Cohen Syndrome

Genetic MONDO:0008999 Pathograph 5 Show in embeddings browser syndromic intellectual disability

Cohen syndrome is an autosomal recessive multisystem disorder caused by biallelic pathogenic variants in VPS13B, and it is the classic example of an intellectual disability syndrome whose mechanism is **not** chromatin, synaptic or metabolic but **intracellular membrane biology**. VPS13B belongs to a family of bulk lipid-transport proteins acting at membrane contact sites; it is concentrated in the Golgi complex, specifically at the interface between the cis and trans Golgi sub-compartments, and Golgi re-formation after pharmacological disruption is delayed in VPS13B-null cells. The unifying hypothesis is that Golgi membrane expansion and hence Golgi-dependent glycosylation and secretion fail, which is why a single gene produces a phenotype spanning brain, retina, marrow and adipose tissue. Clinically the syndrome has an unusually specific and recognisable constellation: early-onset hypotonia with developmental delay and moderate-to-profound intellectual disability - at least a fifth of affected individuals never communicate verbally; a **biphasic growth trajectory** in which poor weight gain from feeding difficulty in infancy and childhood gives way in the early teens to rapid truncal weight gain that occurs without any change in appetite, food intake or activity; progressive high myopia and retinal dystrophy beginning in early childhood; and a mild-to-moderate neutropenia present in almost all affected individuals, which can bring recurrent infections and aphthous ulceration. Two curation points are worth stating plainly. First, the teenage weight gain is explicitly **not** hyperphagic, which distinguishes Cohen syndrome from Prader-Willi syndrome, its main differential; supporting cell work finds accelerated adipogenic differentiation and an increased response to insulin when VPS13B is lost, so the obesity is curated as a cell-intrinsic adipocyte phenotype rather than as an appetite phenotype. Second, a cheerful and friendly disposition is a described part of the phenotype but is deliberately left as prose here rather than bound to an ontology term, because it is a clinical gestalt impression rather than a measurable finding. The disorder shows allelic range: a hypomorphic splice variant has been reported to produce attenuated Cohen syndrome with normal appearance, stature and head size, in which retinal dystrophy, obesity and mild cognitive impairment were the presenting features. Absence of microcephaly or the characteristic facies therefore does not exclude the diagnosis.

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🏷

Classifications

Harrison's Part

👪

Inheritance

Autosomal recessive HP:0000007

Biallelic VPS13B variants are required. Heterozygous parents are asymptomatic carriers; sibling recurrence risk is 25%.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Cohen syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a VPS13B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of..."

States the inheritance pattern and the recurrence figures used in counselling.

⚙

Pathophysiology

VPS13B Loss of Function

Biallelic loss-of-function variation abolishes or severely reduces VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes.

lipid transport GO:0006869 ↓ DECREASED

Downstream

Impaired Golgi Membrane Expansion and Integrity

Show evidence (1 reference)

PMID:38187698 SUPPORT In Vitro

"Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome."

Establishes the molecular identity and presumed function of the protein lost at this node.

Impaired Golgi Membrane Expansion and Integrity

VPS13B is concentrated at the interface between cis and trans Golgi sub-compartments, where its lipid-transport activity is thought to supply membrane for Golgi expansion. In VPS13B-null cells, re-formation of the Golgi complex after Brefeldin A-induced disruption is delayed - a direct functional demonstration that the organelle depends on VPS13B. The same delay follows loss of FAM177A1, a VPS13B interactor whose own mutations also cause a developmental disorder, and the two genes interact genetically in zebrafish.

Golgi apparatus GO:0005794

Downstream

Defective Glycosylation and Secretory Output

Adipocyte Insulin-Response Dysregulation

Show evidence (2 references)

PMID:38187698 SUPPORT In Vitro

"Here we show that VPS13B is localized at the interface between cis and trans Golgi sub-compartments and that Golgi complex re-formation after Brefeldin A (BFA) induced disruption is delayed in VPS13B KO cells."

The core mechanistic observation: precise sub-Golgi localisation plus a functional deficit in Golgi re-formation when VPS13B is absent.

