KIF5B-Related Kyphomelic Dysplasia

Mendelian Pathograph 4 Show in embeddings browser hereditary disease

KIF5B-related kyphomelic dysplasia is a dominantly inherited bent-bone skeletal dysplasia caused by de novo heterozygous variants in KIF5B, which encodes the kinesin-1 heavy chain — the motor subunit that carries cargo along microtubules toward the cell periphery. It is one of two molecularly defined forms of kyphomelic dysplasia, the other being the recessive CCN2-related form. All reported variants alter conserved residues in or near the ATPase-related motifs of the catalytic motor domain, implicating motor function specifically rather than kinesin abundance. Affected individuals have sharp angulation of the femora and humeri, distinctive facial features and neonatal respiratory distress; postnatal osteoporosis with subsequent fractures and optic atrophy are features that distinguish this form from the CCN2 one. Because kinesins carry cargo in every cell type, this disorder also sits within the broader group of kinesinopathies.

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1
Inheritance
3
Pathophys.
6
Phenotypes
1
Gaps
4
Pathograph
1
Genes
1
Differentials
2
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ISDS Skeletal Nosology
bent bone dysplasia
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
All four reported individuals carried de novo heterozygous KIF5B variants, establishing dominant inheritance arising sporadically. This is the clearest single discriminator from the CCN2-related form, which is recessive and was ascertained through consanguineous families with sibling recurrence.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val)."
Documents de novo heterozygous genotypes in all four reported individuals.
?

Discussions and Knowledge Gaps

1
Do KIF5B kyphomelic dysplasia variants actually impair kinesin-1 dependent transport, and which cargo in which cell type accounts for the skeletal phenotype?
KNOWLEDGE GAP OPEN kif5b_kd_transport_step_unevidenced
Attached to
pathophysiology#Disrupted Kinesin-1 Dependent Intracellular Transport
This is why the central node of this entry is PROVISIONAL. The variants' location in the ATPase motifs of the motor domain is a strong argument that motor function is impaired, but no motility, cargo-delivery or patient-cell transport assay has been reported for these alleles. Nor is it known why a ubiquitously expressed motor produces a phenotype concentrated in bone, which is the same tissue-specificity puzzle that recurs across the kinesinopathies. The osteoporosis-with-fractures arm makes the question sharper: bone fragility appearing after birth suggests an ongoing defect in osteoblast or osteoclast function rather than a purely developmental patterning error, and those are different cargo problems.
Proposed experiments
Single-molecule motility assays of the patient alleles
exp_kif5b_kd_single_molecule_motility
Purify recombinant KIF5B carrying p.(Lys91Arg), p.(Thr195Lys) and p.(Gly234Val) and measure ATPase rate, microtubule binding, velocity and run length against wild type, including mixed dimers to test for a dominant-negative effect on the wild-type subunit.
Cargo transport in patient-derived bone cells
exp_kif5b_kd_osteoblast_cargo_transport
Differentiate osteoblasts from patient-derived induced pluripotent stem cells and image anterograde transport of kinesin-1 cargoes, including secretory vesicles carrying bone matrix components, to identify the cargo whose mislocalization explains the skeletal phenotype.
⚙

