Klippel-Feil Syndrome

Mendelian MONDO:0001029 Pathograph 17 Show in embeddings browser Vertebral Malformation Disorders

Klippel-Feil syndrome (KFS) is a congenital axial-skeleton malformation defined by failure of segmentation of the cervical spine, producing fusion of two or more cervical vertebrae. The classic clinical triad is a short neck, low posterior hairline, and restricted neck mobility, often with scoliosis, Sprengel deformity, and cranial-base anomalies. It is an axial serial-homology disorder: the cervical vertebrae are serially repeated somite (sclerotome) derivatives, and KFS represents a failure of the somite-boundary / resegmentation program that normally separates adjacent vertebrae. Autosomal recessive KFS is caused by biallelic loss-of-function variants in MEOX1, a homeobox transcription factor with a nonredundant role in somite development and sclerotome polarity; autosomal dominant forms are caused by GDF6 and GDF3 (BMP-family) variants. KFS conforms to the axial-skeleton serial-homology module at its somite-boundary and vertebral-malsegmentation nodes.

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2
Inheritance
5
Pathophys.
9
Phenotypes
17
Pathograph
5
Genes
2
Medical Actions
4
Subtypes
🏷

Classifications

ISDS Skeletal Nosology
dysostoses with predominant vertebral and costal involvement
👪

Inheritance

2
Autosomal Recessive
Autosomal recessive KFS is caused by biallelic truncating variants in MEOX1. Autosomal dominant forms caused by GDF6 and GDF3 variants also occur.
Show evidence (1 reference)
PMID:24073994 SUPPORT Human Clinical
"Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait."
Documents autosomal recessive inheritance via a truncating MEOX1 variant in a consanguineous KFS family.
Autosomal Dominant
Two autosomal dominant KFS subtypes are recognized: KFS1 (OMIM 118100), caused by GDF6 mutations, and KFS3 (OMIM 613702), caused by GDF3 mutations. The MEOX1-related form (KFS2, OMIM 214300) is the autosomal recessive subtype.
Show evidence (1 reference)
PMID:24073994 SUPPORT Human Clinical
"Genetically, KFS has two subtypes with an autosomal dominant trait: KFS1 (OMIM #118100) is caused by mutations in the GDF6 gene, while KFS3 (OMIM #613702) harbors mutations in the GDF3 gene."
Documents the two autosomal dominant KFS subtypes and their causative genes (GDF6 in KFS1, GDF3 in KFS3).
◆

Subtypes

4
KFS1 (GDF6-related, autosomal dominant) MONDO:0007306
GDF6 hgnc:4221 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GDF6 (hgnc:4221). hgnc:4221 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The GDF6-related dominant form. Reported alleles include a recurrent missense change at a highly conserved residue, found with mirror movements, and an inversion breakpoint downstream of the gene, found with carpal, tarsal and vertebral fusions. GDF6 is expressed at the boundaries of the developing vertebrae, carpals and tarsals, which is why the fusion phenotype of this form extends beyond the cervical spine.
Show evidence (2 references)
PMID:18425797 SUPPORT PRIMARY RESULT Human Clinical
"Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with..."
Original report of GDF6 variants in familial and sporadic Klippel-Feil syndrome, and the source of the recurrent missense allele, the mirror movements and the downstream inversion breakpoint described in this row.
PMID:18425797 SUPPORT BACKGROUND Other
"GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc."
Expression at developing skeletal boundaries is why the GDF6-related form also produces carpal and tarsal fusions. The sentence names no organism or cohort, so no study type is graded.
KFS2 (MEOX1-related, autosomal recessive) MONDO:0008958
MEOX1 hgnc:7013 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MEOX1 (hgnc:7013). hgnc:7013 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The MEOX1-related recessive form, and the mechanism this entry's pathograph is built on. Biallelic truncating and frameshift MEOX1 alleles destabilise the transcript completely, and both reported families are consanguineous.
Show evidence (2 references)
PMID:23290072 SUPPORT PRIMARY RESULT Human Clinical
"We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript."
Maps isolated Klippel-Feil syndrome to MEOX1 at 17q21.31 and shows the frameshift allele destroys the transcript.
PMID:24073994 SUPPORT PRIMARY RESULT Human Clinical
"Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait."
Independent consanguineous family confirming biallelic MEOX1 truncation as a recessive cause, establishing this as a distinct subtype.
KFS3 (GDF3-related, autosomal dominant) MONDO:0013375
GDF3 hgnc:4218 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GDF3 (hgnc:4218). hgnc:4218 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The GDF3-related dominant form. The reported variants are pleiotropic, found in patients with ocular as well as skeletal Klippel-Feil anomalies, and one reported individual carried heterozygous alterations in both GDF3 and GDF6. Inhibiting the zebrafish co-orthologue of GDF3 reproduces the patient phenotypes.
Show evidence (2 references)
PMID:19864492 SUPPORT PRIMARY RESULT Human Clinical
"Multiple mis-sense variants were identified in patients with ocular and/or skeletal (Klippel-Feil) anomalies including one individual with heterozygous alterations in GDF3 and GDF6."
Original report of GDF3 variants in Klippel-Feil anomaly, and the source of the ocular pleiotropy and the co-occurring GDF6 allele noted here.
PMID:19864492 SUPPORT PRIMARY RESULT Model Organism
"Notably, inhibition of the zebrafish co-orthologue of GDF3 accurately recapitulates patient phenotypes."
Zebrafish knockdown of the GDF3 co-orthologue reproduces the patient phenotype, supporting the gene-disease relationship.
KFS4 (MYO18B-related, autosomal recessive, with myopathy) MONDO:0014689
MYO18B hgnc:18150 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYO18B (hgnc:18150). hgnc:18150 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The MYO18B-related recessive form, the one numbered subtype that is syndromic rather than isolated: biallelic MYO18B variants add myopathy, facial dysmorphism and short stature to the Klippel-Feil anomaly. The myopathy is universal and follows a slowly progressive or non-progressive course, affecting mainly the proximal lower-limb musculature. ClinGen's Congenital Myopathies expert panel reads the muscle phenotype as congenital myopathy rather than nemaline myopathy, with nemaline rods a secondary consequence, which is why this row binds a generic myopathy phenotype rather than a nemaline one.
Show evidence (4 references)
PMID:33179433 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature."
Names this concept as Klippel-Feil syndrome 4 and gives its gene, inheritance and the syndromic features beyond the vertebral anomaly.
PMID:33179433 SUPPORT PRIMARY RESULT Human Clinical
"All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb"
Seven-patient natural-history series establishing the myopathy as a universal feature and describing its distribution and course.
CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z SUPPORT Other
"MYO18B | HGNC:18150 | Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome | MONDO:0014689 | AR | Definitive"
ClinGen classifies the MYO18B relationship to this MONDO class as definitive with autosomal recessive inheritance, which is the term this row binds.
+ 1 more reference
⚙