PMID:38187698 SUPPORT In Vitro

"Collectively, these findings raise the possibility that bulk lipid transport by VPS13B may play a role in expanding Golgi membranes"

States the mechanistic interpretation. Note the authors' own hedging ("raise the possibility", "may") - this node is a well-supported model, not a settled mechanism.

Defective Glycosylation and Secretory Output

Golgi dysfunction impairs the glycosylation and secretory processing that the organelle performs. Because every affected tissue depends on Golgi-dependent processing, this is the step that converts a single lipid-transport defect into a multisystem phenotype spanning brain, retina and marrow. No cell type is bound to this node: the sources cited here establish the glycosylation defect but not the mechanism linking it to any particular lineage, and in particular the route from Golgi dysfunction to the near-universal neutropenia is not established, so neutropenia is curated as a phenotype rather than as a mechanistic claim at this node.

Downstream

Multisystem Developmental and Haematologic Phenotype

Show evidence (1 reference)

PMID:26358774 SUPPORT In Vitro

"Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective glycosylation secondary to mutations in the VPS13B gene, which encodes a protein of the Golgi apparatus."

States the glycosylation defect and attributes it to the Golgi localisation of VPS13B, which is the edge into this node.

Adipocyte Insulin-Response Dysregulation

A tissue-specific branch explaining the syndrome's most counterintuitive feature - truncal obesity appearing in the early teens without any increase in appetite or intake. Loss of VPS13B in pre-adipocytes and in patient fibroblasts accelerates adipogenic differentiation through an increased response to insulin stimulation; the resulting fat cells then show reduced AKT2 phosphorylation after insulin, i.e. insulin resistance. This makes the obesity a cell-intrinsic adipocyte phenotype rather than a hypothalamic appetite phenotype, and grounds the increased type 2 diabetes risk.

Downstream

Multisystem Developmental and Haematologic Phenotype

Show evidence (2 references)

PMID:26358774 SUPPORT In Vitro

"In both models, VPS13B invalidation led to accelerated differentiation into fat cells, which was confirmed by the earlier and increased expression of specific adipogenic genes, consequent to the increased response of cells to insulin stimulation."

Direct experimental support in two independent models for accelerated, insulin-driven adipogenesis on VPS13B loss.

PMID:26358774 SUPPORT In Vitro

"At the end of the differentiation protocol, these fat cells exhibited decreased AKT2 phosphorylation after insulin stimulation, which suggests insulin resistance."

Supports the insulin-resistance arm of this node. Note the source's own hedge - it reports decreased AKT2 phosphorylation and says this "suggests" insulin resistance; the increased type 2 diabetes risk is the paper's broader argument and is not asserted by this sentence.

Multisystem Developmental and Haematologic Phenotype

The clinical output: hypotonia with developmental delay and moderate-to-profound intellectual disability, the biphasic growth trajectory ending in truncal obesity with short stature, progressive myopia and retinal dystrophy, near-universal neutropenia with its infection risk, and joint laxity leading to kyphosis and scoliosis.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Cohen syndrome is characterized by early-onset hypotonia, developmental delay, and moderate-to-profound intellectual disability; at least 20% of individuals are unable to communicate verbally."

States the neurodevelopmental output and quantifies the most severe communication outcome.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 1

Neutropenia VERY_FREQUENT Decreased total neutrophil count HP:0001875

Severity: MILD

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Mild-to-moderate neutropenia, present in almost all individuals, may be associated with recurrent infections and/or aphthous ulcers."

Supports the phenotype, the MILD severity qualifier, and the VERY_FREQUENT band ("almost all individuals" maps to the 99-80% HPO range).

Digestive 1

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"In infancy and childhood weight gain is poor due to feeding difficulties."

Supports the phenotype and its causal role in the early poor weight gain.

Eye 2

Progressive high myopia HP:0000545

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Ophthalmologic findings include early childhood onset of progressive high myopia and retinal dystrophy."

Supports the phenotype, its early-childhood onset and the PROGRESSIVE clinical course qualifier.

Retinal dystrophy HP:0000556

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Ophthalmologic findings include early childhood onset of progressive high myopia and retinal dystrophy."

Retinal dystrophy is a core ophthalmic feature.

Musculoskeletal 4

Early-onset hypotonia HP:0001252

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Cohen syndrome is characterized by early-onset hypotonia, developmental delay, and moderate-to-profound intellectual disability"

Hypotonia is a defining early feature.

Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Joint laxity can lead to kyphosis and scoliosis."

Supports joint laxity and its skeletal consequences.

Kyphosis HP:0002808

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Joint laxity can lead to kyphosis and scoliosis."

Kyphosis is a reported skeletal consequence of joint laxity.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Joint laxity can lead to kyphosis and scoliosis."

Scoliosis is a reported skeletal consequence of joint laxity.

Nervous System 2

Intellectual disability HP:0001249

Severity: SEVERE

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Cohen syndrome is characterized by early-onset hypotonia, developmental delay, and moderate-to-profound intellectual disability; at least 20% of individuals are unable to communicate verbally."

Supports both the phenotype and the moderate-to-profound severity qualifier.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Cohen syndrome is characterized by early-onset hypotonia, developmental delay, and moderate-to-profound intellectual disability"

Developmental delay is a defining feature.

Growth 2

Truncal obesity HP:0001956

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"However, in the early teen years rapid weight gain (without a change in appetite, food intake, or activity) leads to significant truncal obesity"

Supports the phenotype, its teenage timing and - critically - its non-hyperphagic character.

Short stature FREQUENT HP:0004322

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"leads to significant truncal obesity; short stature is common."

Qualitative support for the FREQUENT band; the source describes short stature as common. Quoted with the preceding clause so the snippet carries a complete proposition.

🧬

Genetic Associations

VPS13B

Gene: VPS13B hgnc:2183 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20301655 SUPPORT Human Clinical

"The diagnosis of Cohen syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13B identified by molecular genetic testing."

Establishes VPS13B as the causal gene and the biallelic requirement.

PMID:34425733 SUPPORT Human Clinical

"Genomic analysis identified a homozygous rare splice donor variant in the VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis)."

Documents the hypomorphic allele underlying the attenuated presentation, supporting an allelic range rather than a single uniform phenotype.

💊

Medical Actions

Developmental and Rehabilitative Therapy

Action: Physical Therapy NCIT:C15302

Early educational intervention plus physical, occupational and speech therapy directed at the developmental delay and hypotonia.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Early educational intervention and physical, occupational, and speech therapy to help address developmental delay and hypotonia"

States the recommended developmental management.

Refractive Correction and Low Vision Services

Action: Supportive Care NCIT:C15747

Spectacle correction for refractive error, with low vision services once retinal dystrophy impairs vision.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"spectacle correction for refractive errors and low vision services for the visually impaired"

States the recommended ophthalmic management.

Infection Management with Neutrophil-Sparing Caution

Action: Pharmacotherapy NCIT:C15986

Recurrent infections are treated per standard care, but with explicit caution about medications that could further lower the neutrophil count - a disorder-specific prescribing constraint rather than generic supportive care.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"treatment of recurrent infections per standard care (with caution regarding medications that could decrease neutrophil count)"

Supports both the treatment and the neutropenia-specific prescribing caution.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Recessive inheritance, 25% sibling recurrence risk, and the availability of carrier and prenatal/preimplantation testing once the familial variants are known.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"Once the VPS13B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."

Supports the reproductive-testing content of counselling.

🔬

Diagnosis

VPS13B molecular genetic testing

Established by identifying biallelic pathogenic VPS13B variants in a proband with suggestive findings.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"The diagnosis of Cohen syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in VPS13B identified by molecular genetic testing."

States the diagnostic criterion.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Cohen Syndrome:

Prader-Willi syndrome

Overlapping Features The principal differential for the combination of infantile hypotonia, poor early feeding, intellectual disability and later truncal obesity. The discriminator is appetite: in Cohen syndrome the teenage weight gain occurs without any change in appetite or food intake, whereas Prader-Willi obesity is driven by hyperphagia. Neutropenia and retinal dystrophy also point to Cohen syndrome.

Show evidence (1 reference)

PMID:20301655 SUPPORT Human Clinical

"However, in the early teen years rapid weight gain (without a change in appetite, food intake, or activity) leads to significant truncal obesity"

Supplies the discriminating feature - non-hyperphagic weight gain - on which this differential turns.