Pathophysiology

3
KIF5B Motor Domain Dysfunction
KIF5B encodes the kinesin-1 heavy chain, the ATP-hydrolysing motor subunit that moves cargo anterogradely along microtubules. The three reported pathogenic variants — p.(Lys91Arg), p.(Thr195Lys) and p.(Gly234Val) — all affect conserved residues in or close to the ATPase-related motifs of the catalytic motor domain. That clustering is the mechanistic argument: the lesion is in force generation or ATP handling specifically, not in overall kinesin expression, which is consistent with a dominant rather than haploinsufficient mode.
KIF5B hgnc:6324 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KIF5B (hgnc:6324). hgnc:6324 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
De novo heterozygous missense variants clustering in the catalytic motor domain. Dominant action on a motor that functions as a dimer is the straightforward reading, though the specific dominant mechanism was not tested experimentally.
microtubule motor activity GO:0003777 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased microtubule motor activity (GO:0003777). GO:0003777 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Kinesin-1 Dependent Intracellular Transport
Show evidence (2 references)
PMID:35342932 SUPPORT Human Clinical
"All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val)."
Identifies the three pathogenic alleles and the encoded protein.
PMID:35342932 SUPPORT Human Clinical
"All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein."
Establishes that the variants cluster in the catalytic motor domain, implicating motor function.
Disrupted Kinesin-1 Dependent Intracellular Transport
Impaired kinesin-1 motor function is expected to disrupt anterograde microtubule-based transport of organelles and secretory cargo. This node is curated as PROVISIONAL rather than ESTABLISHED because the inference runs from variant location to cellular consequence: the reporting study demonstrated where the variants sit and what they do clinically, but did not directly measure transport, motility or cargo delivery in patient cells. The cell-biological step between a damaged motor domain and a bent femur is therefore not yet evidenced.
microtubule motor activity GO:0003777 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased microtubule motor activity (GO:0003777). GO:0003777 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Bent Bone Skeletal Dysplasia with Bone Fragility
Show evidence (2 references)
PMID:35342932 SUPPORT Human Clinical
"All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein."
Supports impairment of motor function by variant location; marked PARTIAL because transport itself was not measured.
PMID:35342932 SUPPORT Other
"Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies."
Places the disorder in the kinesinopathy class, the disease family defined by impaired kinesin function.
Bent Bone Skeletal Dysplasia with Bone Fragility
The clinical endpoint: sharp angulation of the femora and humeri with distinctive facial features and neonatal respiratory distress. Distinctively for this form, the skeleton is also fragile — three of four individuals developed postnatal osteoporosis with subsequent fractures — and two had optic atrophy, a non-skeletal feature consistent with a motor protein expressed well beyond cartilage.
Show evidence (2 references)
PMID:35342932 SUPPORT Human Clinical
"All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress."
Documents the core skeletal and respiratory phenotype present in every reported individual.
PMID:35342932 SUPPORT Human Clinical
"Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy."
Documents the bone fragility and optic atrophy that distinguish this form.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KIF5B-Related Kyphomelic Dysplasia 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

6
Eye 1
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy."
Documents optic atrophy in two of four individuals.
Head and Neck 1
Brachycephaly HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248). HP:0000248 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy."
Documents brachycephaly in two of four individuals.
Limbs 1
Sharp Angulation of Femora and Humeri Femoral bowing HP:0002980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Femoral bowing (HP:0002980). HP:0002980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress."
Documents the femoral and humeral angulation.
Musculoskeletal 1
Postnatal Osteoporosis with Fractures FREQUENT HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy."
Documents postnatal osteoporosis with fractures in three of four individuals, supporting the FREQUENT band.
Respiratory 1
Neonatal Respiratory Distress HP:0002643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal respiratory distress (HP:0002643). HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35342932 SUPPORT Human Clinical
"All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress."
Documents neonatal respiratory distress in all reported individuals.
Growth 1
Short Stature FREQUENT 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:35342932 SUPPORT Human Clinical
"Short stature was observed in three individuals."
Documents short stature in three of four individuals, supporting the FREQUENT band.
🧬

Genetic Associations

1
KIF5B
Gene: KIF5B hgnc:6324 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KIF5B (hgnc:6324). hgnc:6324 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:35342932 SUPPORT Human Clinical
"All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein."
Establishes the domain clustering of the pathogenic alleles.
PMID:35342932 SUPPORT Other
"Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies."
Places this gene-disease relationship within the kinesinopathy class.
🗃️

External Assertions

2
OMIM kyphomelic dysplasia, Itai-Ikegawa type record
OMIM disease record OMIM:621644
OMIM's record for the dominant KIF5B-anchored form. Recorded structurally because the argument for splitting kyphomelic dysplasia into two disease entries rests on OMIM having split it first: OMIM:621644 is distinct from OMIM:211350 (the recessive CCN2 form). This is also the identifier a future MONDO term for this entity would be minted against, so binding it here is what will make that term findable.
MedGen concept for kyphomelic dysplasia, Itai-Ikegawa type
MedGen concept record MedGen:CN382186
The only ontology-adjacent identifier that currently exists for this entity. MedGen has minted a CUI but MONDO has no corresponding term, which is why this entry carries no `disease_term`.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from KIF5B-Related Kyphomelic Dysplasia:

{ }

Source YAML

click to show 
name: KIF5B-Related Kyphomelic Dysplasia
creation_date: "2026-08-22T00:00:00Z"
description: >-
  KIF5B-related kyphomelic dysplasia is a dominantly inherited bent-bone
  skeletal dysplasia caused by de novo heterozygous variants in KIF5B, which
  encodes the kinesin-1 heavy chain — the motor subunit that carries cargo along
  microtubules toward the cell periphery. It is one of two molecularly defined
  forms of kyphomelic dysplasia, the other being the recessive CCN2-related
  form. All reported variants alter conserved residues in or near the
  ATPase-related motifs of the catalytic motor domain, implicating motor
  function specifically rather than kinesin abundance. Affected individuals have
  sharp angulation of the femora and humeri, distinctive facial features and
  neonatal respiratory distress; postnatal osteoporosis with subsequent
  fractures and optic atrophy are features that distinguish this form from the
  CCN2 one. Because kinesins carry cargo in every cell type, this disorder also
  sits within the broader group of kinesinopathies.
category: Mendelian
parents:
- hereditary disease
synonyms:
- KIF5B-related kyphomelic dysplasia
- kyphomelic dysplasia, KIF5B type
- autosomal dominant kyphomelic dysplasia
- kyphomelic dysplasia, Itai-Ikegawa type
- KDII
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:35342932
      reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings suggest that heterozygous KIF5B deleterious variants cause a
        specific form of kyphomelic dysplasia.
      explanation: >-
        Establishes a single-gene dominant Mendelian basis.
  isds_skeletal_category:
  - classification_value: bent_bone_dysplasia
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (11th edition;
      Unger et al., PMID:36779427), group 20 "Bent bones dysplasia group", entry
      NOS 20-0040, listed there as "Kyphomelic dysplasia with facial
      dysmorphism, KIF5B-related" (AD, KIF5B). This dismech entry is that
      nosology entry. The nosology attaches MIM 211350 to it and adds the
      caveat that "the name 'kyphomelic dysplasia' has been applied to
      heterogeneous conditions"; MIM 211350 has since been resolved to the
      recessive CCN2-related form (PMID:39506047), which dismech curates
      separately as CCN2-related kyphomelic dysplasia. The group assignment
      here rests on the KIF5B gene-phenotype pairing named in the table, not on
      the MIM number.
references:
- reference: PMID:35342932
  title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
- reference: PMID:39506047
  title: "Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia."
external_assertions:
- name: OMIM kyphomelic dysplasia, Itai-Ikegawa type record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:621644
  url: https://omim.org/entry/621644
  description: >-
    OMIM's record for the dominant KIF5B-anchored form. Recorded structurally
    because the argument for splitting kyphomelic dysplasia into two disease
    entries rests on OMIM having split it first: OMIM:621644 is distinct from
    OMIM:211350 (the recessive CCN2 form). This is also the identifier a future
    MONDO term for this entity would be minted against, so binding it here is
    what will make that term findable.
- name: MedGen concept for kyphomelic dysplasia, Itai-Ikegawa type
  source: MedGen
  assertion_type: concept_record
  external_id: MedGen:CN382186
  url: https://www.ncbi.nlm.nih.gov/medgen/?term=CN382186
  description: >-
    The only ontology-adjacent identifier that currently exists for this entity.
    MedGen has minted a CUI but MONDO has no corresponding term, which is why
    this entry carries no `disease_term`.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    All four reported individuals carried de novo heterozygous KIF5B variants,
    establishing dominant inheritance arising sporadically. This is the clearest
    single discriminator from the CCN2-related form, which is recessive and was
    ascertained through consanguineous families with sibling recurrence.
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals had de novo heterozygous variants in KIF5B encoding
      kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with
      c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val).
    explanation: >-
      Documents de novo heterozygous genotypes in all four reported individuals.
pathophysiology:
- name: KIF5B Motor Domain Dysfunction
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    KIF5B encodes the kinesin-1 heavy chain, the ATP-hydrolysing motor subunit
    that moves cargo anterogradely along microtubules. The three reported
    pathogenic variants — p.(Lys91Arg), p.(Thr195Lys) and p.(Gly234Val) — all
    affect conserved residues in or close to the ATPase-related motifs of the
    catalytic motor domain. That clustering is the mechanistic argument: the
    lesion is in force generation or ATP handling specifically, not in overall
    kinesin expression, which is consistent with a dominant rather than
    haploinsufficient mode.
  genes:
  - preferred_term: KIF5B
    term:
      id: hgnc:6324
      label: KIF5B
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    description: >-
      De novo heterozygous missense variants clustering in the catalytic motor
      domain. Dominant action on a motor that functions as a dimer is the
      straightforward reading, though the specific dominant mechanism was not
      tested experimentally.
  molecular_functions:
  - preferred_term: microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0003777
      label: microtubule motor activity
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals had de novo heterozygous variants in KIF5B encoding
      kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with
      c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val).
    explanation: >-
      Identifies the three pathogenic alleles and the encoded protein.
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants involved conserved amino acids in or close to the ATPase
      activity-related motifs in the catalytic motor domain of the KIF5B protein.
    explanation: >-
      Establishes that the variants cluster in the catalytic motor domain,
      implicating motor function.
  downstream:
  - target: Disrupted Kinesin-1 Dependent Intracellular Transport
- name: Disrupted Kinesin-1 Dependent Intracellular Transport
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Impaired kinesin-1 motor function is expected to disrupt anterograde
    microtubule-based transport of organelles and secretory cargo. This node is
    curated as PROVISIONAL rather than ESTABLISHED because the inference runs
    from variant location to cellular consequence: the reporting study
    demonstrated where the variants sit and what they do clinically, but did not
    directly measure transport, motility or cargo delivery in patient cells. The
    cell-biological step between a damaged motor domain and a bent femur is
    therefore not yet evidenced.
  molecular_functions:
  - preferred_term: microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0003777
      label: microtubule motor activity
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants involved conserved amino acids in or close to the ATPase
      activity-related motifs in the catalytic motor domain of the KIF5B protein.
    explanation: >-
      Supports impairment of motor function by variant location; marked PARTIAL
      because transport itself was not measured.
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, alterations in kinesins cause various symptoms known as
      kinesinopathies, and our findings also extend the phenotypic spectrum of
      kinesinopathies.
    explanation: >-
      Places the disorder in the kinesinopathy class, the disease family defined
      by impaired kinesin function.
  downstream:
  - target: Bent Bone Skeletal Dysplasia with Bone Fragility
- name: Bent Bone Skeletal Dysplasia with Bone Fragility
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint: sharp angulation of the femora and humeri with
    distinctive facial features and neonatal respiratory distress. Distinctively
    for this form, the skeleton is also fragile — three of four individuals
    developed postnatal osteoporosis with subsequent fractures — and two had
    optic atrophy, a non-skeletal feature consistent with a motor protein
    expressed well beyond cartilage.
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals had sharp angulation of the femora and humeri, distinctive
      facial features, and neonatal respiratory distress.
    explanation: >-
      Documents the core skeletal and respiratory phenotype present in every
      reported individual.
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three developed postnatal osteoporosis with subsequent fractures, two showed
      brachycephaly, and two were diagnosed with optic atrophy.
    explanation: >-
      Documents the bone fragility and optic atrophy that distinguish this form.
phenotypes:
- category: Musculoskeletal
  name: Sharp Angulation of Femora and Humeri
  description: >-
    The defining radiographic feature, present in every reported individual.
    Involvement of the humeri as well as the femora is notable.
  phenotype_term:
    preferred_term: Femoral bowing
    term:
      id: HP:0002980
      label: Femoral bowing
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals had sharp angulation of the femora and humeri, distinctive
      facial features, and neonatal respiratory distress.
    explanation: >-
      Documents the femoral and humeral angulation.
- category: Musculoskeletal
  name: Postnatal Osteoporosis with Fractures
  description: >-
    Three of four individuals developed osteoporosis after birth with subsequent
    fractures. This is a discriminating feature: bone fragility is not described
    in the CCN2-related form, so the two molecular forms differ in outcome and
    not only in genotype.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  frequency: FREQUENT
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three developed postnatal osteoporosis with subsequent fractures, two showed
      brachycephaly, and two were diagnosed with optic atrophy.
    explanation: >-
      Documents postnatal osteoporosis with fractures in three of four
      individuals, supporting the FREQUENT band.
- category: Respiratory
  name: Neonatal Respiratory Distress
  description: >-
    Present in every reported individual, reflecting thoracic involvement in a
    bent-bone dysplasia.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals had sharp angulation of the femora and humeri, distinctive
      facial features, and neonatal respiratory distress.
    explanation: >-
      Documents neonatal respiratory distress in all reported individuals.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    Diagnosed in two of four individuals. A non-skeletal feature that fits a
    kinesin motor defect — long axons such as those of the optic nerve are
    heavily dependent on microtubule transport — and is not reported in the CCN2
    form.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three developed postnatal osteoporosis with subsequent fractures, two showed
      brachycephaly, and two were diagnosed with optic atrophy.
    explanation: >-
      Documents optic atrophy in two of four individuals.
- category: Craniofacial
  name: Brachycephaly
  description: >-
