Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome

Summary

Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome (MONDO:0012160) is a disease caused by PCYT1A (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PCYT1A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000548	Cone/cone-rod dystrophy	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0002979	Bowing of the legs	Very frequent (80-99%)
HP:0003015	Flared metaphysis	Very frequent (80-99%)
HP:0003025	Metaphyseal irregularity	Very frequent (80-99%)
HP:0003026	Short long bone	Very frequent (80-99%)
HP:0003300	Ovoid vertebral bodies	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005054	Metaphyseal spurs	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0008905	Rhizomelia	Very frequent (80-99%)
HP:0009803	Short phalanx of finger	Very frequent (80-99%)
HP:0010049	Short metacarpal	Very frequent (80-99%)
HP:0010583	Ivory epiphyses	Very frequent (80-99%)
HP:0030329	Retinal thinning	Very frequent (80-99%)
HP:0000539	Abnormality of refraction	Frequent (30-79%)
HP:0000887	Cupped ribs	Frequent (30-79%)
HP:0000946	Hypoplastic ilia	Frequent (30-79%)
HP:0003375	Narrow greater sciatic notch	Frequent (30-79%)
HP:0031171	Femoral spur	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000589	Coloboma	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001105	Retinal atrophy	Occasional (5-29%)
HP:0001132	Lens subluxation	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0007401	Macular atrophy	Occasional (5-29%)
HP:0007688	Undetectable light- and dark-adapted electroretinogram	Occasional (5-29%)
HP:0007957	Corneal opacity	Occasional (5-29%)
HP:0009918	Ectopia pupillae	Occasional (5-29%)
HP:0012153	Hypotriglyceridemia	Occasional (5-29%)
HP:0001249	Intellectual disability	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylometaphyseal dysplasia-cone-rod dystrophy syndrome
Mondo ID	MONDO:0012160
MeSH	C563825
OMIM	608940
Orphanet	85167
DOID	DOID:0112300
UMLS	C1837073
MedGen	324684
GARD	0010647
Is cancer (heuristic)	no

Also known as: SMD-CRD · SmD-CRD · SMDCRD · spondylometaphyseal dysplasia with cone-rod dystrophy · spondylometaphyseal dysplasia-cone-rod dystrophy syndrome

Data availability: 18 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylometaphyseal dysplasia › spondylometaphyseal dysplasia-cone-rod dystrophy syndrome

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, spondylometaphyseal dysplasia, Sedaghatian type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, autosomal recessive spondylometaphyseal dysplasia, Megarbane type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, regressive spondylometaphyseal dysplasia, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal dysplasia

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

18 retrieved; paginated sample, class counts are floors:

6 pathogenic, 5 uncertain significance, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101058	NM_001312673.2(PCYT1A):c.448C>G (p.Pro150Ala)	LOC126806932	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101063	NM_001312673.2(PCYT1A):c.385G>A (p.Glu129Lys)	LOC126806932	Pathogenic	criteria provided, single submitter
101057	NM_001312673.2(PCYT1A):c.296C>T (p.Ala99Val)	PCYT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
101059	NM_001312673.2(PCYT1A):c.295G>A (p.Ala99Thr)	PCYT1A	Pathogenic	criteria provided, single submitter
101062	NM_001312673.2(PCYT1A):c.669G>C (p.Arg223Ser)	PCYT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101064	NM_001312673.2(PCYT1A):c.571T>C (p.Phe191Leu)	PCYT1A	Pathogenic	criteria provided, single submitter
1032965	NM_001312673.2(PCYT1A):c.850G>T (p.Glu284Ter)	PCYT1A	Pathogenic	criteria provided, single submitter
1069192	NM_001312673.2(PCYT1A):c.223C>T (p.Arg75Ter)	PCYT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2431393	NM_001312673.2(PCYT1A):c.935dup (p.Ala313fs)	PCYT1A	Likely pathogenic	criteria provided, single submitter
1032964	NM_001312673.2(PCYT1A):c.389A>G (p.Asn130Ser)	LOC126806932	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
101060	NM_001312673.2(PCYT1A):c.847C>T (p.Arg283Ter)	PCYT1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
101061	NM_001312673.2(PCYT1A):c.990del (p.Ser331fs)	PCYT1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
101065	NM_001312673.2(PCYT1A):c.968dup (p.Ser323fs)	PCYT1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1426118	NM_001312673.2(PCYT1A):c.88G>A (p.Val30Ile)	PCYT1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1434824	NM_001312673.2(PCYT1A):c.1103A>C (p.Ter368Ser)	PCYT1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3589113	NM_001312673.2(PCYT1A):c.36G>T (p.Arg12Ser)	PCYT1A	Uncertain significance	criteria provided, single submitter
862949	NM_001312673.2(PCYT1A):c.224G>A (p.Arg75Gln)	PCYT1A	Uncertain significance	criteria provided, single submitter
956587	NM_001312673.2(PCYT1A):c.325A>G (p.Ile109Val)	PCYT1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PCYT1A	Definitive	Autosomal recessive	spondylometaphyseal dysplasia-cone-rod dystrophy syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCYT1A	Orphanet:65	Leber congenital amaurosis
PCYT1A	Orphanet:85167	Spondylometaphyseal dysplasia-cone-rod dystrophy 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
PCYT1A	HGNC:8754	ENSG00000161217	P49585	Choline-phosphate cytidylyltransferase A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCYT1A	Choline-phosphate cytidylyltransferase A	Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCYT1A	Enzyme (other)	yes	2.7.7.15	Cyt_trans-like, Rossmann-like_a/b/a_fold, CCT

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
monocyte	1
skin of leg	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCYT1A	274	ubiquitous	marker	sural nerve, monocyte, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCYT1A	2,004

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCYT1A	P49585	76.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Synthesis of PC	1	407.9×	0.002	PCYT1A

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
CDP-choline pathway	1	3370.4×	0.001	PCYT1A
isotype switching	1	842.6×	0.002	PCYT1A
phosphatidylcholine biosynthetic process	1	802.5×	0.002	PCYT1A
B cell proliferation	1	481.5×	0.002	PCYT1A

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
PCYT1A	ENCORAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCYT1A	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENCORAFENIB	4	PCYT1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PCYT1A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCYT1A	2.7.7.15	choline-phosphate cytidylyltransferase

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

1 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)
ENCORAFENIB	4	PCYT1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PCYT1A
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.