👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Pilarowski-Bjornsson syndrome is associated with heterozygous CHD1 missense variants, including recurrent de novo events, consistent with autosomal dominant inheritance.

Autosomal dominant inheritance

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Importantly, three of these variants occurred de novo."

This supports autosomal dominant disease through heterozygous de novo CHD1 variants.

◈

Mechanistic Hypotheses

4

CHD1 Missense Dominant-Negative Model

chd1_missense_dominant_negative_model CANONICAL

Evidence balance 1 support

The core human disease model is heterozygous CHD1 missense variation, often de novo, producing neurodevelopmental disability through a dominant-negative effect rather than simple haploinsufficiency.

Pathograph links

CHD1 missense dysfunction -> Neurodevelopmental impairment Epigenetic dysregulation disrupts normal neurodevelopmental trajectories.

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease."

The founding cohort directly frames missense CHD1 variants as a dominant-negative neurodevelopmental disease model.

CHD1 Closed-Chromatin Fibroblast Model

chd1_closed_chromatin_fibroblast_model EMERGING

Evidence balance 1 support

Fibroblast assays from an affected subject support increased H3K27me3 and a closed-chromatin state downstream of CHD1 missense dysfunction; this is separated from the patient genetic evidence because it is cell-assay based.

Classified as emerging because the direct assay evidence is from cultured fibroblasts from one subject rather than neural tissue.

Pathograph links

CHD1 missense dysfunction -> Altered chromatin state CHD1 dysfunction perturbs chromatin remodeling and epigenetic state.

Altered chromatin state -> Neurodevelopmental impairment Altered chromatin regulation contributes to downstream neurodevelopmental dysfunction.

Show evidence (1 reference)

PMID:28866611 SUPPORT In vitro / ex vivo

"Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1."

This distinguishes the cell-assay chromatin evidence from the human clinical genetic evidence.

CHD1 Craniofacial Neural-Crest Model

chd1_craniofacial_neural_crest_model EMERGING

Evidence balance 1 support

Xenopus Chd1 knockdown and CRISPR experiments support a model in which CHD1 disruption impairs cranial neural crest development, jaw cartilage morphology, and cell survival during craniofacial development.

Pathograph links

CHD1 missense dysfunction -> Cranial neural crest and jaw cartilage disruption CHD1 disruption can impair cranial neural crest and jaw cartilage development in model systems.

Cranial neural crest and jaw cartilage disruption -> Abnormal facial shape Cranial neural crest and cartilage disruption may contribute to dysmorphic craniofacial morphology.

Show evidence (1 reference)

PMID:32918369 SUPPORT Model organism

"Further analysis indicated that embryos deficient in Chd1 had defects in cranial neural crest development and jaw cartilage morphology."

Xenopus model data support a craniofacial developmental mechanism that is distinct from patient-only phenotype assertion.

Androgen-Modulated Sex-Dimorphism Model

androgen_modulated_sex_dimorphism_model EMERGING

Evidence balance 2 support

A 2025 preprint proposes androgen-regulated sex-specific penetrance and expressivity in Pilarowski-Bjornsson syndrome, with cohort, mouse-model, and population-variant evidence.

Treated cautiously as preprint evidence until peer-reviewed replication or publication clarifies clinical interpretation.

Show evidence (2 references)

PMID:40385454 SUPPORT Other

"Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented."

The preprint supports a sex-distribution hypothesis in a larger cohort but remains provisional.

PMID:40385454 SUPPORT Model organism

"Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation."

Mouse intervention data support androgen modulation as an experimental mechanism, not an established human treatment.

⚙

Pathophysiology

4

CHD1 missense dysfunction

Pilarowski-Bjornsson syndrome is caused by heterozygous CHD1 missense variants affecting a chromatin remodeler required for normal epigenetic regulation.

CHD1 Closed-Chromatin Fibroblast Model CHD1 Craniofacial Neural-Crest Model CHD1 Missense Dominant-Negative Model

CHD1 hgnc:1915

Downstream

Altered chromatin state CHD1 dysfunction perturbs chromatin remodeling and epigenetic state.

Neurodevelopmental impairment Epigenetic dysregulation disrupts normal neurodevelopmental trajectories.

