Spondyloepimetaphyseal dysplasia, sponastrime type

disease

On this page

Also known as short limb dwarfism with saddle nose, spinal alterations, and metaphyseal striationsponastrime dysplasiaspondylar and nasal changes with striations of the metaphyses (SPONASTRIME) dysplasiaspondylar and nasal changes with triations of the metaphyses (SPONASTRIME) dysplasiaspondyloepimetaphyseal dysplasia Sponastrime type

Summary

Spondyloepimetaphyseal dysplasia, sponastrime type (MONDO:0010068) is a disease caused by TONSL (GenCC Definitive), with 3 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: TONSL (GenCC Definitive)
Cohort genes: 3
ClinVar variants: 61
Phenotypes (HPO): 79

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

79 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000925	Abnormality of the vertebral column	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0008873	Disproportionate short-limb short stature	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0003025	Metaphyseal irregularity	Frequent (30-79%)
HP:0004586	Biconcave vertebral bodies	Frequent (30-79%)
HP:0008905	Rhizomelia	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0031367	Metaphyseal striations	Frequent (30-79%)
HP:0100864	Short femoral neck	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000445	Wide nose	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0000696	Delayed eruption of permanent teeth	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0001169	Broad palm	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001377	Limited elbow extension	Occasional (5-29%)
HP:0001607	Subglottic stenosis	Occasional (5-29%)
HP:0001621	Weak voice	Occasional (5-29%)
HP:0001763	Pes planus	Occasional (5-29%)
HP:0001769	Broad foot	Occasional (5-29%)
HP:0001773	Short foot	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002663	Delayed epiphyseal ossification	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002761	Generalized joint laxity	Occasional (5-29%)
HP:0002812	Coxa vara	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0003015	Flared metaphysis	Occasional (5-29%)
HP:0003016	Metaphyseal widening	Occasional (5-29%)
HP:0003026	Short long bone	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia, sponastrime type
Mondo ID	MONDO:0010068
MeSH	C535786
OMIM	271510
Orphanet	93357
DOID	DOID:5684
NCIT	C129031
SNOMED CT	389161008
UMLS	C1300260
MedGen	266247
GARD	0004970
Is cancer (heuristic)	no

Also known as: short limb dwarfism with saddle nose, spinal alterations, and metaphyseal striation · sponastrime dysplasia · spondylar and nasal changes with striations of the metaphyses (SPONASTRIME) dysplasia · spondylar and nasal changes with triations of the metaphyses (SPONASTRIME) dysplasia · spondyloepimetaphyseal dysplasia Sponastrime type · spondyloepimetaphyseal dysplasia, Sponastrime type · spondyloepimetaphyseal dysplasia, sponastrime type

Data availability: 61 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia, sponastrime 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