Pathophysiology

5
MEOX1 Somite and Sclerotome Polarity Defect
Loss of MEOX1, a homeobox transcription factor with a nonredundant role in somite development, disrupts sclerotome polarity and the somite-boundary / resegmentation program in the paraxial mesoderm. KFS is the human phenotypic equivalent of the sclerotome polarity defect seen in Meox1-null mice. The dominant GDF6- and GDF3-related forms are carried on the separate BMP ligand node below, and the recessive MYO18B-related form on its own node.
Presomitic (Paraxial) Mesoderm Cell CL:0011007 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Presomitic (Paraxial) Mesoderm Cell, annotated with paraxial cell (CL:0011007). CL:0011007 is a cell type from the Cell Ontology.
MEOX1 hgnc:7013 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MEOX1 (hgnc:7013). hgnc:7013 is a gene from the HUGO Gene Nomenclature Committee.
Somitogenesis GO:0001756 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Somitogenesis (GO:0001756). GO:0001756 is a biological process from the Gene Ontology.
Downstream
Cervical Vertebral Fusion Failure of the somite-boundary / resegmentation program leaves adjacent cervical vertebrae fused.
Scoliosis The same somite-boundary defect produces curvature of the spine beyond the fused cervical segments.
Sprengel Anomaly Congenital elevation of the scapula accompanies the axial malformation in the MEOX1-related recessive form.
Show evidence (2 references)
PMID:23290072 SUPPORT Other
"This gene encodes a transcription factor with a well-established and nonredundant role in somite development"
Establishes MEOX1 as a transcription factor with a nonredundant role in somite development, the mechanism disrupted in KFS.
PMID:23290072 SUPPORT Model Organism
"KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice."
Identifies KFS as the human equivalent of the Meox1-null sclerotome polarity defect, the somite-boundary mechanism. Evidence source is MODEL_ORGANISM (mouse).
BMP Ligand Signaling Defect at Developing Vertebral Boundaries
The two dominant Klippel-Feil forms act through GDF6 and GDF3 rather than through the MEOX1 transcription factor. GDF6 is expressed at the boundaries of the developing vertebrae, carpals and tarsals, and losing it in mouse and Xenopus reproduces fusion at those boundaries together with anterior axial defects, so this node is a defect of skeletal boundary patterning rather than of the cervical spine alone. GDF3 is a paralogue investigated for the same reason, and its mutation perturbs BMP signalling.
GDF6 hgnc:4221 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF6 (hgnc:4221). hgnc:4221 is a gene from the HUGO Gene Nomenclature Committee. GDF3 hgnc:4218 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDF3 (hgnc:4218). hgnc:4218 is a gene from the HUGO Gene Nomenclature Committee.
BMP signaling pathway GO:0030509 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated BMP signaling pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology.
Downstream
Cervical Vertebral Fusion Perturbed BMP ligand signalling at the developing vertebral boundaries leaves adjacent cervical vertebrae fused.
Show evidence (4 references)
PMID:18425797 SUPPORT BACKGROUND Other
"GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc."
States where GDF6 acts, the developing skeletal boundaries this node is about. The sentence names no organism or cohort, so no study type is graded.
PMID:18425797 SUPPORT PRIMARY RESULT Model Organism
"GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, diversity, and variability of KFS."
Mouse knockout and Xenopus knockdown both produce the fusion and anterior axial phenotypes, which is the functional support for GDF6 acting at this node.
PMID:19864492 SUPPORT BACKGROUND Other
"Due to the contribution of bone morphogenetic proteins to such processes, the function of the paralogue Growth Differentiation Factor 3 was investigated."
Places GDF3 as a bone-morphogenetic-protein paralogue, which is why this node binds the BMP signalling pathway. The sentence states the study's rationale and names no organism or cohort, so no study type is graded.
+ 1 more reference
MYO18B Loss of Function
Biallelic loss-of-function MYO18B alleles are degraded by nonsense-mediated decay, leaving no functional myosin XVIIIB. ClinGen's expert-panel summary reads the disease mechanism as homozygous loss of function. The deficiency yields the Klippel-Feil anomaly together with a myopathy, facial dysmorphism and short stature, so it is the one Klippel-Feil lesion whose consequences reach outside the axial skeleton.
MYO18B hgnc:18150 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO18B (hgnc:18150). hgnc:18150 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Cervical Vertebral Fusion MYO18B deficiency yields the Klippel-Feil anomaly as well as the myopathy. No intermediate between the loss of myosin XVIIIB and the vertebral fusion is established.
Sarcomeric Myosin Filament Disorganization Loss of myosin XVIIIB disorganizes the sarcomeric myosin filaments of skeletal muscle fibers.
Ptosis Characteristic facial dysmorphism, ptosis among its features, accompanies the MYO18B-related form.
Bulbous Nose Characteristic facial dysmorphism, a bulbous nose among its features, accompanies the MYO18B-related form.
Short Stature Short stature is part of the MYO18B-related syndrome alongside the vertebral anomaly, the myopathy and the facial dysmorphism.
Show evidence (2 references)
PMID:25748484 SUPPORT PRIMARY RESULT Human Clinical
"There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay."
Patient transcript measurement showing the truncating allele is degraded, the loss-of-function state this node asserts.
CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z SUPPORT Other
"the overall mechanism for disease is postulated to be homozygous loss of function"
ClinGen's expert-panel statement of the disease mechanism, which is what this node records.
Sarcomeric Myosin Filament Disorganization
Muscle from individuals with biallelic MYO18B variants shows abnormal myosin filaments on electron microscopy with accompanying myopathic change. This node carries the muscle-fiber consequence of the loss of function, separately from the vertebral malsegmentation, because nothing reported connects the two.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Myofibril assembly GO:0030239 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Myofibril assembly (GO:0030239). GO:0030239 is a biological process from the Gene Ontology.
Downstream
Myopathy The disordered sarcomeric myosin presents clinically as a myopathy, universal in the MYO18B-related form.
Show evidence (1 reference)
PMID:25748484 SUPPORT PRIMARY RESULT Human Clinical
"Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes."
Muscle ultrastructure in an affected individual: the disordered myosin filaments and myopathic change this node binds.
Cervical Vertebral Fusion
The somite-boundary defect manifests as a segmentation malformation of the cervical spine: two or more cervical vertebrae fail to separate and remain fused, frequently accompanied by scoliosis, Sprengel deformity, and cranial-base malformations. Because the vertebrae are serially homologous somite derivatives, the malsegmentation typically involves multiple contiguous segments.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology. Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Embryonic Skeletal System Morphogenesis GO:0048704 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic Skeletal System Morphogenesis (GO:0048704). GO:0048704 is a biological process from the Gene Ontology.
Downstream
Short Neck The cervical segmentation malformation manifests clinically as a short neck with reduced mobility.
Low Posterior Hairline The cervical segmentation malformation manifests clinically as a low posterior hairline.
Show evidence (2 references)
PMID:23290072 SUPPORT Human Clinical
"Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine"
Defines KFS as a segmentation malformation of the cervical spine, the consequence of the somite-boundary defect.
PMID:24073994 SUPPORT Human Clinical
"they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity"
Documents the multi-segment axial malformation bundle — cervical fusion, scoliosis, cranial-base anomalies, and Sprengel deformity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Klippel-Feil Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Eye 1
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33179433 SUPPORT PRIMARY RESULT Human Clinical
"KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients."
Names ptosis among the characteristic dysmorphic features of this subtype and gives its frequency in the reported series.
Head and Neck 3
Short Neck HP:0000470 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short neck (HP:0000470). HP:0000470 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23290072 SUPPORT Human Clinical
"short neck with reduced mobility"
Short neck with reduced mobility is a defining feature of KFS.
Low Posterior Hairline HP:0002162 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low posterior hairline (HP:0002162). HP:0002162 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23290072 SUPPORT Human Clinical
"low posterior hairline"
A low posterior hairline is part of the classic KFS clinical triad.
Bulbous Nose HP:0000414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bulbous nose (HP:0000414). HP:0000414 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33179433 SUPPORT PRIMARY RESULT Human Clinical
"KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients."
Names the bulbous nose among the characteristic dysmorphic features of this subtype and gives its frequency in the reported series.
Musculoskeletal 4
Cervical Vertebral Fusion Cervical segmentation defect HP:0004632 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical segmentation defect (HP:0004632). HP:0004632 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24073994 SUPPORT Human Clinical
"fusion defects and numerical abnormalities in the cervical spine"
KFS is characterized by cervical vertebral fusion defects.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24073994 SUPPORT Human Clinical
"fusion defects and numerical abnormalities in the cervical spine, scoliosis"
Scoliosis is documented among the axial malformations in KFS.
Sprengel Anomaly HP:0000912 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sprengel anomaly (HP:0000912). HP:0000912 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24073994 SUPPORT Human Clinical
"malformations of the cranial base, and Sprengel's deformity"
Sprengel deformity is documented in the KFS phenotype.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33179433 SUPPORT PRIMARY RESULT Human Clinical
"All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb although hand involvement with distal arthrogryposis and abnormal interphalangeal creases was also observed."
Seven-patient natural-history series establishing the myopathy as universal in this subtype and describing its distribution and course.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33179433 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature."
Lists short stature among the features the MYO18B-related syndrome comprises.
🧬

