Spondylocostal dysostosis 1, autosomal recessive

Summary

Spondylocostal dysostosis 1, autosomal recessive (MONDO:0020692) is a disease caused by DLL3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: DLL3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 113

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylocostal dysostosis 1, autosomal recessive
Mondo ID	MONDO:0020692
OMIM	277300
DOID	DOID:0112365
GARD	0010726
Is cancer (heuristic)	no

Also known as: SCDO1 · spondylocostal dysostosis 1, autosomal recessive · spondylothoracic dysostosis · spondylothoracic dysplasia

Data availability: 113 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › vertebral column disorder › spondylocostal dysostosis › autosomal recessive spondylocostal dysostosis › spondylocostal dysostosis 1, autosomal recessive

Related subtypes (4): spondylocostal dysostosis 2, autosomal recessive, spondylocostal dysostosis 3, autosomal recessive, spondylocostal dysostosis 4, autosomal recessive, spondylocostal dysostosis 6, autosomal recessive

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

113 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 21 conflicting classifications of pathogenicity, 12 likely pathogenic, 11 benign/likely benign, 9 pathogenic, 9 benign, 6 pathogenic/likely pathogenic, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324231	NM_203486.3(DLL3):c.366_378del (p.Ile123fs)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332772	NM_203486.3(DLL3):c.871-1G>A	DLL3	Pathogenic	criteria provided, single submitter
1705307	NM_203486.3(DLL3):c.1339_1340insT (p.His447fs)	DLL3	Pathogenic	criteria provided, single submitter
191104	NM_203486.3(DLL3):c.1136G>A (p.Cys379Tyr)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2725640	NM_203486.3(DLL3):c.1036C>T (p.Gln346Ter)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736891	NM_203486.3(DLL3):c.602_614dup (p.Pro206fs)	DLL3	Pathogenic	criteria provided, multiple submitters, no conflicts
419705	NM_203486.3(DLL3):c.621C>A (p.Cys207Ter)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632311	NM_203486.3(DLL3):c.395del (p.Gly132fs)	DLL3	Pathogenic	criteria provided, multiple submitters, no conflicts
6829	NM_203486.3(DLL3):c.945_946del (p.Ala317fs)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6831	NM_203486.3(DLL3):c.1291_1307dup (p.Pro437fs)	DLL3	Pathogenic	criteria provided, single submitter
6832	NM_203486.3(DLL3):c.618del (p.Cys207fs)	DLL3	Pathogenic	criteria provided, multiple submitters, no conflicts
6833	NM_203486.3(DLL3):c.712C>T (p.Arg238Ter)	DLL3	Pathogenic	criteria provided, multiple submitters, no conflicts
6834	NM_203486.3(DLL3):c.1440del (p.Pro481fs)	DLL3	Pathogenic	no assertion criteria provided
6835	NM_203486.3(DLL3):c.1511G>A (p.Gly504Asp)	DLL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6828	NM_203486.3(DLL3):c.599_603dup (p.Pro202fs)	PLEKHG2	Pathogenic	criteria provided, multiple submitters, no conflicts
2572235	NM_203486.3(DLL3):c.1312T>A (p.Cys438Ser)	DLL3	Likely pathogenic	criteria provided, single submitter
2572236	NM_203486.3(DLL3):c.1272dup (p.Asp425fs)	DLL3	Likely pathogenic	criteria provided, single submitter
2842615	NM_203486.3(DLL3):c.652+1G>T	DLL3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065801	NM_203486.3(DLL3):c.474G>A (p.Trp158Ter)	DLL3	Likely pathogenic	criteria provided, single submitter
3583895	NM_203486.3(DLL3):c.241del (p.Ala81fs)	DLL3	Likely pathogenic	criteria provided, single submitter
3583896	NM_203486.3(DLL3):c.546_547del (p.Val183fs)	DLL3	Likely pathogenic	criteria provided, single submitter
3583897	NM_203486.3(DLL3):c.1200C>A (p.Cys400Ter)	DLL3	Likely pathogenic	criteria provided, single submitter
3583898	NM_203486.3(DLL3):c.1441_1459del (p.Pro481fs)	DLL3	Likely pathogenic	criteria provided, single submitter
3779570	NM_203486.3(DLL3):c.128del (p.Pro43fs)	DLL3	Likely pathogenic	criteria provided, single submitter
4849323	NM_203486.3(DLL3):c.1086C>A (p.Cys362Ter)	DLL3	Likely pathogenic	criteria provided, single submitter
559885	NM_203486.3(DLL3):c.534C>A (p.Cys178Ter)	DLL3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779845	NM_001039958.2(MESP2):c.567_585del (p.Gln190fs)	MESP2	Likely pathogenic	criteria provided, single submitter
1634107	NM_203486.3(DLL3):c.915C>T (p.Tyr305=)	DLL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
260775	NM_203486.3(DLL3):c.153C>T (p.Ser51=)	DLL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286841	NM_203486.3(DLL3):c.677C>G (p.Pro226Arg)	DLL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DLL3	Definitive	Autosomal recessive	spondylocostal dysostosis 1, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLL3	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
MESP2	Orphanet:2311	Autosomal recessive spondylocostal dysostosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLL3	HGNC:2909	ENSG00000090932	Q9NYJ7	Delta-like protein 3	gencc,clinvar
PLEKHG2	HGNC:29515	ENSG00000090924	Q9H7P9	Pleckstrin homology domain-containing family G member 2	clinvar
MESP2	HGNC:29659	ENSG00000188095	Q0VG99	Mesoderm posterior protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLL3	Delta-like protein 3	Inhibits primary neurogenesis.
PLEKHG2	Pleckstrin homology domain-containing family G member 2	May be a transforming oncogene with exchange activity for CDC42.
MESP2	Mesoderm posterior protein 2	Transcription factor with important role in somitogenesis.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · 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×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLL3	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, Growth_fac_rcpt_cys_sf
PLEKHG2	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
MESP2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Mesogenin/MesP