Cranial neural crest and jaw cartilage disruption CHD1 disruption can impair cranial neural crest and jaw cartilage development in model systems.

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports CHD1 missense variants as the disease-defining genetic lesion.

Altered chromatin state

CHD1 missense dysfunction is associated in cultured fibroblasts with increased levels of the closed chromatin mark H3K27me3, supporting but not alone proving an epigenetic disease mechanism.

CHD1 Closed-Chromatin Fibroblast Model

chromatin organization GO:0006325 ⚠ ABNORMAL

Downstream

Neurodevelopmental impairment Altered chromatin regulation contributes to downstream neurodevelopmental dysfunction.

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT In vitro / ex vivo

"Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1."

This directly supports epigenetic dysregulation and altered chromatin state in the disorder.

Neurodevelopmental impairment

Downstream neurodevelopmental dysfunction produces the core autism, speech, and developmental phenotype of Pilarowski-Bjornsson syndrome.

Downstream

Global developmental delay Neurodevelopmental dysfunction causes developmental delay.

Autism Altered neurodevelopment contributes to autism phenotype.

Speech apraxia Neurodevelopmental dysfunction contributes to speech motor planning deficits.

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports neurodevelopmental impairment as the major downstream disease consequence.

Cranial neural crest and jaw cartilage disruption

Reduced Chd1 function in Xenopus disrupts cranial neural crest development and jaw cartilage morphology, providing model-organism support for craniofacial features in CHD1-related disease.

CHD1 Craniofacial Neural-Crest Model

Downstream

Abnormal facial shape Cranial neural crest and cartilage disruption may contribute to dysmorphic craniofacial morphology.

Show evidence (1 reference)

PMID:32918369 SUPPORT Model organism

"Further analysis indicated that embryos deficient in Chd1 had defects in cranial neural crest development and jaw cartilage morphology."

This supports a cranial-neural-crest model for CHD1-associated craniofacial abnormalities.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

11

Head and Neck 4

Abnormal facial shape HP:0001999

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports dysmorphic facial features as part of the syndrome phenotype.

Pointed chin HP:0000307

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B)."

This supports pointed chin as a specific dysmorphic feature.

Frontal bossing HP:0002007

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B)."

This supports frontal bossing as a specific dysmorphic feature.

Highly arched eyebrow HP:0002553

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B)."

This supports arched eyebrows as a specific dysmorphic feature.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1)."

This directly supports hypotonia as part of the clinically characterized CHD1 missense cohort.

Nervous System 6

Global developmental delay HP:0001263

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports developmental delay in the syndrome.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features."

The founding cohort summary directly includes intellectual disability in the CHD1-associated disorder.

Autism HP:0000717

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports autism in the syndrome phenotype.

Speech apraxia HP:0011098

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

This directly supports speech apraxia in Pilarowski-Bjornsson syndrome.

Seizure HP:0001250

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features."

The founding summary includes seizures among the associated clinical features.

EEG abnormality HP:0002353

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1)."

The founding cohort reports epileptiform EEG abnormalities in a subset.

🧬

Genetic Associations

1

CHD1 (Causal heterozygous missense variant)

Gene: CHD1 hgnc:1915

Show evidence (2 references)

DOI:10.1136/jmedgenet-2017-104759 SUPPORT Human clinical

"Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease."

This directly supports CHD1 missense causality and the likely dominant-negative mechanism.

PMID:38174187 SUPPORT Human clinical

"Notably, this case is unique due to the coexisting presence of an absent, small, and homeotic disks protein 1 homolog like a histone lysine methyltransferase (ASH1L) variant and developmental dissociation."

This newer case supports additional CHD1 reporting but is treated cautiously because a coexisting ASH1L variant may modify the phenotype.

💊

Medical Actions

5

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling should address dominant CHD1 missense causality, de novo occurrence, recurrence-risk assessment, and the current uncertainty around penetrance and sex-modified expressivity.

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"Importantly, three of these variants occurred de novo."

De novo heterozygous CHD1 variants support genetic counseling for recurrence risk and family testing.

