Klippel-Feil syndrome 1, autosomal dominant
diseaseOn this page
Also known as GDF6 isolated Klippel-Feil syndromeisolated Klippel-Feil syndrome caused by mutation in GDF6KFS1Klippel-Feil Syndrome
Summary
Klippel-Feil syndrome 1, autosomal dominant (MONDO:0007306) is a disease caused by GDF6 (GenCC Definitive), with 3 cohort genes and 2 clinical trials.
At a glance
- Causal gene: GDF6 (GenCC Definitive)
- Cohort genes: 3
- ClinVar variants: 452
- Clinical trials: 2
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Klippel-Feil syndrome 1, autosomal dominant |
| Mondo ID | MONDO:0007306 |
| MeSH | C536887 |
| OMIM | 118100 |
| DOID | DOID:0080589 |
| UMLS | C1861689 |
| MedGen | 396196 |
| GARD | 0015049 |
| NORD | 1336 |
| Is cancer (heuristic) | no |
Also known as: GDF6 isolated Klippel-Feil syndrome · isolated Klippel-Feil syndrome caused by mutation in GDF6 · KFS1 · Klippel-Feil Syndrome · Klippel-Feil syndrome 1, autosomal dominant
Data availability: 452 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.
Disease family
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › Klippel-Feil syndrome › Klippel-Feil syndrome 1, autosomal dominant
Related subtypes (5): 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
452 retrieved; paginated sample, class counts are floors:
238 uncertain significance, 148 likely benign, 35 benign, 23 conflicting classifications of pathogenicity, 7 benign/likely benign, 1 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1679350 | NM_001001557.4(GDF6):c.986_1005del (p.Pro329fs) | GDF6 | Likely pathogenic | criteria provided, single submitter |
| 1002016 | NM_001001557.4(GDF6):c.536C>A (p.Pro179Gln) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1023649 | NM_001001557.4(GDF6):c.902A>G (p.Glu301Gly) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1094356 | NM_001001557.4(GDF6):c.407-3C>T | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1400072 | NM_001001557.4(GDF6):c.923_928dup (p.306GA[3]) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1404300 | NM_001001557.4(GDF6):c.959C>G (p.Pro320Arg) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1938713 | NM_001001557.4(GDF6):c.219C>A (p.Asp73Glu) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1959955 | NM_001001557.4(GDF6):c.454G>A (p.Val152Met) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 286405 | NM_001001557.4(GDF6):c.725C>G (p.Ala242Gly) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2927707 | NM_001001557.4(GDF6):c.625C>T (p.Pro209Ser) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 364042 | NM_001001557.4(GDF6):c.1304C>T (p.Ala435Val) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 364044 | NM_001001557.4(GDF6):c.957C>A (p.Ala319=) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 364047 | NM_001001557.4(GDF6):c.770C>T (p.Pro257Leu) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 60534 | NM_001001557.4(GDF6):c.169G>C (p.Asp57His) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 707560 | NM_001001557.4(GDF6):c.24C>G (p.Leu8=) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 707574 | NM_001001557.4(GDF6):c.112G>C (p.Gly38Arg) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 836995 | NM_001001557.4(GDF6):c.815C>T (p.Pro272Leu) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 8371 | NM_001001557.4(GDF6):c.746C>A (p.Ala249Glu) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 8372 | NM_001001557.4(GDF6):c.866T>C (p.Leu289Pro) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 