Positive Acute Lymphoblastic Leukemia