Spondylocostal dysostosis 5

Summary

Spondylocostal dysostosis 5 (MONDO:0007389) is a disease caused by TBX6 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TBX6 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylocostal dysostosis 5
Mondo ID	MONDO:0007389
OMIM	122600
DOID	DOID:0112363
UMLS	C4083048
MedGen	901825
GARD	0024556
NORD	1915
Is cancer (heuristic)	no

Also known as: costovertebral segmentation anomalies · SCDO5 · scoliosis, congenital, with or without rib anomalies · spondylocostal dysostosis 5 · spondylocostal dysostosis caused by mutation in TBX6 · spondylocostal dysostosis type 5 · spondylothoracic dysostosis · Spondylothoracic Dysplasia · TBX6 spondylocostal dysostosis

Data availability: 35 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 › spondylocostal dysostosis 5

Related subtypes (3): autosomal recessive spondylocostal dysostosis, autosomal dominant spondylocostal dysostosis, spondylocostal dysostosis 7, 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

35 retrieved; paginated sample, class counts are floors:

12 pathogenic, 9 uncertain significance, 6 conflicting classifications of pathogenicity, 4 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
188053	NM_004608.3(TBX6):c.[-48-240A>G;-49+34G>T;1227G>A]		Pathogenic	no assertion criteria provided
100633	NM_004608.4(TBX6):c.1311A>T (p.Ter437Cys)	TBX6	Pathogenic	no assertion criteria provided
1323679	NM_004608.4(TBX6):c.1143dup (p.Tyr382fs)	TBX6	Pathogenic	criteria provided, single submitter
1705370	NM_004608.4(TBX6):c.1018_1019del (p.Leu340fs)	TBX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188054	NM_004608.4(TBX6):c.1250dup (p.Leu419fs)	TBX6	Pathogenic	criteria provided, single submitter
188055	NM_004608.4(TBX6):c.266dup (p.Val91fs)	TBX6	Pathogenic	criteria provided, single submitter
243053	NM_004608.4(TBX6):c.704dup (p.Met236fs)	TBX6	Pathogenic	criteria provided, single submitter
243054	NM_004608.4(TBX6):c.1169dup (p.His391fs)	TBX6	Pathogenic	criteria provided, single submitter
252362	NM_004608.4(TBX6):c.1179_1180del (p.Gly395fs)	TBX6	Pathogenic	criteria provided, single submitter
3339290	NM_004608.4(TBX6):c.990del (p.Glu332fs)	TBX6	Pathogenic	criteria provided, single submitter
599077	NM_004608.4(TBX6):c.221dup (p.Thr75fs)	TBX6	Pathogenic	no assertion criteria provided
827682	NM_004608.4(TBX6):c.1148C>A (p.Ser383Ter)	TBX6	Pathogenic	criteria provided, single submitter
243052	Single allele	TLCD3B	Pathogenic	criteria provided, single submitter
1325177	NM_004608.4(TBX6):c.914-2A>C	TBX6	Likely pathogenic	criteria provided, single submitter
2628423	NM_004608.4(TBX6):c.834dup (p.Lys279Ter)	TBX6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062294	NM_004608.4(TBX6):c.1309T>C (p.Ter437Arg)	TBX6	Likely pathogenic	criteria provided, single submitter
3383213	NM_004608.4(TBX6):c.989_990dup (p.Gly331fs)	TBX6	Likely pathogenic	criteria provided, single submitter
1325178	NM_004608.4(TBX6):c.466_469dup (p.Arg157fs)	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188052	NM_004608.4(TBX6):c.844C>T (p.Arg282Ter)	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188056	NM_004608.4(TBX6):c.434C>T (p.Pro145Leu)	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3020494	NM_004608.4(TBX6):c.617_621+12del	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
427809	NM_004608.4(TBX6):c.-49+34G>T	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694403	NM_004608.4(TBX6):c.356G>A (p.Arg119His)	TBX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022078	NM_004608.4(TBX6):c.699G>C (p.Trp233Cys)	TBX6	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028280	NM_004608.4(TBX6):c.1174G>T (p.Gly392Trp)	TBX6	Uncertain significance	criteria provided, single submitter
1683622	NM_004608.4(TBX6):c.354-762T>C	TBX6	Uncertain significance	criteria provided, single submitter
1705339	NM_004608.4(TBX6):c.448C>A (p.Arg150Ser)	TBX6	Uncertain significance	criteria provided, single submitter
2431421	NM_004608.4(TBX6):c.373C>T (p.Arg125Ter)	TBX6	Uncertain significance	criteria provided, single submitter
3242085	NM_004608.4(TBX6):c.448C>T (p.Arg150Cys)	TBX6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377756	NM_004608.4(TBX6):c.581G>A (p.Arg194His)	TBX6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
TBX6	Strong	Autosomal recessive	spondylocostal dysostosis 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX6	Orphanet:1797	Autosomal dominant spondylocostal dysostosis
TBX6	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
TLCD3B	Orphanet:1872	Cone rod dystrophy

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
TBX6	HGNC:11605	ENSG00000149922	O95947	T-box transcription factor TBX6	gencc,clinvar
TLCD3B	HGNC:25295	ENSG00000149926	Q71RH2	Ceramide synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
TLCD3B	Ceramide synthase	Involved in ceramide synthesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX6	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
TLCD3B	Other/Unknown	no		TLC-dom, TLCD

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
buccal mucosa cell	1
diaphragm	1
lower esophagus mucosa	1
cortical plate	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX6	166	tissue_specific	marker	lower esophagus mucosa, buccal mucosa cell, diaphragm
TLCD3B	198	broad	marker	left testis, cortical plate, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX6	1,426
TLCD3B	1,017

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLCD3B	Q71RH2	89.52
TBX6	O95947	66.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Formation of the posterior neural plate	1	1142.0×	0.004	TBX6
Formation of paraxial mesoderm	1	407.9×	0.005	TBX6
Gastrulation	1	259.6×	0.005	TBX6
Somitogenesis	1	233.1×	0.005	TBX6
Developmental Biology	1	14.5×	0.069	TBX6

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
negative regulation of neuron maturation	1	4213.0×	0.003	TBX6
mesodermal cell fate specification	1	1053.2×	0.006	TBX6
somite rostral/caudal axis specification	1	766.0×	0.006	TBX6
signal transduction involved in regulation of gene expression	1	351.1×	0.009	TBX6
cell fate specification	1	263.3×	0.009	TBX6
mesoderm development	1	263.3×	0.009	TBX6
ceramide biosynthetic process	1	210.7×	0.009	TLCD3B
lipid homeostasis	1	168.5×	0.010	TLCD3B
negative regulation of fat cell differentiation	1	156.0×	0.010	TLCD3B
negative regulation of neuron projection development	1	118.7×	0.012	TBX6
anatomical structure morphogenesis	1	69.6×	0.018	TBX6
negative regulation of transcription by RNA polymerase II	1	8.9×	0.128	TBX6
positive regulation of transcription by RNA polymerase II	1	7.4×	0.140	TBX6
regulation of transcription by RNA polymerase II	1	5.8×	0.164	TBX6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TBX6	0	0
TLCD3B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TBX6, TLCD3B

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)
TBX6	0	—
TLCD3B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.