{ }

Source YAML

click to show

name: Cohen Syndrome
creation_date: "2026-08-22T19:30:00Z"
category: Genetic
synonyms:
- COH1
- Pepper syndrome
- VPS13B-related Cohen syndrome
description: >
  Cohen syndrome is an autosomal recessive multisystem disorder caused by
  biallelic pathogenic variants in VPS13B, and it is the classic example of an
  intellectual disability syndrome whose mechanism is **not** chromatin,
  synaptic or metabolic but **intracellular membrane biology**. VPS13B belongs
  to a family of bulk lipid-transport proteins acting at membrane contact sites;
  it is concentrated in the Golgi complex, specifically at the interface between
  the cis and trans Golgi sub-compartments, and Golgi re-formation after
  pharmacological disruption is delayed in VPS13B-null cells. The unifying
  hypothesis is that Golgi membrane expansion and hence Golgi-dependent
  glycosylation and secretion fail, which is why a single gene produces a
  phenotype spanning brain, retina, marrow and adipose tissue.

  Clinically the syndrome has an unusually specific and recognisable
  constellation: early-onset hypotonia with developmental delay and
  moderate-to-profound intellectual disability - at least a fifth of affected
  individuals never communicate verbally; a **biphasic growth trajectory** in
  which poor weight gain from feeding difficulty in infancy and childhood gives
  way in the early teens to rapid truncal weight gain that occurs without any
  change in appetite, food intake or activity; progressive high myopia and
  retinal dystrophy beginning in early childhood; and a mild-to-moderate
  neutropenia present in almost all affected individuals, which can bring
  recurrent infections and aphthous ulceration.

  Two curation points are worth stating plainly. First, the teenage weight gain
  is explicitly **not** hyperphagic, which distinguishes Cohen syndrome from
  Prader-Willi syndrome, its main differential; supporting cell work finds
  accelerated adipogenic differentiation and an increased response to insulin
  when VPS13B is lost, so the obesity is curated as a cell-intrinsic adipocyte
  phenotype rather than as an appetite phenotype. Second, a cheerful and
  friendly disposition is a described part of the phenotype but is deliberately
  left as prose here rather than bound to an ontology term, because it is a
  clinical gestalt impression rather than a measurable finding.

  The disorder shows allelic range: a hypomorphic splice variant has been
  reported to produce attenuated Cohen syndrome with normal appearance, stature
  and head size, in which retinal dystrophy, obesity and mild cognitive
  impairment were the presenting features. Absence of microcephaly or the
  characteristic facies therefore does not exclude the diagnosis.
disease_term:
  preferred_term: Cohen syndrome
  term:
    id: MONDO:0008999
    label: Cohen syndrome
parents:
- syndromic intellectual disability
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:20301655
  title: "Cohen Syndrome."
  tags:
  - GeneReviews
- reference: PMID:38187698
  title: "VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1."
- reference: PMID:26358774
  title: "Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome."
- reference: PMID:34425733
  title: "A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome."
notes: >-
  Curated as part of a review of Mendelian intellectual disability coverage; the
  disorder was absent from kb/disorders despite being one of the better-known
  recessive ID syndromes. Deliberately curated alongside the chromatinopathy
  work in the same pass as a non-chromatin counterexample: it does NOT conform
  to the `epigenetic_machinery_neurodevelopmental_dysregulation` module, and
  should not be wired to it.

  Prevalence is not curated as a numeric rate. Cohen syndrome is strongly
  enriched in the Finnish population through a founder variant, so a single
  worldwide band would misrepresent it, and no reliable global estimate was
  found in the sources used here.