8373 | NM_001001557.4(GDF6):c.1271A>G (p.Lys424Arg) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 863448 | NM_001001557.4(GDF6):c.322G>A (p.Ala108Thr) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 914077 | NM_001001557.4(GDF6):c.250G>A (p.Glu84Lys) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 914078 | NM_001001557.4(GDF6):c.18C>T (p.Val6=) | GDF6 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 39198 | NM_198578.4(LRRK2):c.4883G>C (p.Arg1628Pro) | LRRK2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1001816 | NM_001001557.4(GDF6):c.1310A>G (p.Asn437Ser) | GDF6 | Uncertain significance | criteria provided, single submitter |
| 1002101 | NM_001001557.4(GDF6):c.896C>T (p.Ser299Leu) | GDF6 | Uncertain significance | criteria provided, single submitter |
| 1007576 | NM_001001557.4(GDF6):c.611C>T (p.Pro204Leu) | GDF6 | Uncertain significance | criteria provided, single submitter |
| 1008100 | NM_001001557.4(GDF6):c.377C>T (p.Thr126Met) | GDF6 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1008463 | NM_001001557.4(GDF6):c.272G>C (p.Arg91Pro) | GDF6 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1015372 | NM_001001557.4(GDF6):c.323C>A (p.Ala108Asp) | GDF6 | Uncertain significance | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 8 · Orphanet: 6 · 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 |
|---|---|---|---|---|
| GDF6 | Definitive | Autosomal dominant | Klippel-Feil syndrome 1, autosomal dominant | 8 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| GDF6 | Orphanet:2345 | Isolated Klippel-Feil syndrome |
| GDF6 | Orphanet:3237 | Multiple synostoses syndrome |
| GDF6 | Orphanet:65 | Leber congenital amaurosis |
| GDF6 | Orphanet:98938 | Colobomatous microphthalmia |
| LRRK2 | Orphanet:2828 | Young-onset Parkinson disease |
| LRRK2 | Orphanet:411602 | Hereditary late-onset Parkinson disease |
Cohort genes → proteins
3 cohort genes, 3 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 3 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| GDF6 | HGNC:4221 | ENSG00000156466 | Q6KF10 | Growth/differentiation factor 6 | gencc,clinvar |
| LRRK2 | HGNC:18618 | ENSG00000188906 | Q5S007 | Leucine-rich repeat serine/threonine-protein kinase 2 | clinvar |
| PLEKHF2 | HGNC:20757 | ENSG00000175895 | Q9H8W4 | Pleckstrin homology domain-containing family F member 2 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| GDF6 | Growth/differentiation factor 6 | Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. |
| LRRK2 | Leucine-rich repeat serine/threonine-protein kinase 2 | Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking. |
| PLEKHF2 | Pleckstrin homology domain-containing family F member 2 | May play a role in early endosome fusion upstream of RAB5, hence regulating receptor trafficking and fluid-phase transport. |
Protein-family classification
Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33
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 |
|---|---|---|---|
| Kinase | 1 | 9.2× | 0.313 |
| Transcription factor | 1 | 2.8× | 0.482 |
| Other/Unknown | 1 | 0.6× | 0.914 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| GDF6 | Other/Unknown | no | TGF-b_propeptide, TGF-b_C, TGF-beta-like | |
| LRRK2 | Kinase | yes | Prot_kinase_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp | |
| PLEKHF2 | Transcription factor | no | Znf_FYVE, PH_domain, Znf_FYVE_PHD |
Expression context
Cohort genes with no expression data: 0.
