Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome

Summary

Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (MONDO:0014689) is a disease caused by MYO18B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MYO18B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 161

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
Mondo ID	MONDO:0014689
OMIM	616549
Orphanet	447974
DOID	DOID:0080592
UMLS	C4225285
MedGen	894399
GARD	0017778
Is cancer (heuristic)	no

Also known as: KFS4 · Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome · Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism

Data availability: 161 ClinVar variants · 6 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 anomaly-myopathy-facial dysmorphism syndrome

Related subtypes (5): Klippel-Feil syndrome 1, autosomal dominant, Klippel-Feil syndrome 2, autosomal recessive, Wildervanck syndrome, Klippel-Feil syndrome 3, autosomal dominant, 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

161 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 14 benign, 11 likely pathogenic, 10 conflicting classifications of pathogenicity, 10 pathogenic, 10 pathogenic/likely pathogenic, 2 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323314	NM_032608.7(MYO18B):c.1195del (p.Gln399fs)	MYO18B	Pathogenic	criteria provided, single submitter
1324761	NM_032608.7(MYO18B):c.169C>T (p.Gln57Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324763	NM_032608.7(MYO18B):c.4796del (p.Asn1599fs)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448838	NM_032608.7(MYO18B):c.31G>T (p.Glu11Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705092	NM_032608.7(MYO18B):c.3110G>A (p.Trp1037Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208842	NM_032608.7(MYO18B):c.6905C>A (p.Ser2302Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2163273	NM_032608.7(MYO18B):c.4087C>T (p.Arg1363Ter)	MYO18B	Pathogenic	criteria provided, multiple submitters, no conflicts
2168464	NM_032608.7(MYO18B):c.3880_3884del (p.Arg1294fs)	MYO18B	Pathogenic	criteria provided, multiple submitters, no conflicts
2193537	NM_032608.7(MYO18B):c.4792C>T (p.Arg1598Ter)	MYO18B	Pathogenic	criteria provided, multiple submitters, no conflicts
224413	NM_032608.7(MYO18B):c.6496G>T (p.Glu2166Ter)	MYO18B	Pathogenic	criteria provided, single submitter
2506003	NM_032608.7(MYO18B):c.6825G>A (p.Trp2275Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506377	NM_032608.7(MYO18B):c.2212-1G>A	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506382	NM_032608.7(MYO18B):c.3775+1G>T	MYO18B	Pathogenic	criteria provided, single submitter
2581587	NM_032608.7(MYO18B):c.2848C>T (p.Gln950Ter)	MYO18B	Pathogenic	criteria provided, multiple submitters, no conflicts
3233821	NM_032608.7(MYO18B):c.7015del (p.Leu2339fs)	MYO18B	Pathogenic	criteria provided, single submitter
590293	NM_032608.7(MYO18B):c.6660_6670del (p.Arg2220fs)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634522	NM_032608.7(MYO18B):c.5038dup (p.Glu1680fs)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807635	NM_032608.7(MYO18B):c.6433C>T (p.Arg2145Ter)	MYO18B	Pathogenic	criteria provided, single submitter
816785	NM_032608.7(MYO18B):c.6322C>T (p.Arg2108Ter)	MYO18B	Pathogenic	criteria provided, single submitter
81924	NM_032608.7(MYO18B):c.2626C>T (p.Arg876Ter)	MYO18B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320169	NM_032608.7(MYO18B):c.3492del (p.Phe1164fs)	MYO18B	Likely pathogenic	criteria provided, single submitter
1320170	NM_032608.7(MYO18B):c.7702T>G (p.Ter2568Glu)	MYO18B	Likely pathogenic	criteria provided, single submitter
1324760	NM_032608.7(MYO18B):c.7039C>T (p.Gln2347Ter)	MYO18B	Likely pathogenic	criteria provided, single submitter
1324762	NM_032608.7(MYO18B):c.3174_3175dup (p.Ala1059fs)	MYO18B	Likely pathogenic	criteria provided, single submitter
1334741	NM_032608.7(MYO18B):c.7373del (p.Ala2458fs)	MYO18B	Likely pathogenic	criteria provided, single submitter
2431965	NM_032608.7(MYO18B):c.699dup (p.Gly234fs)	MYO18B	Likely pathogenic	criteria provided, single submitter
3382538	NM_032608.7(MYO18B):c.1402C>T (p.Gln468Ter)	MYO18B	Likely pathogenic	criteria provided, single submitter
3891784	NM_032608.7(MYO18B):c.4588G>T (p.Glu1530Ter)	MYO18B	Likely pathogenic	criteria provided, single submitter
4796713	NM_032608.7(MYO18B):c.5884C>T (p.Arg1962Ter)	MYO18B	Likely pathogenic	criteria provided, single submitter
4846858	NM_032608.7(MYO18B):c.510_511del (p.His171fs)	MYO18B	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
MYO18B	Definitive	Autosomal recessive	Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome	6

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	gencc,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: 0.