  The "cheerful and friendly disposition" described in GeneReviews is kept in
  the description as prose and is intentionally not bound to an HP term.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic VPS13B variants are required. Heterozygous parents are
    asymptomatic carriers; sibling recurrence risk is 25%.
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohen syndrome is inherited in an autosomal recessive manner. If both
      parents are known to be heterozygous for a VPS13B pathogenic variant, each
      sib of an affected individual has at conception a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance
      of being unaffected and not a carrier.
    explanation: >-
      States the inheritance pattern and the recurrence figures used in
      counselling.
genetic:
- name: VPS13B
  gene_term:
    preferred_term: VPS13B
    term:
      id: hgnc:2183
      label: VPS13B
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic pathogenic VPS13B variants cause Cohen syndrome. The gene encodes a
    Golgi-localised bulk lipid-transport protein. Hypomorphic alleles, including
    an in-frame exon-skipping splice variant, produce an attenuated phenotype.
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Cohen syndrome is established in a proband with
      suggestive findings and biallelic pathogenic variants in VPS13B identified
      by molecular genetic testing.
    explanation: >-
      Establishes VPS13B as the causal gene and the biallelic requirement.
  - reference: PMID:34425733
    reference_title: A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic analysis identified a homozygous rare splice donor variant in the
      VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the
      in-frame exon 31 (p.Gln1607_Ser1675delinsHis).
    explanation: >-
      Documents the hypomorphic allele underlying the attenuated presentation,
      supporting an allelic range rather than a single uniform phenotype.
pathophysiology:
- name: VPS13B Loss of Function
  description: >-
    Biallelic loss-of-function variation abolishes or severely reduces VPS13B, a
    member of a protein family implicated in bulk lipid transport between
    adjacent membranes.
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: lipid transport
    term:
      id: GO:0006869
      label: lipid transport
    modifier: DECREASED
  evidence:
  - reference: PMID:38187698
    reference_title: "VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations in VPS13B, a member of a protein family implicated in bulk lipid
      transport between adjacent membranes, cause Cohen syndrome.
    explanation: >-
      Establishes the molecular identity and presumed function of the protein
      lost at this node.
  downstream:
  - target: Impaired Golgi Membrane Expansion and Integrity
    causal_link_type: DIRECT

- name: Impaired Golgi Membrane Expansion and Integrity
  description: >-
    VPS13B is concentrated at the interface between cis and trans Golgi
    sub-compartments, where its lipid-transport activity is thought to supply
    membrane for Golgi expansion. In VPS13B-null cells, re-formation of the Golgi
    complex after Brefeldin A-induced disruption is delayed - a direct functional
    demonstration that the organelle depends on VPS13B. The same delay follows
    loss of FAM177A1, a VPS13B interactor whose own mutations also cause a
    developmental disorder, and the two genes interact genetically in zebrafish.
  role: central_effector
  biological_scale: CELLULAR
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:38187698
    reference_title: "VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that VPS13B is localized at the interface between cis and
      trans Golgi sub-compartments and that Golgi complex re-formation after
      Brefeldin A (BFA) induced disruption is delayed in VPS13B KO cells.
    explanation: >-
      The core mechanistic observation: precise sub-Golgi localisation plus a
      functional deficit in Golgi re-formation when VPS13B is absent.
  - reference: PMID:38187698
    reference_title: "VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, these findings raise the possibility that bulk lipid
      transport by VPS13B may play a role in expanding Golgi membranes
    explanation: >-
      States the mechanistic interpretation. Note the authors' own hedging
      ("raise the possibility", "may") - this node is a well-supported model, not
      a settled mechanism.
  downstream:
  - target: Defective Glycosylation and Secretory Output
    causal_link_type: DIRECT
  - target: Adipocyte Insulin-Response Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Defective Glycosylation and Secretory Output
  description: >-
    Golgi dysfunction impairs the glycosylation and secretory processing that the
    organelle performs. Because every affected tissue depends on Golgi-dependent
    processing, this is the step that converts a single lipid-transport defect
    into a multisystem phenotype spanning brain, retina and marrow. No cell type
    is bound to this node: the sources cited here establish the glycosylation
    defect but not the mechanism linking it to any particular lineage, and in
    particular the route from Golgi dysfunction to the near-universal
    neutropenia is not established, so neutropenia is curated as a phenotype
    rather than as a mechanistic claim at this node.
  role: effector
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:26358774
    reference_title: Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cohen Syndrome (CS) is a rare autosomal recessive disorder, with defective
      glycosylation secondary to mutations in the VPS13B gene, which encodes a
      protein of the Golgi apparatus.
    explanation: >-
      States the glycosylation defect and attributes it to the Golgi localisation
      of VPS13B, which is the edge into this node.
  downstream:
  - target: Multisystem Developmental and Haematologic Phenotype
    causal_link_type: DIRECT