3 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) | 3 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| placenta | 1 |
| primordial germ cell in gonad | 1 |
| ventricular zone | 1 |
| buccal mucosa cell | 1 |
| leukocyte | 1 |
| monocyte | 1 |
| oocyte | 1 |
| secondary oocyte | 1 |
| upper leg skin | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| GDF6 | 104 | broad | marker | placenta, primordial germ cell in gonad, ventricular zone |
| LRRK2 | 220 | broad | marker | buccal mucosa cell, monocyte, leukocyte |
| PLEKHF2 | 268 | ubiquitous | marker | secondary oocyte, oocyte, upper leg skin |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| LRRK2 | 7,628 |
| PLEKHF2 | 1,324 |
| GDF6 | 1,127 |
Structural data
PDB: 1 · AlphaFold-only: 2 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| LRRK2 | Q5S007 | 44 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| PLEKHF2 | Q9H8W4 | 87.36 |
| GDF6 | Q6KF10 | 70.88 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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 |
|---|---|---|---|---|
| PTK6 promotes HIF1A stabilization | 1 | 1631.4× | 0.002 | LRRK2 |
| Signaling by PTK6 | 1 | 543.8× | 0.002 | LRRK2 |
| Signaling by Non-Receptor Tyrosine Kinases | 1 | 543.8× | 0.002 | LRRK2 |
| Signal Transduction | 1 | 10.2× | 0.098 | LRRK2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| cell migration involved in metanephros development | 1 | 5617.3× | 0.004 | GDF6 |
| cellular response to curcumin | 1 | 5617.3× | 0.004 | LRRK2 |
| Wnt signalosome assembly | 1 | 5617.3× | 0.004 | LRRK2 |
| regulation of kidney size | 1 | 2808.7× | 0.004 | LRRK2 |
| negative regulation of late endosome to lysosome transport | 1 | 2808.7× | 0.004 | LRRK2 |
| obsolete negative regulation of protein processing involved in protein targeting to mitochondrion | 1 | 2808.7× | 0.004 | LRRK2 |
| retinal cell apoptotic process | 1 | 2808.7× | 0.004 | GDF6 |
| regulation of neuron maturation | 1 | 1872.4× | 0.004 | LRRK2 |
| regulation of cAMP/PKA signal transduction | 1 | 1872.4× | 0.004 | LRRK2 |
| positive regulation of protein autoubiquitination | 1 | 1872.4× | 0.004 | LRRK2 |
| regulation of synaptic vesicle transport | 1 | 1872.4× | 0.004 | LRRK2 |
| negative regulation of motile cilium assembly | 1 | 1872.4× | 0.004 | LRRK2 |
| regulation of branching morphogenesis of a nerve | 1 | 1872.4× | 0.004 | LRRK2 |
| regulation of dopamine receptor signaling pathway | 1 | 1404.3× | 0.004 | LRRK2 |
| positive regulation of dopamine receptor signaling pathway | 1 | 1404.3× | 0.004 | LRRK2 |
| regulation of retrograde transport, endosome to Golgi | 1 | 1404.3× | 0.004 | LRRK2 |
| regulation of CAMKK-AMPK signaling cascade | 1 | 1404.3× | 0.004 | LRRK2 |
| tangential migration from the subventricular zone to the olfactory bulb | 1 | 1123.5× | 0.005 | LRRK2 |
| regulation of cell projection organization | 1 | 1123.5× | 0.005 | LRRK2 |
| regulation of neuroblast proliferation | 1 | 1123.5× | 0.005 | LRRK2 |
| regulation of locomotion | 1 | 936.2× | 0.005 | LRRK2 |
| regulation of mitochondrial depolarization | 1 | 936.2× | 0.005 | LRRK2 |
| positive regulation of synaptic vesicle endocytosis | 1 | 936.2× | 0.005 | LRRK2 |
| obsolete negative regulation of protein targeting to mitochondrion | 1 | 936.2× | 0.005 | LRRK2 |
