Klippel-Feil syndrome 2, autosomal recessive

Summary

Klippel-Feil syndrome 2, autosomal recessive (MONDO:0008958) is a disease caused by MEOX1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MEOX1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Klippel-Feil syndrome 2, autosomal recessive
Mondo ID	MONDO:0008958
MeSH	C536888
OMIM	214300
DOID	DOID:0080590
UMLS	C1859209
MedGen	395201
GARD	0015151
Is cancer (heuristic)	no

Also known as: isolated Klippel-Feil syndrome caused by mutation in MEOX1 · KFS2 · Klippel-Feil syndrome 2, autosomal recessive · MEOX1 isolated Klippel-Feil syndrome

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › Klippel-Feil syndrome › Klippel-Feil syndrome 2, autosomal recessive

Related subtypes (5): Klippel-Feil syndrome 1, autosomal dominant, Wildervanck syndrome, Klippel-Feil syndrome 3, autosomal dominant, Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, Calabro syndrome

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

7 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162132	NM_004527.4(MEOX1):c.250C>T (p.Gln84Ter)	MEOX1	Pathogenic	no assertion criteria provided
3722664	NM_004527.4(MEOX1):c.282G>A (p.Trp94Ter)	MEOX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39508	NM_004527.4(MEOX1):c.664C>T (p.Arg222Ter)	MEOX1	Pathogenic	no assertion criteria provided
3362420	NM_004527.4(MEOX1):c.514C>T (p.Arg172Cys)	MEOX1	Likely pathogenic	criteria provided, single submitter
3779844	NM_004527.4(MEOX1):c.268C>T (p.Gln90Ter)	MEOX1	Likely pathogenic	criteria provided, single submitter
39507	NM_004527.4(MEOX1):c.94del (p.Ala32fs)	MEOX1	Likely pathogenic	criteria provided, single submitter
218314	NM_001009994.3(RIPPLY2):c.299del (p.Leu100fs)	RIPPLY2	Likely pathogenic	criteria provided, single submitter

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
MEOX1	Strong	Autosomal recessive	Klippel-Feil syndrome 2, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEOX1	Orphanet:2345	Isolated Klippel-Feil syndrome
RIPPLY2	Orphanet:2311	Autosomal recessive spondylocostal dysostosis

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
MEOX1	HGNC:7013	ENSG00000005102	P50221	Homeobox protein MOX-1	gencc,clinvar
RIPPLY2	HGNC:21390	ENSG00000203877	Q5TAB7	Protein ripply2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEOX1	Homeobox protein MOX-1	Mesodermal transcription factor that plays a key role in somitogenesis and is specifically required for sclerotome development.
RIPPLY2	Protein ripply2	Plays a role in somitogenesis.

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)
MEOX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
RIPPLY2	Other/Unknown	no		Ripply_fam

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
subcutaneous adipose tissue	1
tendon	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEOX1	195	broad	marker	tendon of biceps brachii, tendon, subcutaneous adipose tissue
RIPPLY2	146	broad	yes	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MEOX1	1,458
RIPPLY2	556

Intra-cohort edges

A	B	Sources
MEOX1	RIPPLY2	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MEOX1	P50221	64.33
RIPPLY2	Q5TAB7	62.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Somitogenesis	1	233.1×	0.004	RIPPLY2

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
sclerotome development	1	2808.7×	0.004	MEOX1
somite specification	1	1685.2×	0.004	MEOX1
somite rostral/caudal axis specification	1	766.0×	0.006	RIPPLY2
somite development	1	561.7×	0.006	MEOX1
hematopoietic stem cell differentiation	1	383.0×	0.006	MEOX1
post-anal tail morphogenesis	1	366.4×	0.006	RIPPLY2
bone morphogenesis	1	300.9×	0.006	RIPPLY2
embryonic pattern specification	1	271.8×	0.006	RIPPLY2
somitogenesis	1	187.2×	0.008	RIPPLY2
determination of left/right symmetry	1	127.7×	0.011	RIPPLY2
ossification	1	113.9×	0.011	RIPPLY2
Notch signaling pathway	1	70.8×	0.016	RIPPLY2
negative regulation of transcription by RNA polymerase II	1	8.9×	0.118	RIPPLY2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	MEOX1

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
MEOX1	0	0
RIPPLY2	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	MEOX1, RIPPLY2

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)
MEOX1	0	—
RIPPLY2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.