- name: Adipocyte Insulin-Response Dysregulation
  description: >-
    A tissue-specific branch explaining the syndrome's most counterintuitive
    feature - truncal obesity appearing in the early teens without any increase
    in appetite or intake. Loss of VPS13B in pre-adipocytes and in patient
    fibroblasts accelerates adipogenic differentiation through an increased
    response to insulin stimulation; the resulting fat cells then show reduced
    AKT2 phosphorylation after insulin, i.e. insulin resistance. This makes the
    obesity a cell-intrinsic adipocyte phenotype rather than a hypothalamic
    appetite phenotype, and grounds the increased type 2 diabetes risk.
  role: effector
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:26358774
    reference_title: Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In both models, VPS13B invalidation led to accelerated differentiation into
      fat cells, which was confirmed by the earlier and increased expression of
      specific adipogenic genes, consequent to the increased response of cells to
      insulin stimulation.
    explanation: >-
      Direct experimental support in two independent models for accelerated,
      insulin-driven adipogenesis on VPS13B loss.
  - reference: PMID:26358774
    reference_title: Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      At the end of the differentiation protocol, these fat cells exhibited
      decreased AKT2 phosphorylation after insulin stimulation, which suggests
      insulin resistance.
    explanation: >-
      Supports the insulin-resistance arm of this node. Note the source's own
      hedge - it reports decreased AKT2 phosphorylation and says this
      "suggests" insulin resistance; the increased type 2 diabetes risk is the
      paper's broader argument and is not asserted by this sentence.
  downstream:
  - target: Multisystem Developmental and Haematologic Phenotype
    causal_link_type: DIRECT