Developmental therapy and rehabilitation

Action: occupational therapy Ontology label: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Developmental, occupational, and physical-therapy supports should be individualized for developmental delay, intellectual disability, and hypotonia.

Target Phenotypes: Global developmental delay HP:0001263 Intellectual disability HP:0001249 Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1)."

Developmental delay and hypotonia support rehabilitation-focused management, although the citation is phenotype rather than treatment-trial evidence.

Speech therapy

Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language therapy is relevant for speech apraxia and related communication needs.

Target Phenotypes: Speech apraxia HP:0011098

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"Four of our subjects with CHD1 mutations carried a diagnosis of speech apraxia."

Speech apraxia supports speech-language therapy as symptomatic supportive management.

Behavioral and autism support

Action: behavioral counseling Ontology label: Behavioral Counseling NCIT:C181743

Platform: Behavioral / lifestyle

Behavioral counseling and autism-focused supports should be individualized for social communication and behavioral needs.

Target Phenotypes: Autism HP:0000717

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"Three of these patients also received a diagnosis of autism, although one (Subject 1) no longer carries this diagnosis."

Autism diagnoses in the cohort support autism-focused behavioral support, while the evidence is not a treatment-efficacy study.

Seizure-directed neurologic management

Action: Anticonvulsant Therapy NCIT:C64172

Neurology evaluation and seizure-directed pharmacotherapy should be guided by clinical seizure history and EEG findings where present.

Mechanism Target:

INHIBITS Seizure — Anti-seizure pharmacotherapy suppresses epileptic activity downstream of the CHD1 chromatin dysregulation-driven excitation/inhibition imbalance.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features."

Seizures in the clinical spectrum support seizure-directed management when clinically indicated; this is not a disease-specific medication trial.

🔬

Diagnosis

2

CHD1 molecular genetic testing (Identification of a pathogenic heterozygous CHD1 missense variant confirms the diagnosis.)

Molecular testing of CHD1 is the key confirmatory diagnostic procedure for Pilarowski-Bjornsson syndrome.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."

The defining patient cohort supports CHD1 sequencing as confirmatory molecular diagnosis.

Electroencephalography

EEG evaluation is relevant when seizures, spells, regression, or other paroxysmal neurologic concerns are present because epileptiform EEG abnormalities occur in a subset.

electroencephalography NCIT:C38054

Results: Epileptiform EEG abnormalities support seizure-focused clinical management.

Show evidence (1 reference)

PMID:28866611 SUPPORT Human clinical

"All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1)."

The founding cohort supports EEG assessment when clinically indicated.

🐁

Animal Models

1

Chd1 knockdown or mosaic CRISPR/Cas9-mediated mutagenesis Xenopus laevis

Xenopus Chd1 reduction models craniofacial developmental disruption through cranial neural crest defects, abnormal jaw cartilage morphology, increased apoptosis in the developing head, and interaction with retinoic-acid signaling.

Species

Xenopus laevis

Genotype

Chd1 knockdown or mosaic CRISPR/Cas9-mediated mutagenesis

Show evidence (1 reference)

PMID:32918369 SUPPORT Model organism

"Protein and gene knockdown techniques in Xenopus, including antisense oligos and mosaic Crispr/Cas9-mediated mutagenesis, recapitulated the craniofacial defects observed in humans."

This establishes the Xenopus Chd1 perturbation model for craniofacial features relevant to CHD1-associated disorders.

