Spondylocostal dysostosis 3, autosomal recessive

Summary

Spondylocostal dysostosis 3, autosomal recessive (MONDO:0012349) is a disease caused by LFNG (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: LFNG (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 238

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylocostal dysostosis 3, autosomal recessive
Mondo ID	MONDO:0012349
OMIM	609813
DOID	DOID:0112361
UMLS	C1853296
MedGen	377871
GARD	0004973
Is cancer (heuristic)	no

Also known as: autosomal recessive spondylocostal dysostosis caused by mutation in LFNG · LFNG autosomal recessive spondylocostal dysostosis · SCDO3 · SCOD3 · spondylocostal dysostosis 3 · spondylocostal dysostosis 3, autosomal recessive

Data availability: 238 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 › vertebral column disorder › spondylocostal dysostosis › autosomal recessive spondylocostal dysostosis › spondylocostal dysostosis 3, autosomal recessive

Related subtypes (4): spondylocostal dysostosis 2, 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

238 retrieved; paginated sample, class counts are floors:

132 likely benign, 78 uncertain significance, 11 benign, 6 conflicting classifications of pathogenicity, 5 pathogenic, 4 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1976681	NM_001040167.2(LFNG):c.443dup (p.Thr149fs)	LFNG	Pathogenic	criteria provided, single submitter
2035397	NM_001040167.2(LFNG):c.216_217del (p.His72fs)	LFNG	Pathogenic	criteria provided, single submitter
619139	NM_001040167.2(LFNG):c.601G>A (p.Asp201Asn)	LFNG	Pathogenic	no assertion criteria provided
619140	NM_001040167.2(LFNG):c.372del (p.Lys124fs)	LFNG	Pathogenic	no assertion criteria provided
6999	NM_001040167.2(LFNG):c.564C>A (p.Phe188Leu)	LFNG	Pathogenic	no assertion criteria provided
3220895	NM_001040167.2(LFNG):c.434C>T (p.Thr145Met)	LFNG	Likely pathogenic	criteria provided, single submitter
3377130	NM_001040167.2(LFNG):c.736-2A>G	LFNG	Likely pathogenic	criteria provided, single submitter
3638207	NM_001040167.2(LFNG):c.987+1G>A	LFNG	Likely pathogenic	criteria provided, single submitter
4845695	NM_001166355.2(LFNG):c.159_166dup (p.Glu56fs)	LFNG	Likely pathogenic	criteria provided, single submitter
1394653	NM_001040167.2(LFNG):c.368A>G (p.Lys123Arg)	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286065	NM_001040167.2(LFNG):c.573C>T (p.Ser191=)	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497705	NM_001040167.2(LFNG):c.735+9C>T	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498512	NM_001040167.2(LFNG):c.1036G>C (p.Val346Leu)	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
593371	NM_001040167.2(LFNG):c.327G>T (p.Pro109=)	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
971848	NM_001040167.2(LFNG):c.1021C>T (p.Arg341Trp)	LFNG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1514588	NC_000007.13:g.(?2559496)(2587132_?)dup	BRAT1	Uncertain significance	criteria provided, single submitter
1003507	NM_001040167.2(LFNG):c.766G>A (p.Gly256Ser)	LFNG	Uncertain significance	criteria provided, single submitter
1018847	NM_001040167.2(LFNG):c.307C>G (p.Pro103Ala)	LFNG	Uncertain significance	criteria provided, single submitter
1035758	NM_001040167.2(LFNG):c.557A>G (p.Asp186Gly)	LFNG	Uncertain significance	criteria provided, single submitter
1037213	NM_001040167.2(LFNG):c.295G>A (p.Ala99Thr)	LFNG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1038450	NM_001040167.2(LFNG):c.37C>G (p.Leu13Val)	LFNG	Uncertain significance	criteria provided, single submitter
1040157	NM_001040167.2(LFNG):c.100C>A (p.Pro34Thr)	LFNG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1040378	NM_001040167.2(LFNG):c.842C>T (p.Thr281Met)	LFNG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1045090	NM_001040167.2(LFNG):c.131G>T (p.Ser44Ile)	LFNG	Uncertain significance	criteria provided, single submitter
1057386	NM_001040167.2(LFNG):c.308C>T (p.Pro103Leu)	LFNG	Uncertain significance	criteria provided, single submitter
1059562	NM_001040167.2(LFNG):c.1124G>A (p.Arg375His)	LFNG	Uncertain significance	criteria provided, single submitter
1062453	NM_001040167.2(LFNG):c.521G>A (p.Arg174His)	LFNG	Uncertain significance	criteria provided, single submitter
1063078	NM_001040167.2(LFNG):c.788G>A (p.Arg263His)	LFNG	Uncertain significance	criteria provided, single submitter
1064285	NM_001040167.2(LFNG):c.559C>T (p.Arg187Cys)	LFNG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1252056	NM_001040167.2(LFNG):c.761C>T (p.Thr254Met)	LFNG	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
LFNG	Definitive	Autosomal recessive	spondylocostal dysostosis 3, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LFNG	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
BRAT1	Orphanet:435845	Lethal neonatal spasticity-epileptic encephalopathy syndrome

