Autosomal recessive spondylocostal dysostosis

Summary

Autosomal recessive spondylocostal dysostosis (MONDO:0010180) is a disease (an umbrella term covering 5 Mondo subtypes) with 5 cohort genes. The dominant Reactome pathway is Somitogenesis (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 5
• Phenotypes (HPO): 38

Clinical features

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000902	Rib fusion	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0003422	Vertebral segmentation defect	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005108	Abnormal intervertebral disk morphology	Very frequent (80-99%)
HP:0006655	Rib segmentation abnormalities	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)
HP:0010978	Abnormality of immune system physiology	Very frequent (80-99%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0000008	Abnormal morphology of female internal genitalia	Occasional (5-29%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000069	Abnormality of the ureter	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000269	Prominent occiput	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000776	Congenital diaphragmatic hernia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0002435	Meningocele	Occasional (5-29%)
HP:0003298	Spina bifida occulta	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0010772	Anomalous pulmonary venous return	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)
HP:0100589	Urogenital fistula	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spondylocostal dysostosis
Mondo ID	MONDO:0010180
MeSH	C535781
Orphanet	2311
SNOMED CT	61367005
GARD	0006798
Is cancer (heuristic)	no

Also known as: Jarcho-Levin syndrome · SCDO1 · spondylocostal dysostosis 1, autosomal recessive · spondylocostal dysostosis, autosomal recessive

Data availability: 5 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (3): spondylocostal dysostosis 5, autosomal dominant spondylocostal dysostosis, spondylocostal dysostosis 7, autosomal recessive

Subtypes (5): spondylocostal dysostosis 2, autosomal recessive, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
DLL3	Definitive	Autosomal recessive	spondylocostal dysostosis 1, autosomal recessive	4
LFNG	Definitive	Autosomal recessive	spondylocostal dysostosis 3, autosomal recessive	5
MESP2	Definitive	Autosomal recessive	spondylocostal dysostosis 2, autosomal recessive	4
HES7	Strong	Autosomal recessive	spondylocostal dysostosis 4, autosomal recessive	3
RIPPLY2	Strong	Autosomal recessive	spondylocostal dysostosis 6, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HES7	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
RIPPLY2	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
DLL3	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
MESP2	Orphanet:2311	Autosomal recessive spondylocostal dysostosis
LFNG	Orphanet:2311	Autosomal recessive spondylocostal dysostosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HES7	HGNC:15977	ENSG00000179111	Q9BYE0	Transcription factor HES-7	gencc
RIPPLY2	HGNC:21390	ENSG00000203877	Q5TAB7	Protein ripply2	gencc
DLL3	HGNC:2909	ENSG00000090932	Q9NYJ7	Delta-like protein 3	gencc
MESP2	HGNC:29659	ENSG00000188095	Q0VG99	Mesoderm posterior protein 2	gencc
LFNG	HGNC:6560	ENSG00000106003	Q8NES3	Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HES7	Transcription factor HES-7	Transcriptional repressor.
RIPPLY2	Protein ripply2	Plays a role in somitogenesis.
DLL3	Delta-like protein 3	Inhibits primary neurogenesis.
MESP2	Mesoderm posterior protein 2	Transcription factor with important role in somitogenesis.
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: 2 · Unknown: 2 · Druggable fraction: 0.2

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	2	3.3×	0.343
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HES7	Transcription factor	no		Orange_dom, bHLH_dom, HES-7_bHLH-O
RIPPLY2	Other/Unknown	no		Ripply_fam
DLL3	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, Growth_fac_rcpt_cys_sf
MESP2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Mesogenin/MesP
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)	5
unknown	0

Top tissues across cohort

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

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HES7	142	broad	yes	cortical plate, right hemisphere of cerebellum, upper arm skin
RIPPLY2	146	broad	yes	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
DLL3	62	broad	marker	ganglionic eminence, primordial germ cell in gonad, cortical plate
MESP2	140	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
LFNG	167	ubiquitous	marker	granulocyte, body of pancreas, monocyte

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLL3	1,586
LFNG	835
MESP2	673
RIPPLY2	556
HES7	365