{ }

Source YAML

click to show

name: Pilarowski-Bjornsson syndrome
creation_date: "2026-04-13T22:47:36Z"
description: >-
  Pilarowski-Bjornsson syndrome is a CHD1-related neurodevelopmental disorder
  associated with heterozygous missense variants and characterized by autism,
  speech apraxia, developmental delay/intellectual disability, hypotonia,
  seizures or EEG abnormalities in a subset, and facial dysmorphic features.
  Current evidence is most consistent with a dominant-negative
  chromatin-remodeling mechanism.
category: Mendelian
parents:
- hereditary disease
- neurodevelopmental disorder
disease_term:
  preferred_term: Pilarowski-Bjornsson syndrome
  term:
    id: MONDO:0060568
    label: Pilarowski-Bjornsson syndrome
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Pilarowski-Bjornsson syndrome is associated with heterozygous CHD1 missense
    variants, including recurrent de novo events, consistent with autosomal
    dominant inheritance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, three of these variants occurred de novo."
    explanation: This supports autosomal dominant disease through heterozygous de novo CHD1 variants.
mechanistic_hypotheses:
- hypothesis_group_id: chd1_missense_dominant_negative_model
  hypothesis_label: CHD1 Missense Dominant-Negative Model
  status: CANONICAL
  description: >-
    The core human disease model is heterozygous CHD1 missense variation, often
    de novo, producing neurodevelopmental disability through a dominant-negative
    effect rather than simple haploinsufficiency.
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
    explanation: >-
      The founding cohort directly frames missense CHD1 variants as a
      dominant-negative neurodevelopmental disease model.
- hypothesis_group_id: chd1_closed_chromatin_fibroblast_model
  hypothesis_label: CHD1 Closed-Chromatin Fibroblast Model
  status: EMERGING
  description: >-
    Fibroblast assays from an affected subject support increased H3K27me3 and a
    closed-chromatin state downstream of CHD1 missense dysfunction; this is
    separated from the patient genetic evidence because it is cell-assay based.
  notes: >-
    Classified as emerging because the direct assay evidence is from cultured
    fibroblasts from one subject rather than neural tissue.
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.
    explanation: >-
      This distinguishes the cell-assay chromatin evidence from the human
      clinical genetic evidence.
- hypothesis_group_id: chd1_craniofacial_neural_crest_model
  hypothesis_label: CHD1 Craniofacial Neural-Crest Model
  status: EMERGING
  description: >-
    Xenopus Chd1 knockdown and CRISPR experiments support a model in which CHD1
    disruption impairs cranial neural crest development, jaw cartilage
    morphology, and cell survival during craniofacial development.
  evidence:
  - reference: PMID:32918369
    reference_title: "Using an aquatic model, Xenopus laevis, to uncover the role of chromodomain 1 in craniofacial disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further analysis indicated that embryos deficient in Chd1 had defects in cranial neural crest development and jaw cartilage morphology.
    explanation: >-
      Xenopus model data support a craniofacial developmental mechanism that is
      distinct from patient-only phenotype assertion.
- hypothesis_group_id: androgen_modulated_sex_dimorphism_model
  hypothesis_label: Androgen-Modulated Sex-Dimorphism Model
  status: EMERGING
  description: >-
    A 2025 preprint proposes androgen-regulated sex-specific penetrance and
    expressivity in Pilarowski-Bjornsson syndrome, with cohort, mouse-model, and
    population-variant evidence.
  notes: >-
    Treated cautiously as preprint evidence until peer-reviewed replication or
    publication clarifies clinical interpretation.
  evidence:
  - reference: PMID:40385454
    reference_title: Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented.
    explanation: >-
      The preprint supports a sex-distribution hypothesis in a larger cohort but
      remains provisional.
  - reference: PMID:40385454
    reference_title: Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation.
    explanation: >-
      Mouse intervention data support androgen modulation as an experimental
      mechanism, not an established human treatment.
pathophysiology:
- name: CHD1 missense dysfunction
  description: >-
    Pilarowski-Bjornsson syndrome is caused by heterozygous CHD1 missense
    variants affecting a chromatin remodeler required for normal epigenetic
    regulation.
  gene:
    preferred_term: CHD1
    description: Chromodomain helicase DNA binding protein 1 chromatin remodeler.
    term:
      id: hgnc:1915
      label: CHD1
  genes:
  - preferred_term: CHD1
    term:
      id: hgnc:1915
      label: CHD1
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports CHD1 missense variants as the disease-defining genetic lesion.
  downstream:
  - target: Altered chromatin state
    description: CHD1 dysfunction perturbs chromatin remodeling and epigenetic state.
    hypothesis_groups:
    - chd1_closed_chromatin_fibroblast_model
  - target: Neurodevelopmental impairment
    description: Epigenetic dysregulation disrupts normal neurodevelopmental trajectories.
    hypothesis_groups:
    - chd1_missense_dominant_negative_model
  - target: Cranial neural crest and jaw cartilage disruption
    description: CHD1 disruption can impair cranial neural crest and jaw cartilage development in model systems.
    hypothesis_groups:
    - chd1_craniofacial_neural_crest_model
- name: Altered chromatin state
  description: >-
    CHD1 missense dysfunction is associated in cultured fibroblasts with
    increased levels of the closed chromatin mark H3K27me3, supporting but not
    alone proving an epigenetic disease mechanism.
  biological_processes:
  - preferred_term: chromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0006325
      label: chromatin organization
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1."
    explanation: This directly supports epigenetic dysregulation and altered chromatin state in the disorder.
  downstream:
  - target: Neurodevelopmental impairment