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
LFNG	HGNC:6560	ENSG00000106003	Q8NES3	Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe	gencc,clinvar
BRAT1	HGNC:21701	ENSG00000106009	Q6PJG6	Integrator complex assembly factor BRAT1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
BRAT1	Integrator complex assembly factor BRAT1	Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LFNG	Enzyme (other)	yes	2.4.1.222	Fringe-like_glycosylTrfase, Fringe
BRAT1	Other/Unknown	no		HEAT, ARM-like, ARM-type_fold

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
granulocyte	2
body of pancreas	1
monocyte	1
left adrenal gland cortex	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LFNG	167	ubiquitous	marker	granulocyte, body of pancreas, monocyte
BRAT1	176	ubiquitous	marker	left adrenal gland cortex, granulocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAT1	1,105
LFNG	835

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAT1	Q6PJG6	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LFNG	Q8NES3	83.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Defective LFNG causes SCDO3	1	2284.0×	0.006	LFNG
Nephron development	1	878.5×	0.006	LFNG
Kidney development	1	815.7×	0.006	LFNG
Pre-NOTCH Processing in Golgi	1	634.4×	0.006	LFNG
Formation of paraxial mesoderm	1	407.9×	0.007	LFNG
Pre-NOTCH Expression and Processing	1	368.4×	0.007	LFNG
Gastrulation	1	259.6×	0.008	LFNG
Somitogenesis	1	233.1×	0.008	LFNG
Diseases associated with O-glycosylation of proteins	1	215.5×	0.008	LFNG
Signaling by NOTCH	1	175.7×	0.009	LFNG
Diseases of glycosylation	1	131.3×	0.010	LFNG
Diseases of metabolism	1	80.4×	0.016	LFNG
Developmental Biology	1	14.5×	0.080	LFNG
Disease	1	13.1×	0.082	LFNG
Signal Transduction	1	10.2×	0.098	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
integrator complex assembly	1	8426.0×	0.001	BRAT1
obsolete negative regulation of Notch signaling pathway involved in somitogenesis	1	8426.0×	0.001	LFNG
positive regulation of meiotic cell cycle	1	4213.0×	0.002	LFNG
compartment pattern specification	1	2106.5×	0.003	LFNG
regulation of somitogenesis	1	1404.3×	0.003	LFNG
marginal zone B cell differentiation	1	936.2×	0.004	LFNG
mitochondrion localization	1	842.6×	0.004	BRAT1
regulation of Notch signaling pathway	1	421.3×	0.007	LFNG
response to ionizing radiation	1	205.5×	0.009	BRAT1
ovarian follicle development	1	195.9×	0.009	LFNG
T cell differentiation	1	191.5×	0.009	LFNG
somitogenesis	1	187.2×	0.009	LFNG
protein localization to nucleus	1	175.5×	0.009	BRAT1
positive regulation of Notch signaling pathway	1	175.5×	0.009	LFNG
positive regulation of protein phosphorylation	1	138.1×	0.011	BRAT1
glucose metabolic process	1	127.7×	0.011	BRAT1
animal organ morphogenesis	1	95.8×	0.013	LFNG
positive regulation of cell growth	1	91.6×	0.013	BRAT1
cell population proliferation	1	51.4×	0.022	BRAT1
cell migration	1	30.8×	0.035	BRAT1
DNA damage response	1	26.8×	0.039	BRAT1
apoptotic process	1	14.3×	0.068	BRAT1

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
LFNG	0	0
BRAT1	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: 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	1	LFNG
E	Difficult family or no structure, no drug	1	BRAT1

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)
LFNG	0	—
BRAT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.