Genetic Associations

5
MEOX1 (Biallelic loss-of-function variants)
Gene: MEOX1 hgnc:7013 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MEOX1 (hgnc:7013). hgnc:7013 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:23290072 SUPPORT PRIMARY RESULT Human Clinical
"We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript."
Establishes MEOX1 at 17q21.31 as the isolated-KFS locus and the frameshift allele as transcript-destroying, the loss-of-function mechanism recorded here.
PMID:24073994 SUPPORT PRIMARY RESULT Human Clinical
"Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status."
Second consanguineous family with a segregating nonsense MEOX1 allele, independent confirmation of the recessive gene-disease relationship.
GDF6 (Heterozygous variants and a downstream inversion breakpoint)
Gene: GDF6 hgnc:4221 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF6 (hgnc:4221). hgnc:4221 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:18425797 SUPPORT PRIMARY RESULT Human Clinical
"Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS"
Original report of GDF6 variants in familial and sporadic Klippel-Feil syndrome.
PMID:32278351 NO_EVIDENCE PRIMARY RESULT Human Clinical
"We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B."
A 37-patient exome cohort in which none of the four reported dominant or recessive KFS genes carried a pathogenic variant. It bears on diagnostic yield, which is the caveat in this note, and not on GDF6 causality, so it is graded NO_EVIDENCE for the causal claim this record makes.
GDF3 (Heterozygous missense variants)
Gene: GDF3 hgnc:4218 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDF3 (hgnc:4218). hgnc:4218 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:19864492 SUPPORT PRIMARY RESULT Human Clinical
"Multiple mis-sense variants were identified in patients with ocular and/or skeletal (Klippel-Feil) anomalies including one individual with heterozygous alterations in GDF3 and GDF6."
Original report of GDF3 variants in Klippel-Feil anomaly and the source of the co-occurring GDF6 allele noted here.
PMID:19864492 SUPPORT PRIMARY RESULT Other
"By demonstrating the pleiotropic effects of GDF3 mutation, these results extend the contribution of perturbed BMP signaling to human disease and potentially implicate multi-allelic inheritance of BMP variants in developmental disorders."
The study's own concluding synthesis over its biochemical and zebrafish analyses, which is why no single study type is graded here; it is the source of the multi-allelic possibility recorded in this note.
MYO18B (Biallelic loss-of-function variants)
Gene: MYO18B hgnc:18150 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYO18B (hgnc:18150). hgnc:18150 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:25748484 SUPPORT PRIMARY RESULT Human Clinical
"They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay."
Original report linking a truncating MYO18B allele, subject to nonsense-mediated decay, to this syndrome in two consanguineous families.
CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z SUPPORT Other
"MYO18B | HGNC:18150 | Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome | MONDO:0014689 | AR | Definitive"
ClinGen classifies the MYO18B relationship as definitive with autosomal recessive inheritance.
CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z SUPPORT Other
"Although heterozygous MYO18B missense variants were reported in patients affected by Klippel-Feil syndrome (PMID: 32278351), the overall mechanism for disease is postulated to be homozygous loss of function"
ClinGen's statement of the disease mechanism and of the heterozygous missense reports, both recorded in this note.
RIPPLY2 (Reported association)
Gene: RIPPLY2 hgnc:21390 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RIPPLY2 (hgnc:21390). hgnc:21390 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (1 reference)
PMID:32278351 SUPPORT PRIMARY RESULT Human Clinical
"We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B."
Lists RIPPLY2 among the five genes reported as associated with Klippel-Feil syndrome, which is the whole of the claim this record makes.
💊