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
cortical plate	1
ganglionic eminence	1
descending thoracic aorta	1
right coronary artery	1
sural nerve	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLL3	62	broad	marker	ganglionic eminence, primordial germ cell in gonad, cortical plate
PLEKHG2	178	ubiquitous	marker	sural nerve, descending thoracic aorta, right coronary artery
MESP2	140	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLL3	1,586
PLEKHG2	858
MESP2	673

Intra-cohort edges

A	B	Sources
DLL3	MESP2	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DLL3	Q9NYJ7	65.42
MESP2	Q0VG99	54.92
PLEKHG2	Q9H7P9	48.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of paraxial mesoderm	2	271.9×	1e-04	DLL3, MESP2
Somitogenesis	2	155.4×	2e-04	DLL3, MESP2
Gastrulation	1	86.5×	0.031	MESP2
NRAGE signals death through JNK	1	61.4×	0.032	PLEKHG2
G alpha (12/13) signalling events	1	45.9×	0.035	PLEKHG2
CDC42 GTPase cycle	1	24.1×	0.055	PLEKHG2
RAC1 GTPase cycle	1	20.4×	0.055	PLEKHG2
Developmental Biology	1	4.8×	0.194	MESP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Notch signaling pathway	2	94.4×	0.002	DLL3, MESP2
compartment pattern specification	1	1404.3×	0.005	DLL3
paraxial mesoderm development	1	561.7×	0.006	DLL3
somite rostral/caudal axis specification	1	510.7×	0.006	MESP2
negative regulation of neurogenesis	1	208.1×	0.010	DLL3
regulation of actin filament polymerization	1	193.7×	0.010	PLEKHG2
mesoderm formation	1	165.2×	0.010	MESP2
negative regulation of Notch signaling pathway	1	144.0×	0.010	DLL3
somitogenesis	1	124.8×	0.010	DLL3
heart morphogenesis	1	124.8×	0.010	MESP2
skeletal system development	1	41.9×	0.028	DLL3
cell differentiation	1	9.7×	0.108	DLL3
regulation of transcription by RNA polymerase II	1	3.9×	0.236	MESP2

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
DLL3	0	0
PLEKHG2	0	0
MESP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	DLL3, PLEKHG2, MESP2

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)
DLL3	0	—
PLEKHG2	0	—
MESP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.