Spondylocostal dysostosis 2, autosomal recessive

Summary

Spondylocostal dysostosis 2, autosomal recessive (MONDO:0012097) is a disease caused by MESP2 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Somitogenesis (4 cohort genes).

At a glance

• Causal gene: MESP2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 181

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylocostal dysostosis 2, autosomal recessive
Mondo ID	MONDO:0012097
OMIM	608681
DOID	DOID:0112362
UMLS	C1837549
MedGen	332481
GARD	0009703
Is cancer (heuristic)	no

Also known as: SCDO2 · spondylocostal dysostosis 2 · spondylocostal dysostosis 2, autosomal recessive

Data availability: 181 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 2, autosomal recessive

Related subtypes (4): spondylocostal dysostosis 3, autosomal recessive, spondylocostal dysostosis 4, autosomal recessive, spondylocostal dysostosis 6, autosomal recessive, spondylocostal dysostosis 1, 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

181 retrieved; paginated sample, class counts are floors:

75 uncertain significance, 34 likely pathogenic, 23 likely benign, 15 conflicting classifications of pathogenicity, 10 pathogenic, 10 benign, 8 pathogenic/likely pathogenic, 4 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
30696	NM_001165967.2(HES7):c.73C>T (p.Arg25Trp)	HES7	Pathogenic	no assertion criteria provided
6999	NM_001040167.2(LFNG):c.564C>A (p.Phe188Leu)	LFNG	Pathogenic	no assertion criteria provided
2815183	NM_001039958.2(MESP2):c.288del (p.Leu97fs)	LOC130057891	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38907	NM_001039958.2(MESP2):c.241G>T (p.Gly81Ter)	LOC130057891	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5184	NM_001039958.2(MESP2):c.307G>T (p.Glu103Ter)	LOC130057891	Pathogenic	criteria provided, multiple submitters, no conflicts
551651	NM_001039958.2(MESP2):c.349C>T (p.Gln117Ter)	LOC130057891	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555370	NM_001039958.2(MESP2):c.258_261del (p.Glu88fs)	LOC130057891	Pathogenic	criteria provided, multiple submitters, no conflicts
557590	NM_001039958.2(MESP2):c.249_256dup (p.Ala86fs)	LOC130057891	Pathogenic	criteria provided, single submitter
2506245	NM_001039958.2(MESP2):c.83G>A (p.Trp28Ter)	MESP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627573	NM_001039958.2(MESP2):c.49del (p.Ile17fs)	MESP2	Pathogenic	criteria provided, single submitter
3020752	NM_001039958.2(MESP2):c.125C>A (p.Ser42Ter)	MESP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081733	NM_001039958.2(MESP2):c.413del (p.Val138fs)	MESP2	Pathogenic	criteria provided, single submitter
5183	NM_001039958.2(MESP2):c.500_503dup (p.Gly169fs)	MESP2	Pathogenic	no assertion criteria provided
5186	NM_001039958.2(MESP2):c.700G>T (p.Glu234Ter)	MESP2	Pathogenic	no assertion criteria provided
551110	NM_001039958.2(MESP2):c.229G>T (p.Gly77Ter)	MESP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554878	NM_001039958.2(MESP2):c.11C>A (p.Ser4Ter)	MESP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555826	NM_001039958.2(MESP2):c.116C>A (p.Ser39Ter)	MESP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100633	NM_004608.4(TBX6):c.1311A>T (p.Ter437Cys)	TBX6	Pathogenic	no assertion criteria provided
4814563	NM_001039958.2(MESP2):c.255_262dup (p.Glu88fs)	LOC130057891	Likely pathogenic	criteria provided, single submitter
4814564	NM_001039958.2(MESP2):c.280_299del (p.Met94fs)	LOC130057891	Likely pathogenic	criteria provided, single submitter
557334	NM_001039958.2(MESP2):c.250C>T (p.Gln84Ter)	LOC130057891	Likely pathogenic	no assertion criteria provided
3578145	NM_001039958.2(MESP2):c.-4_7del (p.Met1fs)	MESP2	Likely pathogenic	criteria provided, single submitter
3578146	NM_001039958.2(MESP2):c.178_188delinsGGCTCGG (p.Ser60fs)	MESP2	Likely pathogenic	criteria provided, single submitter
3578147	NM_001039958.2(MESP2):c.611del (p.Gln204fs)	MESP2	Likely pathogenic	criteria provided, single submitter
3578148	NM_001039958.2(MESP2):c.776del (p.Pro259fs)	MESP2	Likely pathogenic	criteria provided, single submitter
3578150	NM_001039958.2(MESP2):c.994del (p.Gln332fs)	MESP2	Likely pathogenic	criteria provided, single submitter
3779845	NM_001039958.2(MESP2):c.567_585del (p.Gln190fs)	MESP2	Likely pathogenic	criteria provided, single submitter
4057645	NM_001039958.2(MESP2):c.479G>A (p.Trp160Ter)	MESP2	Likely pathogenic	criteria provided, single submitter
4057650	NM_001039958.2(MESP2):c.555_561del (p.Gln186fs)	MESP2	Likely pathogenic	criteria provided, single submitter
4057671	NM_001039958.2(MESP2):c.1017del (p.Arg341fs)	MESP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
MESP2	Definitive	Autosomal recessive	spondylocostal dysostosis 2, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MESP2	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
TBX6	Orphanet:1797	Autosomal dominant spondylocostal dysostosis
TBX6	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
HES7	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
LFNG	Orphanet:2311	Autosomal recessive spondylocostal dysostosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MESP2	HGNC:29659	ENSG00000188095	Q0VG99	Mesoderm posterior protein 2	gencc,clinvar
TBX6	HGNC:11605	ENSG00000149922	O95947	T-box transcription factor TBX6	clinvar
HES7	HGNC:15977	ENSG00000179111	Q9BYE0	Transcription factor HES-7	clinvar
LFNG	HGNC:6560	ENSG00000106003	Q8NES3	Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MESP2	Mesoderm posterior protein 2	Transcription factor with important role in somitogenesis.
TBX6	T-box transcription factor TBX6	T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal.
HES7	Transcription factor HES-7	Transcriptional repressor.
LFNG	Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe	Glycosyltransferase that initiates the elongation of O-linked fucose residues attached to EGF-like repeats in the extracellular domain of Notch molecules.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.25

