Klippel-Feil syndrome

Summary

Klippel-Feil syndrome (MONDO:0001029) is a disease (an umbrella term covering 6 Mondo subtypes) with 1 cohort gene and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 33
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Europe	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000324	Facial asymmetry	Very frequent (80-99%)
HP:0000465	Webbed neck	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000925	Abnormality of the vertebral column	Very frequent (80-99%)
HP:0002162	Low posterior hairline	Very frequent (80-99%)
HP:0004602	Cervical C2/C3 vertebral fusion	Very frequent (80-99%)
HP:0005640	Abnormal vertebral segmentation and fusion	Very frequent (80-99%)
HP:0005986	Limitation of neck motion	Very frequent (80-99%)
HP:0000119	Abnormality of the genitourinary system	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000772	Abnormal rib morphology	Frequent (30-79%)
HP:0000912	Sprengel anomaly	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003043	Abnormality of the shoulder	Frequent (30-79%)
HP:0003298	Spina bifida occulta	Frequent (30-79%)
HP:0005988	Congenital muscular torticollis	Frequent (30-79%)
HP:0030833	Neck pain	Frequent (30-79%)
HP:0000086	Ectopic kidney	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0001291	Abnormal cranial nerve morphology	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0002023	Anal atresia	Occasional (5-29%)
HP:0002414	Spina bifida	Occasional (5-29%)
HP:0003416	Spinal canal stenosis	Occasional (5-29%)
HP:0004374	Hemiplegia/hemiparesis	Occasional (5-29%)
HP:0004397	Ectopic anus	Occasional (5-29%)
HP:0005107	Abnormal sacrum morphology	Occasional (5-29%)
HP:0008678	Renal hypoplasia/aplasia	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0034980	Synkinesis	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Klippel-Feil syndrome
Mondo ID	MONDO:0001029
MeSH	D007714
OMIM	118100
Orphanet	2345
DOID	DOID:10426
ICD-10-CM	Q76.1
ICD-11	2139186992
NCIT	C98967
SNOMED CT	5601008
UMLS	C0022738
MedGen	9645
GARD	0010280
Is cancer (heuristic)	no

Also known as: cervical vertebral fusion · Klippel Feil syndrome · Klippel-Feil Sequence

Data availability: 2 ClinVar variants · 2 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

Related subtypes (21): autoimmune disorder of musculoskeletal system, musculoskeletal system benign neoplasm, musculoskeletal system cancer, enthesopathy, muscle tissue disorder, fasciitis, skeletal system disorder, synovial chondromatosis, auriculoosteodysplasia, hypertrophic osteoarthropathy, primary, autosomal dominant, Upington disease, Ramon syndrome, osteoporosis-oculocutaneous hypopigmentation syndrome, short stature, Brussels type, wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia, CINCA syndrome, chondrodysplasia with joint dislocations, gPAPP type, ligament disorder, synovium disorder, disease of the tendon, Short stature, Dauber-Argente type

Subtypes (6): Klippel-Feil syndrome 1, autosomal dominant, Klippel-Feil syndrome 2, autosomal recessive, 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

2 retrieved; paginated sample, class counts are floors:

1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
634522	NM_032608.7(MYO18B):c.5038dup (p.Glu1680fs)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587504	NM_032608.7(MYO18B):c.736G>T (p.Gly246Trp)	MYO18B	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYO18B	Orphanet:447974	Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYO18B	HGNC:18150	ENSG00000133454	Q8IUG5	Unconventional myosin-XVIIIb	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYO18B	Unconventional myosin-XVIIIb	May be involved in intracellular trafficking of the muscle cell when in the cytoplasm, whereas entering the nucleus, may be involved in the regulation of muscle specific genes.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYO18B	Other/Unknown	no		Myosin_head_motor_dom-like, P-loop_NTPase, MYSc_Myo18

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYO18B	148	broad	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYO18B	1,775

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYO18B	Q8IUG5	60.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell development	1	624.1×	0.005	MYO18B
vasculogenesis	1	255.3×	0.006	MYO18B
in utero embryonic development	1	72.0×	0.014	MYO18B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
MYO18B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	MYO18B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYO18B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03741790	Not specified	ACTIVE_NOT_RECRUITING	Airway Management of Pediatric Patients With Klippel-Feil Syndrome
NCT03565224	Not specified	COMPLETED	Study of Titanium-Coated PEEK Cages for Degenerative Disc Disease
NCT06489392	Not specified	COMPLETED	Mehri Turki Webbed Neck Classification