    description: Altered chromatin regulation contributes to downstream neurodevelopmental dysfunction.
    hypothesis_groups:
    - chd1_closed_chromatin_fibroblast_model
- name: Neurodevelopmental impairment
  description: >-
    Downstream neurodevelopmental dysfunction produces the core autism, speech,
    and developmental phenotype of Pilarowski-Bjornsson syndrome.
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports neurodevelopmental impairment as the major downstream disease consequence.
  downstream:
  - target: Global developmental delay
    description: Neurodevelopmental dysfunction causes developmental delay.
  - target: Autism
    description: Altered neurodevelopment contributes to autism phenotype.
  - target: Speech apraxia
    description: Neurodevelopmental dysfunction contributes to speech motor planning deficits.
- name: Cranial neural crest and jaw cartilage disruption
  description: >-
    Reduced Chd1 function in Xenopus disrupts cranial neural crest development
    and jaw cartilage morphology, providing model-organism support for
    craniofacial features in CHD1-related disease.
  evidence:
  - reference: PMID:32918369
    reference_title: "Using an aquatic model, Xenopus laevis, to uncover the role of chromodomain 1 in craniofacial disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further analysis indicated that embryos deficient in Chd1 had defects in cranial neural crest development and jaw cartilage morphology.
    explanation: >-
      This supports a cranial-neural-crest model for CHD1-associated
      craniofacial abnormalities.
  downstream:
  - target: Abnormal facial shape
    description: Cranial neural crest and cartilage disruption may contribute to dysmorphic craniofacial morphology.
    hypothesis_groups:
    - chd1_craniofacial_neural_crest_model
phenotypes:
- name: Global developmental delay
  category: Neurodevelopmental
  diagnostic: true
  description: Developmental delay is one of the core presenting features of Pilarowski-Bjornsson syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports developmental delay in the syndrome.
- name: Intellectual disability
  category: Neurodevelopmental
  description: Intellectual disability is included in the founding summary of the CHD1-related neurodevelopmental disorder.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features.
    explanation: >-
      The founding cohort summary directly includes intellectual disability in
      the CHD1-associated disorder.
- name: Hypotonia
  category: Neurologic
  description: Hypotonia was reported across the clinically characterized founding patients.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1).
    explanation: >-
      This directly supports hypotonia as part of the clinically characterized
      CHD1 missense cohort.
- name: Autism
  category: Neurodevelopmental
  description: Autism is a frequent neurobehavioral feature in the original CHD1 missense cohort.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports autism in the syndrome phenotype.
- name: Speech apraxia
  category: Neurodevelopmental
  description: Speech apraxia is a distinctive and recurring neurodevelopmental feature.
  phenotype_term:
    preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports speech apraxia in Pilarowski-Bjornsson syndrome.
- name: Seizure
  category: Neurologic
  description: Seizures are reported in the founding CHD1-associated neurodevelopmental disorder summary.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features.
    explanation: >-
      The founding summary includes seizures among the associated clinical
      features.
- name: EEG abnormality
  category: Neurologic
  description: Epileptiform EEG abnormalities were present in a subset of the clinically described patients.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  electrophysiology:
    electrophysiology_modality: EEG
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1).
    explanation: >-
      The founding cohort reports epileptiform EEG abnormalities in a subset.
- name: Abnormal facial shape
  category: Craniofacial
  description: Facial dysmorphic features are part of the syndrome gestalt.
  phenotype_term:
    preferred_term: facial dysmorphic features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features."
    explanation: This directly supports dysmorphic facial features as part of the syndrome phenotype.
- name: Pointed chin
  category: Craniofacial
  description: Pointed chin is one of the more specific dysmorphic features reported in a subset.
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B).
    explanation: This supports pointed chin as a specific dysmorphic feature.
- name: Frontal bossing
  category: Craniofacial
  description: Frontal bossing is one of the more specific dysmorphic features reported in a subset.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B).
    explanation: This supports frontal bossing as a specific dysmorphic feature.
- name: Highly arched eyebrow
  category: Craniofacial
  description: Arched eyebrows are one of the more specific dysmorphic features reported in a subset.
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A subset of patients had dysmorphic features including a pointed chin, frontal bossing and arched eyebrows (Figure 1B).
    explanation: This supports arched eyebrows as a specific dysmorphic feature.
genetic:
- name: CHD1
  gene_term:
    preferred_term: CHD1
    term:
      id: hgnc:1915
      label: CHD1
  association: Causal heterozygous missense variant
  notes: >-
    The neurodevelopmental phenotype appears restricted to CHD1 missense
    variants, consistent with a dominant-negative disease mechanism.
  evidence:
  - reference: DOI:10.1136/jmedgenet-2017-104759
    reference_title: "Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease."
    explanation: This directly supports CHD1 missense causality and the likely dominant-negative mechanism.
  - reference: PMID:38174187
    reference_title: A Saudi Girl With Co-occurring CHD1 (Pilarowski-Bjornsson Syndrome) and ASH1L Gene Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, this case is unique due to the coexisting presence of an absent, small, and homeotic disks protein 1 homolog like a histone lysine methyltransferase (ASH1L) variant and developmental dissociation.