Intra-cohort edges

A	B	Sources
DLL3	HES7	string_interaction
DLL3	LFNG	string_interaction
DLL3	MESP2	string_interaction
DLL3	RIPPLY2	string_interaction
HES7	LFNG	string_interaction
HES7	MESP2	string_interaction
HES7	RIPPLY2	string_interaction
LFNG	MESP2	string_interaction
LFNG	RIPPLY2	string_interaction
MESP2	RIPPLY2	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 5 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LFNG	Q8NES3	83.66
HES7	Q9BYE0	74.31
DLL3	Q9NYJ7	65.42
RIPPLY2	Q5TAB7	62.67
MESP2	Q0VG99	54.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Somitogenesis	5	233.1×	2e-11	HES7, RIPPLY2, DLL3, MESP2, LFNG
Formation of paraxial mesoderm	3	244.7×	1e-06	DLL3, MESP2, LFNG
Gastrulation	2	103.8×	7e-04	MESP2, LFNG
Defective LFNG causes SCDO3	1	456.8×	0.008	LFNG
Nephron development	1	175.7×	0.015	LFNG
Kidney development	1	163.1×	0.015	LFNG
Pre-NOTCH Processing in Golgi	1	126.9×	0.017	LFNG
Pre-NOTCH Expression and Processing	1	73.7×	0.025	LFNG
Diseases associated with O-glycosylation of proteins	1	43.1×	0.038	LFNG
Signaling by NOTCH	1	35.1×	0.042	LFNG
Diseases of glycosylation	1	26.2×	0.051	LFNG
Developmental Biology	2	5.8×	0.052	MESP2, LFNG
Diseases of metabolism	1	16.1×	0.070	LFNG
Disease	1	2.6×	0.352	LFNG
Signal Transduction	1	2.0×	0.404	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
somitogenesis	4	299.6×	7e-09	HES7, RIPPLY2, DLL3, LFNG
Notch signaling pathway	4	113.3×	2e-07	HES7, RIPPLY2, DLL3, MESP2
compartment pattern specification	2	1685.2×	4e-06	DLL3, LFNG
somite rostral/caudal axis specification	2	612.8×	3e-05	RIPPLY2, MESP2
post-anal tail morphogenesis	2	293.1×	1e-04	HES7, RIPPLY2
obsolete negative regulation of Notch signaling pathway involved in somitogenesis	1	3370.4×	0.002	LFNG
positive regulation of meiotic cell cycle	1	1685.2×	0.002	LFNG
skeletal system development	2	50.3×	0.002	HES7, DLL3
regulation of somitogenesis	1	561.7×	0.006	LFNG
marginal zone B cell differentiation	1	374.5×	0.008	LFNG
paraxial mesoderm development	1	337.0×	0.008	DLL3
regulation of Notch signaling pathway	1	168.5×	0.015	LFNG
negative regulation of neurogenesis	1	124.8×	0.018	DLL3
bone morphogenesis	1	120.4×	0.018	RIPPLY2
embryonic pattern specification	1	108.7×	0.018	RIPPLY2
mesoderm development	1	105.3×	0.018	HES7
mesoderm formation	1	99.1×	0.018	MESP2
negative regulation of Notch signaling pathway	1	86.4×	0.019	DLL3
regulation of neurogenesis	1	80.2×	0.019	HES7
ovarian follicle development	1	78.4×	0.019	LFNG
T cell differentiation	1	76.6×	0.019	LFNG
heart morphogenesis	1	74.9×	0.019	MESP2
positive regulation of Notch signaling pathway	1	70.2×	0.019	LFNG
determination of left/right symmetry	1	51.1×	0.024	RIPPLY2
rhythmic process	1	50.3×	0.024	HES7
ossification	1	45.5×	0.026	RIPPLY2
animal organ morphogenesis	1	38.3×	0.030	LFNG
anterior/posterior pattern specification	1	36.2×	0.030	HES7
negative regulation of transcription by RNA polymerase II	2	7.1×	0.030	HES7, RIPPLY2
regulation of transcription by RNA polymerase II	2	4.7×	0.064	HES7, MESP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HES7	0	0
RIPPLY2	0	0
DLL3	0	0
MESP2	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: 5; 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	4	HES7, RIPPLY2, DLL3, MESP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HES7	0	—
RIPPLY2	0	—
DLL3	0	—
MESP2	0	—
LFNG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.