Medical Actions

2
Physical Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Symptomatic management with physical therapy to maintain mobility and manage neck and back pain; the mainstay of KFS care is symptomatic.
Cervical Spine Surgical Stabilization
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Platform: Surgery
Surgical stabilization or decompression for cervical instability, neurologic compromise, or significant scoliosis.
📊

Prevalence

1
General
Unknown Unknown
KFS is rare and mostly sporadic; familial cases (including the autosomal recessive MEOX1 subtype) are uncommon and described in consanguineous families. Formal population-prevalence estimates are not well established.
{ }

Source YAML

click to show 
name: Klippel-Feil Syndrome
creation_date: "2026-06-29T00:00:00Z"
category: Mendelian
description: >-
  Klippel-Feil syndrome (KFS) is a congenital axial-skeleton malformation
  defined by failure of segmentation of the cervical spine, producing fusion of
  two or more cervical vertebrae. The classic clinical triad is a short neck,
  low posterior hairline, and restricted neck mobility, often with scoliosis,
  Sprengel deformity, and cranial-base anomalies. It is an axial serial-homology
  disorder: the cervical vertebrae are serially repeated somite (sclerotome)
  derivatives, and KFS represents a failure of the somite-boundary / resegmentation
  program that normally separates adjacent vertebrae. Autosomal recessive KFS is
  caused by biallelic loss-of-function variants in MEOX1, a homeobox
  transcription factor with a nonredundant role in somite development and
  sclerotome polarity; autosomal dominant forms are caused by GDF6 and GDF3
  (BMP-family) variants. KFS conforms to the axial-skeleton serial-homology
  module at its somite-boundary and vertebral-malsegmentation nodes.
disease_term:
  preferred_term: Klippel-Feil syndrome
  term:
    id: MONDO:0001029
    label: Klippel-Feil syndrome
parents:
- Vertebral Malformation Disorders
has_subtypes:
- name: KFS1
  display_name: KFS1 (GDF6-related, autosomal dominant)
  subtype_term:
    preferred_term: GDF6-related Klippel-Feil syndrome
    term:
      id: MONDO:0007306
      label: Klippel-Feil syndrome 1, autosomal dominant
  genes:
  - preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The GDF6-related dominant form. Reported alleles include a recurrent missense
    change at a highly conserved residue, found with mirror movements, and an
    inversion breakpoint downstream of the gene, found with carpal, tarsal and
    vertebral fusions. GDF6 is expressed at the boundaries of the developing
    vertebrae, carpals and tarsals, which is why the fusion phenotype of this form
    extends beyond the cervical spine.
  evidence:
  - reference: PMID:18425797
    reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here we report mutations at the GDF6 gene locus in familial and sporadic
      cases of KFS including the recurrent missense mutation of an extremely
      conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements
      and an inversion breakpoint downstream of the gene in association with
      carpal, tarsal, and vertebral fusions.
    explanation: >-
      Original report of GDF6 variants in familial and sporadic Klippel-Feil
      syndrome, and the source of the recurrent missense allele, the mirror
      movements and the downstream inversion breakpoint described in this row.
  - reference: PMID:18425797
    reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      GDF6 is expressed at the boundaries of the developing carpals, tarsals, and
      vertebrae and within the adult vertebral disc.
    explanation: >-
      Expression at developing skeletal boundaries is why the GDF6-related form
      also produces carpal and tarsal fusions. The sentence names no organism or
      cohort, so no study type is graded.
- name: KFS2
  display_name: KFS2 (MEOX1-related, autosomal recessive)
  subtype_term:
    preferred_term: MEOX1-related Klippel-Feil syndrome
    term:
      id: MONDO:0008958
      label: Klippel-Feil syndrome 2, autosomal recessive
  genes:
  - preferred_term: MEOX1
    term:
      id: hgnc:7013
      label: MEOX1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    The MEOX1-related recessive form, and the mechanism this entry's pathograph is
    built on. Biallelic truncating and frameshift MEOX1 alleles destabilise the
    transcript completely, and both reported families are consanguineous.
  evidence:
  - reference: PMID:23290072
    reference_title: "Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We describe a multiplex consanguineous family in which isolated KFS maps to
      a single 17q21.31 locus that harbors a homozygous frameshift deletion in
      MEOX1; this deletion results in complete instability of the transcript.
    explanation: >-
      Maps isolated Klippel-Feil syndrome to MEOX1 at 17q21.31 and shows the
      frameshift allele destroys the transcript.
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait.
    explanation: >-
      Independent consanguineous family confirming biallelic MEOX1 truncation as a
      recessive cause, establishing this as a distinct subtype.
- name: KFS3
  display_name: KFS3 (GDF3-related, autosomal dominant)
  subtype_term:
    preferred_term: GDF3-related Klippel-Feil syndrome
    term:
      id: MONDO:0013375
      label: Klippel-Feil syndrome 3, autosomal dominant
  genes:
  - preferred_term: GDF3
    term:
      id: hgnc:4218
      label: GDF3
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    The GDF3-related dominant form. The reported variants are pleiotropic, found
    in patients with ocular as well as skeletal Klippel-Feil anomalies, and one
    reported individual carried heterozygous alterations in both GDF3 and GDF6.
    Inhibiting the zebrafish co-orthologue of GDF3 reproduces the patient
    phenotypes.
  evidence:
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Multiple mis-sense variants were identified in patients with ocular and/or
      skeletal (Klippel-Feil) anomalies including one individual with
      heterozygous alterations in GDF3 and GDF6.
    explanation: >-
      Original report of GDF3 variants in Klippel-Feil anomaly, and the source of
      the ocular pleiotropy and the co-occurring GDF6 allele noted here.
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Notably, inhibition of the zebrafish co-orthologue of GDF3 accurately recapitulates patient phenotypes.
    explanation: >-
      Zebrafish knockdown of the GDF3 co-orthologue reproduces the patient
      phenotype, supporting the gene-disease relationship.
- name: KFS4
  display_name: KFS4 (MYO18B-related, autosomal recessive, with myopathy)
  subtype_term:
    preferred_term: MYO18B-related Klippel-Feil syndrome with myopathy and facial dysmorphism
    term:
      id: MONDO:0014689
      label: Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
  genes:
  - preferred_term: MYO18B
    term:
      id: hgnc:18150
      label: MYO18B
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    The MYO18B-related recessive form, the one numbered subtype that is
    syndromic rather than isolated: biallelic MYO18B variants add myopathy, facial
    dysmorphism and short stature to the Klippel-Feil anomaly. The myopathy is
    universal and follows a slowly progressive or non-progressive course,
    affecting mainly the proximal lower-limb musculature. ClinGen's Congenital
    Myopathies expert panel reads the muscle phenotype as congenital myopathy
    rather than nemaline myopathy, with nemaline rods a secondary consequence,
    which is why this row binds a generic myopathy phenotype rather than a
    nemaline one.
  evidence:
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive
      disorder caused by biallelic pathogenic variants in MYO18B and comprises, in
      addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial
      dysmorphism, and short stature.
    explanation: >-
      Names this concept as Klippel-Feil syndrome 4 and gives its gene, inheritance
      and the syndromic features beyond the vertebral anomaly.
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      All patients had myopathy of varying severity that followed a slowly
      progressive or non-progressive course, affecting primarily the proximal
      musculature of the lower limb
    explanation: >-
      Seven-patient natural-history series establishing the myopathy as a universal
      feature and describing its distribution and course.
  - reference: CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z
    reference_title: "MYO18B / Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYO18B | HGNC:18150 | Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome | MONDO:0014689 | AR | Definitive"
    explanation: >-
      ClinGen classifies the MYO18B relationship to this MONDO class as definitive
      with autosomal recessive inheritance, which is the term this row binds.
  - reference: CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z
    reference_title: "MYO18B / Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      both clinical and functional evidence to date suggest variants in MYO18B are
      associated with congenital myopathy, not nemaline myopathy, although nemaline
      rods may occur as a secondary consequence of disease
    explanation: >-
      ClinGen's expert-panel reading of the muscle phenotype, which this row
      follows in binding a generic myopathy rather than a nemaline-myopathy term.
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive KFS is caused by biallelic truncating variants in MEOX1.
    Autosomal dominant forms caused by GDF6 and GDF3 variants also occur.
  evidence:
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait.
    explanation: >-
      Documents autosomal recessive inheritance via a truncating MEOX1 variant in
      a consanguineous KFS family.
- name: Autosomal Dominant
  description: >-
    Two autosomal dominant KFS subtypes are recognized: KFS1 (OMIM 118100),
    caused by GDF6 mutations, and KFS3 (OMIM 613702), caused by GDF3 mutations.
    The MEOX1-related form (KFS2, OMIM 214300) is the autosomal recessive
    subtype.
  evidence:
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetically, KFS has two subtypes with an autosomal dominant trait: KFS1 (OMIM #118100) is caused by mutations in the GDF6 gene, while KFS3 (OMIM #613702) harbors mutations in the GDF3 gene."
    explanation: >-
      Documents the two autosomal dominant KFS subtypes and their causative
      genes (GDF6 in KFS1, GDF3 in KFS3).
classifications:
  isds_skeletal_category:
  - classification_value: dysostoses_with_predominant_vertebral_and_costal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 35 "Dysostoses with
      predominant vertebral with and without costal involvement"; listed as
      "Klippel-Feil syndrome".
prevalence:
- population: General
  prevalence_class: UNKNOWN
  percentage: Unknown
  notes: >-
    KFS is rare and mostly sporadic; familial cases (including the autosomal
    recessive MEOX1 subtype) are uncommon and described in consanguineous
    families. Formal population-prevalence estimates are not well established.
pathophysiology:
- name: MEOX1 Somite and Sclerotome Polarity Defect
  conforms_to: "axial_segmentation_serial_homology#Disrupted Somite Boundary Formation"
  description: >-
    Loss of MEOX1, a homeobox transcription factor with a nonredundant role in
    somite development, disrupts sclerotome polarity and the somite-boundary /
    resegmentation program in the paraxial mesoderm. KFS is the human phenotypic
    equivalent of the sclerotome polarity defect seen in Meox1-null mice. The
    dominant GDF6- and GDF3-related forms are carried on the separate BMP ligand
    node below, and the recessive MYO18B-related form on its own node.
  role: central_effector
  genes:
  - preferred_term: MEOX1
    term:
      id: hgnc:7013
      label: MEOX1
  cell_types:
  - preferred_term: Presomitic (Paraxial) Mesoderm Cell
    term:
      id: CL:0011007
      label: paraxial cell
  biological_processes:
  - preferred_term: Somitogenesis
    term:
      id: GO:0001756
      label: somitogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23290072
    reference_title: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This gene encodes a transcription factor with a well-established and nonredundant role in somite development
    explanation: >-
      Establishes MEOX1 as a transcription factor with a nonredundant role in
      somite development, the mechanism disrupted in KFS.
  - reference: PMID:23290072
    reference_title: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.
    explanation: >-
      Identifies KFS as the human equivalent of the Meox1-null sclerotome
      polarity defect, the somite-boundary mechanism. Evidence source is
      MODEL_ORGANISM (mouse).
  downstream:
  - target: Cervical Vertebral Fusion
    description: Failure of the somite-boundary / resegmentation program leaves adjacent cervical vertebrae fused.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of sclerotome resegmentation between adjacent somites
  - target: Scoliosis
    description: >-
      The same somite-boundary defect produces curvature of the spine beyond the
      fused cervical segments.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24073994
      reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Radiological examinations revealed that they carry fusion defects and
        numerical abnormalities in the cervical spine, scoliosis, malformations of
        the cranial base, and Sprengel's deformity.
      explanation: >-
        Radiological findings in the family carrying the segregating nonsense MEOX1
        allele, which is why this malformation is attributed to the MEOX1 defect
        rather than only co-observed with the cervical fusion.
  - target: Sprengel Anomaly
    description: >-
      Congenital elevation of the scapula accompanies the axial malformation in the
      MEOX1-related recessive form.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24073994
      reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Radiological examinations revealed that they carry fusion defects and
        numerical abnormalities in the cervical spine, scoliosis, malformations of
        the cranial base, and Sprengel's deformity.
      explanation: >-
        Radiological findings in the family carrying the segregating nonsense MEOX1
        allele, which is why this malformation is attributed to the MEOX1 defect
        rather than only co-observed with the cervical fusion.
- name: BMP Ligand Signaling Defect at Developing Vertebral Boundaries
  description: >-
    The two dominant Klippel-Feil forms act through GDF6 and GDF3 rather than
    through the MEOX1 transcription factor. GDF6 is expressed at the boundaries of
    the developing vertebrae, carpals and tarsals, and losing it in mouse and
    Xenopus reproduces fusion at those boundaries together with anterior axial
    defects, so this node is a defect of skeletal boundary patterning rather than
    of the cervical spine alone. GDF3 is a paralogue investigated for the same
    reason, and its mutation perturbs BMP signalling.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  - preferred_term: GDF3
    term:
      id: hgnc:4218
      label: GDF3
  biological_processes:
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:18425797
    reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      GDF6 is expressed at the boundaries of the developing carpals, tarsals, and
      vertebrae and within the adult vertebral disc.
    explanation: >-
      States where GDF6 acts, the developing skeletal boundaries this node is
      about. The sentence names no organism or cohort, so no study type is graded.