- name: Multisystem Developmental and Haematologic Phenotype
  description: >-
    The clinical output: hypotonia with developmental delay and
    moderate-to-profound intellectual disability, the biphasic growth trajectory
    ending in truncal obesity with short stature, progressive myopia and retinal
    dystrophy, near-universal neutropenia with its infection risk, and joint
    laxity leading to kyphosis and scoliosis.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohen syndrome is characterized by early-onset hypotonia, developmental
      delay, and moderate-to-profound intellectual disability; at least 20% of
      individuals are unable to communicate verbally.
    explanation: >-
      States the neurodevelopmental output and quantifies the most severe
      communication outcome.
phenotypes:
- category: Neurologic
  name: Intellectual disability
  description: Moderate to profound; at least 20% never communicate verbally.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    severity: SEVERE
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohen syndrome is characterized by early-onset hypotonia, developmental
      delay, and moderate-to-profound intellectual disability; at least 20% of
      individuals are unable to communicate verbally.
    explanation: >-
      Supports both the phenotype and the moderate-to-profound severity
      qualifier.
- category: Neurologic
  name: Early-onset hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohen syndrome is characterized by early-onset hypotonia, developmental
      delay, and moderate-to-profound intellectual disability
    explanation: Hypotonia is a defining early feature.
- category: Neurologic
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cohen syndrome is characterized by early-onset hypotonia, developmental
      delay, and moderate-to-profound intellectual disability
    explanation: Developmental delay is a defining feature.
- category: Ophthalmologic
  name: Progressive high myopia
  description: Onset in early childhood and progressive.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic findings include early childhood onset of progressive high
      myopia and retinal dystrophy.
    explanation: >-
      Supports the phenotype, its early-childhood onset and the PROGRESSIVE
      clinical course qualifier.
- category: Ophthalmologic
  name: Retinal dystrophy
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic findings include early childhood onset of progressive high
      myopia and retinal dystrophy.
    explanation: Retinal dystrophy is a core ophthalmic feature.
- category: Hematologic
  name: Neutropenia
  frequency: VERY_FREQUENT
  description: >-
    Mild to moderate, present in almost all affected individuals; may cause
    recurrent infections and aphthous ulcers.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    severity: MILD
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild-to-moderate neutropenia, present in almost all individuals, may be
      associated with recurrent infections and/or aphthous ulcers.
    explanation: >-
      Supports the phenotype, the MILD severity qualifier, and the VERY_FREQUENT
      band ("almost all individuals" maps to the 99-80% HPO range).
- category: Growth
  name: Truncal obesity
  description: >-
    Develops in the early teen years after a period of poor weight gain, and
    notably without any change in appetite, food intake or activity - the feature
    that distinguishes Cohen syndrome from Prader-Willi syndrome.
  phenotype_term:
    preferred_term: Truncal obesity
    term:
      id: HP:0001956
      label: Truncal obesity
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in the early teen years rapid weight gain (without a change in
      appetite, food intake, or activity) leads to significant truncal obesity
    explanation: >-
      Supports the phenotype, its teenage timing and - critically - its
      non-hyperphagic character.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >-
    In infancy and childhood, causing poor weight gain; the first phase of the
    biphasic growth trajectory.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In infancy and childhood weight gain is poor due to feeding difficulties.
    explanation: >-
      Supports the phenotype and its causal role in the early poor weight gain.
- category: Growth
  name: Short stature
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leads to significant truncal obesity; short stature is common.
    explanation: >-
      Qualitative support for the FREQUENT band; the source describes short
      stature as common. Quoted with the preceding clause so the snippet carries
      a complete proposition.
- category: Musculoskeletal
  name: Joint hypermobility
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Joint laxity can lead to kyphosis and scoliosis.
    explanation: >-
      Supports joint laxity and its skeletal consequences.
- category: Musculoskeletal
  name: Kyphosis
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Joint laxity can lead to kyphosis and scoliosis.
    explanation: Kyphosis is a reported skeletal consequence of joint laxity.
- category: Musculoskeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Joint laxity can lead to kyphosis and scoliosis.
    explanation: Scoliosis is a reported skeletal consequence of joint laxity.
diagnosis:
- name: VPS13B molecular genetic testing
  description: >-
    Established by identifying biallelic pathogenic VPS13B variants in a proband
    with suggestive findings.
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Cohen syndrome is established in a proband with
      suggestive findings and biallelic pathogenic variants in VPS13B identified
      by molecular genetic testing.
    explanation: States the diagnostic criterion.
treatments:
- name: Developmental and Rehabilitative Therapy
  description: >-
    Early educational intervention plus physical, occupational and speech therapy
    directed at the developmental delay and hypotonia.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early educational intervention and physical, occupational, and speech
      therapy to help address developmental delay and hypotonia
    explanation: States the recommended developmental management.
- name: Refractive Correction and Low Vision Services
  description: >-
    Spectacle correction for refractive error, with low vision services once
    retinal dystrophy impairs vision.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      spectacle correction for refractive errors and low vision services for the
      visually impaired
    explanation: States the recommended ophthalmic management.
- name: Infection Management with Neutrophil-Sparing Caution
  description: >-
    Recurrent infections are treated per standard care, but with explicit caution
    about medications that could further lower the neutrophil count - a
    disorder-specific prescribing constraint rather than generic supportive care.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment of recurrent infections per standard care (with caution
      regarding medications that could decrease neutrophil count)
    explanation: >-
      Supports both the treatment and the neutropenia-specific prescribing
      caution.
- name: Genetic Counseling
  description: >-
    Recessive inheritance, 25% sibling recurrence risk, and the availability of
    carrier and prenatal/preimplantation testing once the familial variants are
    known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the VPS13B pathogenic variants have been identified in an affected
      family member, carrier testing for at-risk relatives and
      prenatal/preimplantation genetic testing are possible.
    explanation: Supports the reproductive-testing content of counselling.
differential_diagnoses:
- name: Prader-Willi syndrome
  description: >-
    The principal differential for the combination of infantile hypotonia, poor
    early feeding, intellectual disability and later truncal obesity. The
    discriminator is appetite: in Cohen syndrome the teenage weight gain occurs
    without any change in appetite or food intake, whereas Prader-Willi obesity
    is driven by hyperphagia. Neutropenia and retinal dystrophy also point to
    Cohen syndrome.
  evidence:
  - reference: PMID:20301655
    reference_title: "Cohen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in the early teen years rapid weight gain (without a change in
      appetite, food intake, or activity) leads to significant truncal obesity
    explanation: >-
      Supplies the discriminating feature - non-hyperphagic weight gain - on
      which this differential turns.

📚

References & Deep Research

References

PMID:20301655

Cohen Syndrome.

No top-level findings curated for this source.

PMID:38187698

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1.

No top-level findings curated for this source.

PMID:26358774

Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome.

No top-level findings curated for this source.

PMID:34425733

A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.

No top-level findings curated for this source.

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