| intracellular distribution of mitochondria | 1 | 802.5× | 0.005 | LRRK2 |
| cellular response to manganese ion | 1 | 802.5× | 0.005 | LRRK2 |
| cellular response to dopamine | 1 | 802.5× | 0.005 | LRRK2 |
| obsolete regulation of lysosomal lumen pH | 1 | 702.2× | 0.005 | LRRK2 |
| regulation of ER to Golgi vesicle-mediated transport | 1 | 702.2× | 0.005 | LRRK2 |
| protein localization to endoplasmic reticulum exit site | 1 | 702.2× | 0.005 | LRRK2 |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2
Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| LRRK2 | PONATINIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| LRRK2 | 42 | 4 |
| GDF6 | 0 | 0 |
| PLEKHF2 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| PONATINIB | 4 | LRRK2 |
| FEDRATINIB | 4 | LRRK2 |
| AXITINIB | 4 | LRRK2 |
| RUXOLITINIB | 4 | LRRK2 |
| PALBOCICLIB | 4 | LRRK2 |
| ENTRECTINIB | 4 | LRRK2 |
| TOFACITINIB CITRATE | 4 | LRRK2 |
| TOFACITINIB | 4 | LRRK2 |
| VANDETANIB | 4 | LRRK2 |
| BOSUTINIB | 4 | LRRK2 |
| BRIGATINIB | 4 | LRRK2 |
| NINTEDANIB | 4 | LRRK2 |
| SUNITINIB | 4 | LRRK2 |
| ERLOTINIB | 4 | LRRK2 |
| MIDOSTAURIN | 4 | LRRK2 |
| DACTOLISIB | 3 | LRRK2 |
| ADENINE | 3 | LRRK2 |
| OLVEREMBATINIB | 3 | LRRK2 |
| CANERTINIB | 3 | LRRK2 |
| FASUDIL | 3 | LRRK2 |
| ALVOCIDIB | 3 | LRRK2 |
| ABIVERTINIB | 3 | LRRK2 |
| ALISERTIB | 3 | LRRK2 |
| DOVITINIB | 3 | LRRK2 |
| LESTAURTINIB | 3 | LRRK2 |
| RUBOXISTAURIN | 3 | LRRK2 |
| SU-014813 | 2 | LRRK2 |
| REBASTINIB | 2 | LRRK2 |
| CENISERTIB | 2 | LRRK2 |
| ADAVOSERTIB | 2 | LRRK2 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| LRRK2 | 809 | Binding:799, ADMET:7, Functional:3 |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| LRRK2 | 809 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 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.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| PONATINIB | 4 | LRRK2 |
| FEDRATINIB | 4 | LRRK2 |
| AXITINIB | 4 | LRRK2 |
| RUXOLITINIB | 4 | LRRK2 |
| PALBOCICLIB | 4 | LRRK2 |
| ENTRECTINIB | 4 | LRRK2 |
| TOFACITINIB CITRATE | 4 | LRRK2 |
| TOFACITINIB | 4 | LRRK2 |
| VANDETANIB | 4 | LRRK2 |
| BOSUTINIB | 4 | LRRK2 |
| BRIGATINIB | 4 | LRRK2 |
| NINTEDANIB | 4 | LRRK2 |
| SUNITINIB | 4 | LRRK2 |
| ERLOTINIB | 4 | LRRK2 |
| MIDOSTAURIN | 4 | LRRK2 |
| DACTOLISIB | 3 | LRRK2 |
| ADENINE | 3 | LRRK2 |
| OLVEREMBATINIB | 3 | LRRK2 |
| CANERTINIB | 3 | LRRK2 |
| FASUDIL | 3 | LRRK2 |
| ALVOCIDIB | 3 | LRRK2 |
| ABIVERTINIB | 3 | LRRK2 |
| ALISERTIB | 3 | LRRK2 |
| DOVITINIB | 3 | LRRK2 |
| LESTAURTINIB | 3 | LRRK2 |
| RUBOXISTAURIN | 3 | LRRK2 |
| SU-014813 | 2 | LRRK2 |
| REBASTINIB | 2 | LRRK2 |
| CENISERTIB | 2 | LRRK2 |
| ADAVOSERTIB | 2 | LRRK2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 1 | LRRK2 |
| 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 | GDF6, PLEKHF2 |
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) |
|---|---|---|
| GDF6 | 0 | — |
| PLEKHF2 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 2.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 2 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03741790 | Not specified | ACTIVE_NOT_RECRUITING | Airway Management of Pediatric Patients With Klippel-Feil Syndrome |
| NCT06489392 | Not specified | COMPLETED | Mehri Turki Webbed Neck Classification |