  - reference: PMID:18425797
    reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      GDF6 knockout mice are best distinguished by fusion of carpals and tarsals
      and GDF6 knockdown in Xenopus results in a high incidence of anterior axial
      defects consistent with a role for GDF6 in the etiology, diversity, and
      variability of KFS.
    explanation: >-
      Mouse knockout and Xenopus knockdown both produce the fusion and anterior
      axial phenotypes, which is the functional support for GDF6 acting at this
      node.
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Due to the contribution of bone morphogenetic proteins to such processes, the
      function of the paralogue Growth Differentiation Factor 3 was investigated.
    explanation: >-
      Places GDF3 as a bone-morphogenetic-protein paralogue, which is why this node
      binds the BMP signalling pathway. The sentence states the study's rationale
      and names no organism or cohort, so no study type is graded.
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      By demonstrating the pleiotropic effects of GDF3 mutation, these results
      extend the contribution of perturbed BMP signaling to human disease and
      potentially implicate multi-allelic inheritance of BMP variants in
      developmental disorders.
    explanation: >-
      The study's own concluding synthesis over its biochemical and zebrafish
      analyses, attributing the phenotypes to perturbed BMP signalling; no single
      study type applies to the sentence, hence OTHER.
  downstream:
  - target: Cervical Vertebral Fusion
    description: >-
      Perturbed BMP ligand signalling at the developing vertebral boundaries
      leaves adjacent cervical vertebrae fused.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18425797
      reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        GDF6 knockout mice are best distinguished by fusion of carpals and tarsals
        and GDF6 knockdown in Xenopus results in a high incidence of anterior axial
        defects consistent with a role for GDF6 in the etiology, diversity, and
        variability of KFS.
      explanation: >-
        Loss of GDF6 in two model organisms produces skeletal fusion and anterior
        axial defects, the consequence this edge asserts.
- name: MYO18B Loss of Function
  description: >-
    Biallelic loss-of-function MYO18B alleles are degraded by nonsense-mediated
    decay, leaving no functional myosin XVIIIB. ClinGen's expert-panel summary
    reads the disease mechanism as homozygous loss of function. The deficiency
    yields the Klippel-Feil anomaly together with a myopathy, facial dysmorphism
    and short stature, so it is the one Klippel-Feil lesion whose consequences
    reach outside the axial skeleton.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: MYO18B
    term:
      id: hgnc:18150
      label: MYO18B
  evidence:
  - reference: PMID:25748484
    reference_title: "A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      There was virtually complete loss of the transcript in peripheral blood,
      indicative of nonsense-mediated decay.
    explanation: >-
      Patient transcript measurement showing the truncating allele is degraded, the
      loss-of-function state this node asserts.
  - reference: CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z
    reference_title: "MYO18B / Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the overall mechanism for disease is postulated to be homozygous loss of
      function
    explanation: >-
      ClinGen's expert-panel statement of the disease mechanism, which is what this
      node records.
  downstream:
  - target: Cervical Vertebral Fusion
    description: >-
      MYO18B deficiency yields the Klippel-Feil anomaly as well as the myopathy. No
      intermediate between the loss of myosin XVIIIB and the vertebral fusion is
      established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25748484
      reference_title: "A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Deficiency of MYO18B is linked to a novel developmental disorder which
        combines KFA with myopathy.
      explanation: >-
        Attributes the Klippel-Feil anomaly, alongside the myopathy, to MYO18B
        deficiency, without naming an intervening mechanism.
  - target: Sarcomeric Myosin Filament Disorganization
    description: >-
      Loss of myosin XVIIIB disorganizes the sarcomeric myosin filaments of skeletal
      muscle fibers.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25748484
      reference_title: "A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Electron microscopy of muscle confirms abnormal myosin filaments with
        accompanying myopathic changes.
      explanation: >-
        Muscle ultrastructure in an affected individual, the filament disorder this
        edge reaches.
  - target: Ptosis
    description: >-
      Characteristic facial dysmorphism, ptosis among its features, accompanies the
      MYO18B-related form.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33179433
      reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        KFA and characteristic dysmorphic features, including ptosis and bulbous
        nose, were observed in all but two patients.
      explanation: >-
        Names ptosis among the dysmorphic features observed in this cohort of
        individuals with biallelic MYO18B variants.
  - target: Bulbous Nose
    description: >-
      Characteristic facial dysmorphism, a bulbous nose among its features,
      accompanies the MYO18B-related form.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33179433
      reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        KFA and characteristic dysmorphic features, including ptosis and bulbous
        nose, were observed in all but two patients.
      explanation: >-
        Names the bulbous nose among the dysmorphic features observed in this cohort
        of individuals with biallelic MYO18B variants.
  - target: Short Stature
    description: >-
      Short stature is part of the MYO18B-related syndrome alongside the vertebral
      anomaly, the myopathy and the facial dysmorphism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33179433
      reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive
        disorder caused by biallelic pathogenic variants in MYO18B and comprises, in
        addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial
        dysmorphism, and short stature.
      explanation: >-
        Lists short stature among the features the MYO18B-related syndrome comprises.
- name: Sarcomeric Myosin Filament Disorganization
  description: >-
    Muscle from individuals with biallelic MYO18B variants shows abnormal myosin
    filaments on electron microscopy with accompanying myopathic change. This node
    carries the muscle-fiber consequence of the loss of function, separately from
    the vertebral malsegmentation, because nothing reported connects the two.
  biological_scale: CELLULAR
  role: effector
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Myofibril assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25748484
    reference_title: "A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Electron microscopy of muscle confirms abnormal myosin filaments with
      accompanying myopathic changes.
    explanation: >-
      Muscle ultrastructure in an affected individual: the disordered myosin
      filaments and myopathic change this node binds.
  downstream:
  - target: Myopathy
    description: >-
      The disordered sarcomeric myosin presents clinically as a myopathy, universal
      in the MYO18B-related form.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33179433
      reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        All patients had myopathy of varying severity that followed a slowly