    Present in two of four individuals, alongside the distinctive facial
    features reported in all.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three developed postnatal osteoporosis with subsequent fractures, two showed
      brachycephaly, and two were diagnosed with optic atrophy.
    explanation: >-
      Documents brachycephaly in two of four individuals.
- category: Growth
  name: Short Stature
  description: >-
    Observed in three of the four reported individuals.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature was observed in three individuals.
    explanation: >-
      Documents short stature in three of four individuals, supporting the
      FREQUENT band.
genetic:
- name: KIF5B
  gene_term:
    preferred_term: KIF5B
    term:
      id: hgnc:6324
      label: KIF5B
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: De novo heterozygous in all four reported individuals
  notes: >-
    KIF5B (10p11.22) encodes the kinesin-1 heavy chain. The three reported
    pathogenic alleles — p.(Lys91Arg) recurring in two individuals,
    p.(Thr195Lys) and p.(Gly234Val) — all affect conserved residues in or near
    the ATPase-related motifs of the catalytic motor domain. Recurrence of
    p.(Lys91Arg) in two unrelated individuals strengthens the gene-disease
    assertion beyond what four cases would otherwise support. KIF5B disease
    belongs to the kinesinopathies, and this phenotype extends that spectrum.
  evidence:
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants involved conserved amino acids in or close to the ATPase
      activity-related motifs in the catalytic motor domain of the KIF5B protein.
    explanation: >-
      Establishes the domain clustering of the pathogenic alleles.
  - reference: PMID:35342932
    reference_title: "De novo heterozygous variants in KIF5B cause kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, alterations in kinesins cause various symptoms known as
      kinesinopathies, and our findings also extend the phenotypic spectrum of
      kinesinopathies.
    explanation: >-
      Places this gene-disease relationship within the kinesinopathy class.
differential_diagnoses:
- name: CCN2-Related Kyphomelic Dysplasia
  description: >-
    The other molecularly defined form under the same clinical label, and the
    primary differential. It is autosomal recessive rather than de novo dominant,
    arises in a matricellular protein controlling chondrocyte proliferation
    rather than in a microtubule motor, and characteristically includes cleft
    palate, micro-retrognathia and radial head dislocation while lacking the
    postnatal osteoporosis and optic atrophy of the KIF5B form.
  evidence:
  - reference: PMID:39506047
    reference_title: "Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the probands had short stature, cleft palate, and micro-retrognathia.
    explanation: >-
      Documents the craniofacial features characteristic of the CCN2 form.
discussions:
- discussion_id: kif5b_kd_transport_step_unevidenced
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do KIF5B kyphomelic dysplasia variants actually impair kinesin-1 dependent
    transport, and which cargo in which cell type accounts for the skeletal
    phenotype?
  attaches_to:
  - "pathophysiology#Disrupted Kinesin-1 Dependent Intracellular Transport"
  rationale: >-
    This is why the central node of this entry is PROVISIONAL. The variants'
    location in the ATPase motifs of the motor domain is a strong argument that
    motor function is impaired, but no motility, cargo-delivery or patient-cell
    transport assay has been reported for these alleles. Nor is it known why a
    ubiquitously expressed motor produces a phenotype concentrated in bone,
    which is the same tissue-specificity puzzle that recurs across the
    kinesinopathies. The osteoporosis-with-fractures arm makes the question
    sharper: bone fragility appearing after birth suggests an ongoing defect in
    osteoblast or osteoclast function rather than a purely developmental
    patterning error, and those are different cargo problems.
  proposed_experiments:
  - experiment_id: exp_kif5b_kd_single_molecule_motility
    name: Single-molecule motility assays of the patient alleles
    description: >-
      Purify recombinant KIF5B carrying p.(Lys91Arg), p.(Thr195Lys) and
      p.(Gly234Val) and measure ATPase rate, microtubule binding, velocity and
      run length against wild type, including mixed dimers to test for a
      dominant-negative effect on the wild-type subunit.
  - experiment_id: exp_kif5b_kd_osteoblast_cargo_transport
    name: Cargo transport in patient-derived bone cells
    description: >-
      Differentiate osteoblasts from patient-derived induced pluripotent stem
      cells and image anterograde transport of kinesin-1 cargoes, including
      secretory vesicles carrying bone matrix components, to identify the cargo
      whose mislocalization explains the skeletal phenotype.
tracked_issues:
- url: https://github.com/monarch-initiative/dismech/issues/9274
  title: "Upstream MONDO requests for kyphomelic dysplasia: stale definition on MONDO:0008881, missing term for OMIM:621644"
  tracked_issue_role: ontology_term_request
  tracked_issue_status: OPEN
  notes: >-
    MONDO has no term for OMIM:621644, so this entry carries no `disease_term`.
    Filing and landing that new-term request is the unblocking action for this
    entry; when the term is minted it should be bound here.
notes: >-
  Scope. This entry curates the KIF5B-anchored dominant form of kyphomelic
  dysplasia. It is a member of the `Kyphomelic_Dysplasia` grouping, which unions
  it with the CCN2-related recessive form; the grouping carries the MONDO
  mapping and the reasoning for treating the clinical label as a grouping.