    explanation: >-
      This newer case supports additional CHD1 reporting but is treated
      cautiously because a coexisting ASH1L variant may modify the phenotype.
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling should address dominant CHD1 missense causality, de novo
    occurrence, recurrence-risk assessment, and the current uncertainty around
    penetrance and sex-modified expressivity.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, three of these variants occurred de novo.
    explanation: >-
      De novo heterozygous CHD1 variants support genetic counseling for
      recurrence risk and family testing.
- name: Developmental therapy and rehabilitation
  description: >-
    Developmental, occupational, and physical-therapy supports should be
    individualized for developmental delay, intellectual disability, and
    hypotonia.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1).
    explanation: >-
      Developmental delay and hypotonia support rehabilitation-focused
      management, although the citation is phenotype rather than treatment-trial
      evidence.
- name: Speech therapy
  description: >-
    Speech-language therapy is relevant for speech apraxia and related
    communication needs.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of our subjects with CHD1 mutations carried a diagnosis of speech apraxia.
    explanation: >-
      Speech apraxia supports speech-language therapy as symptomatic supportive
      management.
- name: Behavioral and autism support
  description: >-
    Behavioral counseling and autism-focused supports should be individualized
    for social communication and behavioral needs.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  target_phenotypes:
  - preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these patients also received a diagnosis of autism, although one (Subject 1) no longer carries this diagnosis.
    explanation: >-
      Autism diagnoses in the cohort support autism-focused behavioral support,
      while the evidence is not a treatment-efficacy study.
- name: Seizure-directed neurologic management
  description: >-
    Neurology evaluation and seizure-directed pharmacotherapy should be guided
    by clinical seizure history and EEG findings where present.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, our data show that missense variants in the chromatin remodeler CHD1 are associated with a novel neurodevelopmental disorder with intellectual disability, autism, seizures, speech apraxia, and dysmorphic features.
    explanation: >-
      Seizures in the clinical spectrum support seizure-directed management when
      clinically indicated; this is not a disease-specific medication trial.
  target_mechanisms:
  - target: Seizure
    treatment_effect: INHIBITS
    description: >-
      Anti-seizure pharmacotherapy suppresses epileptic activity downstream of
      the CHD1 chromatin dysregulation-driven excitation/inhibition imbalance.
diagnosis:
- name: CHD1 molecular genetic testing
  presence: Identification of a pathogenic heterozygous CHD1 missense variant confirms the diagnosis.
  description: Molecular testing of CHD1 is the key confirmatory diagnostic procedure for Pilarowski-Bjornsson syndrome.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CHD1
        term:
          id: hgnc:1915
          label: CHD1
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features.
    explanation: >-
      The defining patient cohort supports CHD1 sequencing as confirmatory
      molecular diagnosis.
- name: Electroencephalography
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  description: >-
    EEG evaluation is relevant when seizures, spells, regression, or other
    paroxysmal neurologic concerns are present because epileptiform EEG
    abnormalities occur in a subset.
  results: Epileptiform EEG abnormalities support seizure-focused clinical management.
  evidence:
  - reference: PMID:28866611
    reference_title: Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five patients had developmental delay and hypotonia, all are female and some had epileptiform abnormalities on an EEG (Table 1).
    explanation: >-
      The founding cohort supports EEG assessment when clinically indicated.
differential_diagnoses: []
animal_models:
- species: Xenopus laevis
  genotype: Chd1 knockdown or mosaic CRISPR/Cas9-mediated mutagenesis
  description: >-
    Xenopus Chd1 reduction models craniofacial developmental disruption through
    cranial neural crest defects, abnormal jaw cartilage morphology, increased
    apoptosis in the developing head, and interaction with retinoic-acid
    signaling.
  associated_phenotypes:
  - Craniofacial defects
  - Cranial neural crest defects
  - Jaw cartilage morphology defects
  evidence:
  - reference: PMID:32918369
    reference_title: "Using an aquatic model, Xenopus laevis, to uncover the role of chromodomain 1 in craniofacial disorders."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Protein and gene knockdown techniques in Xenopus, including antisense oligos and mosaic Crispr/Cas9-mediated mutagenesis, recapitulated the craniofacial defects observed in humans.
    explanation: >-
      This establishes the Xenopus Chd1 perturbation model for craniofacial
      features relevant to CHD1-associated disorders.
clinical_trials: []
datasets: []
notes: >-
  Asta deep research was completed for this disorder. Current curation anchors
  the clinical syndrome to the founding CHD1 missense cohort, treats the
  co-occurring CHD1/ASH1L case as phenotype-boundary caution rather than clean
  expansion, and records the androgen/sex-dimorphism report as emerging preprint
  evidence rather than established clinical management.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Asta deep research was completed for this disorder. Current curation anchors the clinical syndrome to the founding CHD1 missense cohort, treats the co-occurring CHD1/ASH1L case as phenotype-boundary caution rather than clean expansion, and records the androgen/sex-dimorphism report as emerging preprint evidence rather than established clinical management.