        progressive or non-progressive course, affecting primarily the proximal
        musculature of the lower limb
      explanation: >-
        Seven-patient series in which every individual with biallelic MYO18B
        variants had a myopathy, the phenotype this edge reaches.
- name: Cervical Vertebral Fusion
  conforms_to: "axial_segmentation_serial_homology#Vertebral and Costal Malsegmentation"
  description: >-
    The somite-boundary defect manifests as a segmentation malformation of the
    cervical spine: two or more cervical vertebrae fail to separate and remain
    fused, frequently accompanied by scoliosis, Sprengel deformity, and
    cranial-base malformations. Because the vertebrae are serially homologous
    somite derivatives, the malsegmentation typically involves multiple
    contiguous segments.
  role: consequence
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Embryonic Skeletal System Morphogenesis
    term:
      id: GO:0048704
      label: embryonic skeletal system morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23290072
    reference_title: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine
    explanation: >-
      Defines KFS as a segmentation malformation of the cervical spine, the
      consequence of the somite-boundary defect.
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity
    explanation: >-
      Documents the multi-segment axial malformation bundle — cervical fusion,
      scoliosis, cranial-base anomalies, and Sprengel deformity.
  downstream:
  - target: Short Neck
    description: >-
      The cervical segmentation malformation manifests clinically as a short neck
      with reduced mobility.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23290072
      reference_title: "Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical
        spine; clinically, it manifests as a short neck with reduced mobility and a
        low posterior hairline.
      explanation: >-
        States that the cervical segmentation malformation is what manifests
        clinically as the short neck and low posterior hairline, which is the edge
        asserted here.
  - target: Low Posterior Hairline
    description: >-
      The cervical segmentation malformation manifests clinically as a low
      posterior hairline.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23290072
      reference_title: "Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical
        spine; clinically, it manifests as a short neck with reduced mobility and a
        low posterior hairline.
      explanation: >-
        States that the cervical segmentation malformation is what manifests
        clinically as the short neck and low posterior hairline, which is the edge
        asserted here.
genetic:
- name: MEOX1
  gene_term:
    preferred_term: MEOX1
    term:
      id: hgnc:7013
      label: MEOX1
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  subtype: KFS2
  notes: >-
    Both reported families are consanguineous and both alleles destroy the
    transcript, one by frameshift and one by nonsense, so the recessive mechanism
    is complete loss of MEOX1 function. The locus maps to 17q21.31.
  evidence:
  - reference: PMID:23290072
    reference_title: "Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We describe a multiplex consanguineous family in which isolated KFS maps to
      a single 17q21.31 locus that harbors a homozygous frameshift deletion in
      MEOX1; this deletion results in complete instability of the transcript.
    explanation: >-
      Establishes MEOX1 at 17q21.31 as the isolated-KFS locus and the frameshift
      allele as transcript-destroying, the loss-of-function mechanism recorded here.
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene,
      which is segregated based on pedigree status.
    explanation: >-
      Second consanguineous family with a segregating nonsense MEOX1 allele,
      independent confirmation of the recessive gene-disease relationship.
- name: GDF6
  gene_term:
    preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  association: Heterozygous variants and a downstream inversion breakpoint
  relationship_type: CAUSATIVE
  subtype: KFS1
  notes: >-
    Reported in both familial and sporadic Klippel-Feil syndrome, with a recurrent
    missense allele at a highly conserved residue and, separately, an inversion
    breakpoint downstream of the gene. Diagnostic yield is low: a whole-exome
    study of 37 consecutively recruited Chinese patients with Klippel-Feil
    syndrome found no pathogenic variant in GDF6, MEOX1, GDF3 or RIPPLY2 and only
    variants of uncertain significance in MYO18B.
  evidence:
  - reference: PMID:18425797
    reference_title: Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Here we report mutations at the GDF6 gene locus in familial and sporadic
      cases of KFS
    explanation: >-
      Original report of GDF6 variants in familial and sporadic Klippel-Feil
      syndrome.
  - reference: PMID:32278351
    reference_title: The mutational burden and oligogenic inheritance in Klippel-Feil syndrome.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We primarily examined rare variants in five reported genes (GDF6, MEOX1,
      GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of
      uncertain significance in MYO18B.
    explanation: >-
      A 37-patient exome cohort in which none of the four reported dominant or
      recessive KFS genes carried a pathogenic variant. It bears on diagnostic
      yield, which is the caveat in this note, and not on GDF6 causality, so it is
      graded NO_EVIDENCE for the causal claim this record makes.
- name: GDF3
  gene_term:
    preferred_term: GDF3
    term:
      id: hgnc:4218
      label: GDF3
  association: Heterozygous missense variants
  relationship_type: CAUSATIVE
  subtype: KFS3
  notes: >-
    A paralogue of GDF6 in the same BMP family. Reported variants are pleiotropic
    across ocular and skeletal phenotypes, and one reported individual carried
    heterozygous alterations in GDF3 and GDF6 together, so a multi-allelic
    contribution of BMP variants has been raised for this form.
  evidence:
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Multiple mis-sense variants were identified in patients with ocular and/or
      skeletal (Klippel-Feil) anomalies including one individual with
      heterozygous alterations in GDF3 and GDF6.
    explanation: >-
      Original report of GDF3 variants in Klippel-Feil anomaly and the source of
      the co-occurring GDF6 allele noted here.
  - reference: PMID:19864492
    reference_title: Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      By demonstrating the pleiotropic effects of GDF3 mutation, these results
      extend the contribution of perturbed BMP signaling to human disease and
      potentially implicate multi-allelic inheritance of BMP variants in
      developmental disorders.
    explanation: >-
      The study's own concluding synthesis over its biochemical and zebrafish
      analyses, which is why no single study type is graded here; it is the source
      of the multi-allelic possibility recorded in this note.
- name: MYO18B
  gene_term:
    preferred_term: MYO18B
    term:
      id: hgnc:18150
      label: MYO18B
  association: Biallelic loss-of-function variants
  relationship_type: CAUSATIVE
  subtype: KFS4
  notes: >-
    The one Klippel-Feil gene with a ClinGen gene-disease validity assertion:
    Definitive, autosomal recessive, curated against MONDO:0014689 by the
    Congenital Myopathies expert panel in 2025. ClinGen's summary attributes the
    disease mechanism to homozygous loss of function and notes that heterozygous
    missense variants have also been reported in Klippel-Feil syndrome. MEOX1,
    GDF6 and GDF3 have no ClinGen gene-disease validity row for Klippel-Feil