  Note on the MONDO anchor, and why `disease_term` is absent. OMIM has already
  split this label: OMIM 211350 is kyphomelic dysplasia (KMD, the CCN2 form) and
  OMIM 621644 is kyphomelic dysplasia, Itai-Ikegawa type (KDII, this KIF5B
  entity). MONDO has caught up with only the first — there is no MONDO term for
  the KIF5B entity, only a MedGen CUI (CN382186). This entry therefore omits
  `disease_term` rather than borrowing MONDO:0008881 from the grouping, which
  would assert an equivalence the literature does not support. When a MONDO term
  for OMIM:621644 is created it should be bound here. Filing that MONDO request
  is the unblocking action for this entry.

  A caution for curators extending this entry. The chain from motor domain to
  bent bone is one inferential step longer than it looks. The reporting study
  established genotype and phenotype well but measured no cell biology, so the
  transport node is PROVISIONAL and should not be promoted without an actual
  motility or cargo assay. The postnatal onset of the osteoporosis is a
  particularly interesting loose end, since it points at continuing bone cell
  dysfunction rather than a one-off developmental error.

  Evidence base. Four individuals in a single report, with one recurrent allele
  across two of them. No functional, animal-model or treatment data, so no
  treatments or animal_models blocks are curated.
📚

References & Deep Research

References

2
PMID:35342932
De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.
No top-level findings curated for this source.
PMID:39506047
Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia.
No top-level findings curated for this source.