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
Transcription factor	3	6.2×	0.013
Enzyme (other)	1	3.0×	0.294

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MESP2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Mesogenin/MesP
TBX6	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
HES7	Transcription factor	no		Orange_dom, bHLH_dom, HES-7_bHLH-O
LFNG	Enzyme (other)	yes	2.4.1.222	Fringe-like_glycosylTrfase, Fringe

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
diaphragm	1
lower esophagus mucosa	1
cortical plate	1
right hemisphere of cerebellum	1
upper arm skin	1
body of pancreas	1
granulocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MESP2	140	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
TBX6	166	tissue_specific	marker	lower esophagus mucosa, buccal mucosa cell, diaphragm
HES7	142	broad	yes	cortical plate, right hemisphere of cerebellum, upper arm skin
LFNG	167	ubiquitous	marker	granulocyte, body of pancreas, monocyte

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX6	1,426
LFNG	835
MESP2	673
HES7	365

Intra-cohort edges

A	B	Sources
HES7	LFNG	string_interaction
HES7	MESP2	string_interaction
HES7	TBX6	string_interaction
LFNG	MESP2	string_interaction
LFNG	TBX6	string_interaction
MESP2	TBX6	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 4 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LFNG	Q8NES3	83.66
HES7	Q9BYE0	74.31
TBX6	O95947	66.18
MESP2	Q0VG99	54.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Somitogenesis	4	233.1×	5e-09	MESP2, TBX6, HES7, LFNG
Formation of paraxial mesoderm	3	305.9×	4e-07	MESP2, TBX6, LFNG
Gastrulation	3	194.7×	1e-06	MESP2, TBX6, LFNG
Developmental Biology	3	10.8×	0.005	MESP2, TBX6, LFNG
Defective LFNG causes SCDO3	1	571.0×	0.006	LFNG
Formation of the posterior neural plate	1	285.5×	0.009	TBX6
Nephron development	1	219.6×	0.010	LFNG
Kidney development	1	203.9×	0.010	LFNG
Pre-NOTCH Processing in Golgi	1	158.6×	0.011	LFNG
Pre-NOTCH Expression and Processing	1	92.1×	0.017	LFNG
Diseases associated with O-glycosylation of proteins	1	53.9×	0.027	LFNG
Signaling by NOTCH	1	43.9×	0.030	LFNG
Diseases of glycosylation	1	32.8×	0.037	LFNG
Diseases of metabolism	1	20.1×	0.056	LFNG
Disease	1	3.3×	0.291	LFNG
Signal Transduction	1	2.5×	0.339	LFNG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somite rostral/caudal axis specification	2	766.0×	7e-05	MESP2, TBX6
mesoderm development	2	263.3×	3e-04	TBX6, HES7
somitogenesis	2	187.2×	4e-04	HES7, LFNG
obsolete negative regulation of Notch signaling pathway involved in somitogenesis	1	4213.0×	0.002	LFNG
Notch signaling pathway	2	70.8×	0.002	MESP2, HES7
negative regulation of neuron maturation	1	2106.5×	0.002	TBX6
positive regulation of meiotic cell cycle	1	2106.5×	0.002	LFNG
compartment pattern specification	1	1053.2×	0.004	LFNG
regulation of somitogenesis	1	702.2×	0.005	LFNG
mesodermal cell fate specification	1	526.6×	0.006	TBX6
marginal zone B cell differentiation	1	468.1×	0.006	LFNG
regulation of transcription by RNA polymerase II	3	8.7×	0.006	MESP2, TBX6, HES7
regulation of Notch signaling pathway	1	210.7×	0.011	LFNG
post-anal tail morphogenesis	1	183.2×	0.011	HES7
signal transduction involved in regulation of gene expression	1	175.5×	0.011	TBX6
cell fate specification	1	131.7×	0.014	TBX6
mesoderm formation	1	123.9×	0.014	MESP2
regulation of neurogenesis	1	100.3×	0.015	HES7
ovarian follicle development	1	98.0×	0.015	LFNG
T cell differentiation	1	95.8×	0.015	LFNG
heart morphogenesis	1	93.6×	0.015	MESP2
positive regulation of Notch signaling pathway	1	87.8×	0.015	LFNG
rhythmic process	1	62.9×	0.021	HES7
negative regulation of neuron projection development	1	59.3×	0.021	TBX6
negative regulation of transcription by RNA polymerase II	2	8.9×	0.021	TBX6, HES7
animal organ morphogenesis	1	47.9×	0.024	LFNG
anterior/posterior pattern specification	1	45.3×	0.024	HES7
anatomical structure morphogenesis	1	34.8×	0.030	TBX6
skeletal system development	1	31.4×	0.033	HES7
positive regulation of transcription by RNA polymerase II	1	3.7×	0.243	TBX6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
MESP2	0	0
TBX6	0	0
HES7	0	0
LFNG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LFNG	2.4.1.222	O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	LFNG
E	Difficult family or no structure, no drug	3	MESP2, TBX6, HES7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MESP2	0	—
TBX6	0	—
HES7	0	—
LFNG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.