61 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 13 likely pathogenic, 12 benign, 6 pathogenic/likely pathogenic, 6 pathogenic, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1325216	NM_013432.5(TONSL):c.1531C>T (p.Gln511Ter)	TONSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343381	NM_013432.5(TONSL):c.787C>T (p.Arg263Ter)	TONSL	Pathogenic	criteria provided, single submitter
1429349	NM_013432.5(TONSL):c.2623C>T (p.Arg875Ter)	TONSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805067	NM_013432.5(TONSL):c.3549del (p.Ser1183fs)	TONSL	Pathogenic	criteria provided, multiple submitters, no conflicts
3595449	NM_013432.5(TONSL):c.674dup (p.Leu225fs)	TONSL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638059	NM_013432.5(TONSL):c.2800C>T (p.Arg934Trp)	TONSL	Pathogenic	criteria provided, multiple submitters, no conflicts
638060	NM_013432.5(TONSL):c.2407C>T (p.Gln803Ter)	TONSL	Pathogenic	criteria provided, single submitter
638061	NM_013432.5(TONSL):c.3589T>C (p.Ser1197Pro)	TONSL	Pathogenic/Likely pathogenic	no assertion criteria provided
638063	NM_013432.5(TONSL):c.1602_1612del (p.Ala536fs)	TONSL	Pathogenic/Likely pathogenic	no assertion criteria provided
638068	NM_013432.5(TONSL):c.3559+287_3735+546del	TONSL	Pathogenic	no assertion criteria provided
982174	NM_013432.5(TONSL):c.1864dup (p.Ala622fs)	TONSL	Pathogenic	criteria provided, single submitter
638064	NM_013432.5(TONSL):c.2638_2647delinsGG (p.Arg880fs)	TONSL-AS1	Pathogenic/Likely pathogenic	no assertion criteria provided
4849282	NM_013432.5(TONSL):c.34_35insT (p.Lys12fs)	LOC130001399	Likely pathogenic	criteria provided, single submitter
1683464	NM_013432.5(TONSL):c.2776-2A>G	MIR6893	Likely pathogenic	criteria provided, single submitter
1683467	NM_013432.5(TONSL):c.3967_3968dup (p.Leu1324fs)	TONSL	Likely pathogenic	criteria provided, single submitter
2500921	NM_013432.5(TONSL):c.1435del (p.Glu479fs)	TONSL	Likely pathogenic	criteria provided, single submitter
2583174	NM_013432.5(TONSL):c.2952_2953delinsT (p.Ala985fs)	TONSL	Likely pathogenic	criteria provided, single submitter
3382171	NM_013432.5(TONSL):c.3166C>T (p.Gln1056Ter)	TONSL	Likely pathogenic	criteria provided, single submitter
3382384	NM_013432.5(TONSL):c.3006_3006+1del	TONSL	Likely pathogenic	criteria provided, single submitter
3780728	NM_013432.5(TONSL):c.546del (p.Asn182fs)	TONSL	Likely pathogenic	criteria provided, single submitter
4846953	NM_013432.5(TONSL):c.2477del (p.Pro826fs)	TONSL	Likely pathogenic	criteria provided, single submitter
982172	NM_013432.5(TONSL):c.3096dup (p.Gln1033fs)	TONSL	Likely pathogenic	no assertion criteria provided
982173	NM_013432.5(TONSL):c.460C>T (p.Gln154Ter)	TONSL	Likely pathogenic	no assertion criteria provided
982175	NM_013432.5(TONSL):c.122-5C>G	TONSL	Likely pathogenic	no assertion criteria provided
982176	NM_013432.5(TONSL):c.3796dup (p.Arg1266fs)	TONSL	Likely pathogenic	no assertion criteria provided
1060889	NM_013432.5(TONSL):c.1156G>A (p.Val386Met)	TONSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638062	NM_013432.5(TONSL):c.1459G>A (p.Glu487Lys)	TONSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638065	NM_013432.5(TONSL):c.1480G>A (p.Glu494Lys)	TONSL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638069	NM_013432.5(TONSL):c.1673G>A (p.Arg558Gln)	TONSL-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417492	NM_013432.5(TONSL):c.67C>T (p.Arg23Trp)	LOC130001399	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TONSL	Definitive	Autosomal recessive	spondyloepimetaphyseal dysplasia, sponastrime type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TONSL	Orphanet:93357	SPONASTRIME dysplasia

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TONSL	HGNC:7801	ENSG00000160949	Q96HA7	Tonsoku-like protein	gencc,clinvar
MIR6893	HGNC:50130	ENSG00000276598		microRNA 6893	clinvar
TONSL-AS1	HGNC:51556	ENSG00000232600		TONSL antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TONSL	Tonsoku-like protein	Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
TONSL	Scaffold/PPI	no	Leu-rich_rpt, Ankyrin_rpt, TPR-like_helical_dom_sf
MIR6893	Other/Unknown	no
TONSL-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
mucosa of transverse colon	1
primordial germ cell in gonad	1
ventricular zone	1
adrenal tissue	1
bone marrow	1
prefrontal cortex	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TONSL	155	ubiquitous	marker	mucosa of transverse colon, primordial germ cell in gonad, ventricular zone
MIR6893	71		yes	bone marrow, adrenal tissue, prefrontal cortex
TONSL-AS1	124		yes	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TONSL	3,418
MIR6893	0
TONSL-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TONSL	Q96HA7	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to chromatin	1	581.1×	0.004	TONSL
replication fork processing	1	421.3×	0.004	TONSL
double-strand break repair via homologous recombination	1	156.0×	0.006	TONSL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TONSL	0	0
MIR6893	0	0
TONSL-AS1	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	3	TONSL, MIR6893, TONSL-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)
TONSL	0	—
MIR6893	0	—
TONSL-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: TONSL, MIR6893, TONSL-AS1