Review: Pilarowski-Bjornsson syndrome (Changes required) · 2026-05-30T02:53:59Z · View source

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3411 Issue state: OPEN Issue created: 2026-05-30T02:53:59Z Issue updated: 2026-05-30T02:58:57Z Issue closed: not closed Review decision: Changes required Labels: curation, medium_effort, review ## Completed curation review - Disease: **Pilarowski-Bjornsson syndrome** - Entry: `kb/disorders/Pilarowski-Bjornsson_syndrome.yaml` - Selection basis: #24 of 50 least-recently edited Mendelian entries - Review decision: **Changes required** - Validation stance: assumes schema/term/reference validation passes; this is a biological and clinical-content review. ## Findings 1. **The entry is too sparse for an actionable review state.** It has four phenotypes, three pathophysiology nodes, one genetic item, and one diagnosis item, with no treatments/management. A curator should add developmental, speech, hypotonia, behavioral/autism, seizure/EEG, and dysmorphism details from the primary CHD1 cohort where supported. 2. **Management is missing.** For a CHD1 neurodevelopmental syndrome, supportive developmental therapy, speech/language therapy, behavioral/autism supports, seizure evaluation/management where present, and genetic counseling should be represented. 3. **Evidence base is small and should be signposted.** Pilarowski-Bjornsson syndrome is rare; frequencies and broad mechanism statements should avoid overconfidence from limited cases. 4. **Mechanistic statements need evidence-source separation.** `Altered chromatin state` and `Neurodevelopmental impairment` are reasonable, but CHD1 chromatin-remodeler mechanisms should distinguish patient genetic evidence from cell/model chromatin assays. 5. **Recent reports should be reviewed.** Newer reports include co-occurring variants and adult characterization; these may not expand core syndrome boundaries but should be checked to avoid outdated phenotype coverage. ## Research-artifact cross-check Checked `research/Pilarowski-Bjornsson_syndrome-deep-research-asta.md` and `.citations.md`. The Asta artifact is a lead list and should not be considered a full synthesis; primary CHD1/Pilarowski-Bjornsson literature is needed. ## Content-completeness summary - **Phenotypes:** incomplete for speech/language, hypotonia, seizures, and behavioral details. - **Subtype/lumping:** likely appropriate as CHD1-related Pilarowski-Bjornsson syndrome; note co-occurring-variant reports cautiously. - **Pathophysiology:** needs evidence-source stratification. - **Management/diagnosis:** treatment/management missing beyond molecular testing. - **References:** add primary cohort/case references if updating YAML. ## Suggested remediation Expand clinical phenotype, add management/supportive care, and re-anchor mechanisms to primary CHD1 evidence. ## Sources used - CHD1/Pilarowski-Bjornsson case report, PMID:38174187: https://pubmed.ncbi.nlm.nih.gov/38174187/ - CHD1 mechanism/review context: https://pmc.ncbi.nlm.nih.gov/articles/PMC9909554/ No YAML files or `references_cache/*.md` files were edited.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Pilarowski-Bjornsson syndrome. Core disease mechanisms, molecular and cell...