    syndrome in the committed 2026-08-13 snapshot, so their support here rests on
    primary literature.
  evidence:
  - reference: PMID:25748484
    reference_title: "A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in MYO18B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      They shared a single founder autozygous interval in which whole exome
      sequencing revealed a truncating mutation in MYO18B. There was virtually
      complete loss of the transcript in peripheral blood, indicative of
      nonsense-mediated decay.
    explanation: >-
      Original report linking a truncating MYO18B allele, subject to
      nonsense-mediated decay, to this syndrome in two consanguineous families.
  - reference: CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z
    reference_title: "MYO18B / Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYO18B | HGNC:18150 | Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome | MONDO:0014689 | AR | Definitive"
    explanation: >-
      ClinGen classifies the MYO18B relationship as definitive with autosomal
      recessive inheritance.
  - reference: CGGV:assertion_00998e50-dd3f-4bfa-8500-34d34980d5c8-2025-04-28T160000.000Z
    reference_title: "MYO18B / Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although heterozygous MYO18B missense variants were reported in patients
      affected by Klippel-Feil syndrome (PMID: 32278351), the overall mechanism for
      disease is postulated to be homozygous loss of function
    explanation: >-
      ClinGen's statement of the disease mechanism and of the heterozygous
      missense reports, both recorded in this note.
- name: RIPPLY2
  gene_term:
    preferred_term: RIPPLY2
    term:
      id: hgnc:21390
      label: RIPPLY2
  association: Reported association
  relationship_type: UNKNOWN
  notes: >-
    RIPPLY2 is the fifth gene named in the literature as associated with
    Klippel-Feil syndrome alongside GDF6, MEOX1, GDF3 and MYO18B, and MONDO
    defines no numbered Klippel-Feil subtype on it. It is recorded here as a
    reported association only: no RIPPLY2-specific mechanism, subtype row or
    pathophysiology node is asserted, because the support found for it is a
    background citation rather than a primary series read for this entry.
  evidence:
  - reference: PMID:32278351
    reference_title: The mutational burden and oligogenic inheritance in Klippel-Feil syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We primarily examined rare variants in five reported genes (GDF6, MEOX1,
      GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of
      uncertain significance in MYO18B.
    explanation: >-
      Lists RIPPLY2 among the five genes reported as associated with Klippel-Feil
      syndrome, which is the whole of the claim this record makes.
phenotypes:
- name: Cervical Vertebral Fusion
  description: Fusion of two or more cervical vertebrae from failed segmentation.
  phenotype_term:
    preferred_term: Cervical segmentation defect
    term:
      id: HP:0004632
      label: Cervical segmentation defect
  evidence:
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fusion defects and numerical abnormalities in the cervical spine
    explanation: KFS is characterized by cervical vertebral fusion defects.
- name: Short Neck
  description: A short neck with reduced mobility, part of the classic KFS triad.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:23290072
    reference_title: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: short neck with reduced mobility
    explanation: Short neck with reduced mobility is a defining feature of KFS.
- name: Low Posterior Hairline
  description: A low posterior hairline, part of the classic KFS triad.
  phenotype_term:
    preferred_term: Low posterior hairline
    term:
      id: HP:0002162
      label: Low posterior hairline
  evidence:
  - reference: PMID:23290072
    reference_title: Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low posterior hairline
    explanation: A low posterior hairline is part of the classic KFS clinical triad.
- name: Scoliosis
  description: Scoliosis frequently accompanies the cervical segmentation defect.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fusion defects and numerical abnormalities in the cervical spine, scoliosis
    explanation: Scoliosis is documented among the axial malformations in KFS.
- name: Sprengel Anomaly
  description: Congenital elevation of the scapula (Sprengel deformity) is a recognized association.
  phenotype_term:
    preferred_term: Sprengel anomaly
    term:
      id: HP:0000912
      label: Sprengel anomaly
  evidence:
  - reference: PMID:24073994
    reference_title: Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: malformations of the cranial base, and Sprengel's deformity
    explanation: Sprengel deformity is documented in the KFS phenotype.
- name: Myopathy
  subtype: KFS4
  description: >-
    Myopathy of varying severity, universal in the MYO18B-related recessive form.
    It follows a slowly progressive or non-progressive course and affects mainly
    the proximal musculature of the lower limb; distal arthrogryposis and abnormal
    interphalangeal creases are also reported.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      All patients had myopathy of varying severity that followed a slowly
      progressive or non-progressive course, affecting primarily the proximal
      musculature of the lower limb although hand involvement with distal
      arthrogryposis and abnormal interphalangeal creases was also observed.
    explanation: >-
      Seven-patient natural-history series establishing the myopathy as universal in
      this subtype and describing its distribution and course.
- name: Ptosis
  subtype: KFS4
  description: >-
    Ptosis, one of the characteristic dysmorphic features of the MYO18B-related
    form, observed in all but two of the seven reported patients.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      KFA and characteristic dysmorphic features, including ptosis and bulbous
      nose, were observed in all but two patients.
    explanation: >-
      Names ptosis among the characteristic dysmorphic features of this subtype and
      gives its frequency in the reported series.
- name: Bulbous Nose
  subtype: KFS4
  description: >-
    A bulbous nose, one of the characteristic dysmorphic features of the
    MYO18B-related form, observed in all but two of the seven reported patients.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      KFA and characteristic dysmorphic features, including ptosis and bulbous
      nose, were observed in all but two patients.
    explanation: >-
      Names the bulbous nose among the characteristic dysmorphic features of this
      subtype and gives its frequency in the reported series.
- name: Short Stature
  subtype: KFS4
  description: >-
    Short stature is one of the features the MYO18B-related syndrome comprises,
    alongside the Klippel-Feil anomaly, the myopathy and the facial dysmorphism.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33179433
    reference_title: Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive
      disorder caused by biallelic pathogenic variants in MYO18B and comprises, in
      addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial
      dysmorphism, and short stature.
    explanation: >-
      Lists short stature among the features the MYO18B-related syndrome comprises.
treatments:
- name: Physical Therapy
  description: >-
    Symptomatic management with physical therapy to maintain mobility and manage
    neck and back pain; the mainstay of KFS care is symptomatic.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Cervical Spine Surgical Stabilization
  description: >-
    Surgical stabilization or decompression for cervical instability, neurologic
    compromise, or significant scoliosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure