spondyloepimetaphyseal dysplasia, Genevieve type

Summary

spondyloepimetaphyseal dysplasia, Genevieve type (MONDO:0012495) is a disease caused by NANS (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NANS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22

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

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia, Genevieve type
Mondo ID	MONDO:0012495
MeSH	C535785
OMIM	610442
Orphanet	168454
DOID	DOID:0080576
ICD-11	1383217537
UMLS	C1864872
MedGen	355314
GARD	0010057
Is cancer (heuristic)	no

Also known as: SEMD Genevieve type · SEMD, Geneviève type · SEMDG · spondyloepimetaphyseal dysplasia Genevieve type · spondyloepimetaphyseal dysplasia, Camera-Genevieve type · spondyloepimetaphyseal dysplasia, Genevieve type

Data availability: 22 ClinVar variants · 4 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 › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia, Genevieve type

Related subtypes (22): spondyloepimetaphyseal dysplasia-hypotrichosis syndrome, spondyloepimetaphyseal dysplasia, Maroteaux type, spondyloepimetaphyseal dysplasia, Strudwick type, spondyloepimetaphyseal dysplasia, sponastrime type, spondyloepimetaphyseal dysplasia, Irapa type, spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, spondyloepimetaphyseal dysplasia, Bieganski type, spondyloepimetaphyseal dysplasia-abnormal dentition syndrome, spondyloepimetaphyseal dysplasia, Missouri type, spondyloepimetaphyseal dysplasia, Shohat type, spondyloepimetaphyseal dysplasia, matrilin-3 type, spondyloepimetaphyseal dysplasia, aggrecan type, spondyloepimetaphyseal dysplasia, Handigodu type, spondyloepimetaphyseal dysplasia, Isidor type, spondyloepimetaphyseal dysplasia, PAPSS2 type, spondyloepimetaphyseal dysplasia with joint laxity, spondyloepimetaphyseal dysplasia, Krakow type, spondyloepimetaphyseal dysplasia, Isidor-Toutain type, spondyloepimetaphyseal dysplasia, di rocco type, COL2A1-related spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia, Guo-Campeau type, spondyloepimetaphyseal dysplasia, Li-Shao-Li 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

22 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 6 likely pathogenic, 4 pathogenic, 2 benign, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684568	NM_018946.4(NANS):c.133-12T>A	NANS	Pathogenic	no assertion criteria provided
235186	NM_018946.4(NANS):c.448+1G>A	NANS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235188	NM_018946.4(NANS):c.398G>T (p.Gly133Val)	NANS	Pathogenic	no assertion criteria provided
235190	NM_018946.4(NANS):c.562T>C (p.Tyr188His)	NANS	Pathogenic/Likely pathogenic	no assertion criteria provided
2507214	NM_018946.4(NANS):c.772G>T (p.Glu258Ter)	NANS	Pathogenic	criteria provided, multiple submitters, no conflicts
235185	NM_018946.4(NANS):c.389dup (p.Lys131fs)	TRIM14	Pathogenic	no assertion criteria provided
1341506	NM_018946.4(NANS):c.476T>G (p.Met159Arg)	NANS	Likely pathogenic	no assertion criteria provided
1684567	NM_018946.4(NANS):c.207del (p.Arg69fs)	NANS	Likely pathogenic	no assertion criteria provided
1686634	NM_018946.4(NANS):c.607T>C (p.Tyr203His)	NANS	Likely pathogenic	no assertion criteria provided
235184	NM_018946.4(NANS):c.449-10_449-5delinsATGG	NANS	Likely pathogenic	criteria provided, single submitter
2572433	NM_018946.4(NANS):c.735G>A (p.Trp245Ter)	NANS	Likely pathogenic	criteria provided, single submitter
810396	NM_018946.4(NANS):c.1A>G (p.Met1Val)	NANS	Likely pathogenic	criteria provided, single submitter
1968748	NM_018946.4(NANS):c.133-5del	NANS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2182027	NM_018946.4(NANS):c.10GAGCTG[1] (p.4EL[1])	LOC130002203	Uncertain significance	criteria provided, multiple submitters, no conflicts
2070608	NM_018946.4(NANS):c.52C>G (p.Pro18Ala)	NANS	Uncertain significance	criteria provided, single submitter
235189	NM_018946.4(NANS):c.979_981dup (p.Ile327dup)	NANS	Uncertain significance	criteria provided, single submitter
235191	NM_018946.4(NANS):c.709C>T (p.Arg237Cys)	NANS	Uncertain significance	criteria provided, single submitter
2434037	NM_018946.4(NANS):c.937A>G (p.Thr313Ala)	NANS	Uncertain significance	criteria provided, single submitter
2572591	NM_018946.4(NANS):c.668T>C (p.Ile223Thr)	NANS	Uncertain significance	criteria provided, single submitter
235187	NM_018946.4(NANS):c.452G>A (p.Arg151His)	TRIM14	Uncertain significance	criteria provided, multiple submitters, no conflicts
1241755	NM_018946.4(NANS):c.102C>T (p.Asp34=)	NANS	Benign	criteria provided, multiple submitters, no conflicts
1250394	NM_018946.4(NANS):c.153T>C (p.Ala51=)	NANS	Benign	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
NANS	Strong	Autosomal recessive	spondyloepimetaphyseal dysplasia, Genevieve type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NANS	Orphanet:168454	Spondyloepimetaphyseal dysplasia, Geneviève type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NANS	HGNC:19237	ENSG00000095380	Q9NR45	N-acetylneuraminate-9-phosphate synthase	gencc,clinvar
TRIM14	HGNC:16283	ENSG00000106785	Q14142	Tripartite motif-containing protein 14	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NANS	N-acetylneuraminate-9-phosphate synthase	Catalyzes the condensation of phosphoenolpyruvate (PEP) and N-acetylmannosamine 6-phosphate (ManNAc-6-P) to synthesize N-acetylneuraminate-9-phosphate (Neu5Ac-9-P).
TRIM14	Tripartite motif-containing protein 14	Plays an essential role in the innate immune defense against viruses and bacteria.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NANS	Enzyme (other)	yes	2.5.1.132	Antifreeze_III, SAF_AFP_Neu5Ac, PseI/NeuA/B-like_N
TRIM14	Transcription factor	no		Znf_B-box, B30.2/SPRY, SPRY_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of sigmoid colon	1
mucosa of transverse colon	1
rectum	1
jejunal mucosa	1
palpebral conjunctiva	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NANS	285	ubiquitous	marker	mucosa of sigmoid colon, mucosa of transverse colon, rectum
TRIM14	265	ubiquitous	marker	palpebral conjunctiva, jejunal mucosa, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIM14	2,182
NANS	1,531

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NANS	Q9NR45	1
TRIM14	Q14142	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Sialic acid metabolism	1	163.1×	0.022	NANS
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.022	NANS
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.022	NANS
Interferon gamma signaling	1	62.8×	0.028	TRIM14
Asparagine N-linked glycosylation	1	30.1×	0.046	NANS
Post-translational protein modification	1	9.6×	0.118	NANS
Metabolism of proteins	1	6.2×	0.155	NANS

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
N-acetylneuraminate biosynthetic process	1	2808.7×	0.002	NANS
CMP-N-acetylneuraminate biosynthetic process	1	1404.3×	0.002	NANS
carbohydrate biosynthetic process	1	766.0×	0.003	NANS
negative regulation of viral transcription	1	526.6×	0.003	TRIM14
inflammatory response	1	18.9×	0.059	TRIM14
innate immune response	1	16.8×	0.059	TRIM14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NANS	0	0
TRIM14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NANS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NANS	2.5.1.132, 2.5.1.56, 2.5.1.57	3-deoxy-D-glycero-D-galacto-nonulopyranosonate 9-phosphate synthase, N-acetylneuraminate synthase, N-acylneuraminate-9-phosphate synthase

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	NANS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TRIM14

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NANS	1	—
TRIM14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.