Asta Scientific Corpus Retrieval 20 citations 2026-04-13T18:49:47.450921

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Pilarowski-Bjornsson syndrome. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.381) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[2] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.374) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[3] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.371) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[4] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
Year: 2016
Venue: Molecular Psychiatry
URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
DOI: 10.1038/mp.2016.89
PMID: 27240529
PMCID: 4995546
Citations: 77
Influential citations: 2
Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
Evidence snippets:
Snippet 1 (score: 0.360) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[5] Role of Transcriptomics in Precision Oncology

Authors: Ruby Srivastava
Year: 2024
Venue: Reports of Radiotherapy and Oncology
URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
DOI: 10.5812/rro-142195
Citations: 4
Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
Evidence snippets:
Snippet 1 (score: 0.359) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[6] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
Year: 2026
Venue: Nucleus
URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
DOI: 10.1080/19491034.2025.2611484
PMID: 41489464
PMCID: 12773485
Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
Evidence snippets:
Snippet 1 (score: 0.359) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[7] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

Authors: I. Condò
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
DOI: 10.3390/ijms23126525
PMID: 35742964
PMCID: 9223693
Citations: 15
Influential citations: 2
Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
Evidence snippets:
Snippet 1 (score: 0.359) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[8] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
Year: 2023
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
DOI: 10.3389/fphar.2023.1290253
PMID: 38026943
PMCID: 10662320
Citations: 3
Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
Evidence snippets:
Snippet 1 (score: 0.357) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[9] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

Authors: Hao Xiong, Jinsheng Guo
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
DOI: 10.3390/ph18040507
PMID: 40283943
PMCID: 12030350
Citations: 8
Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
Evidence snippets:
Snippet 1 (score: 0.357) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[10] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
Year: 2025
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
DOI: 10.1038/s41598-025-97642-8
PMID: 40229542
PMCID: 11997208
Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
Evidence snippets:
Snippet 1 (score: 0.356) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[11] In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

Authors: Eirini Nikolouli, Janne Reichstein, G. Hansen, N. Lachmann
Year: 2022
Venue: Frontiers in Immunology
URL: https://www.semanticscholar.org/paper/50f330ee9584168734b8cc8a22dc702c4cbe8ec5
DOI: 10.3389/fimmu.2022.1024935
PMID: 36466870
PMCID: 9713844
Citations: 1
Summary: This review aims to provide an overview of the current available in vitro models used to study IEI and which could lay the foundation for new therapeutic approaches and elaborate in particular on the use of induced pluripotent stem cell-based systems.
Evidence snippets:
Snippet 1 (score: 0.354) > of drug-resistant pathogens, which can cause lifethreatening infections. In some cases, like in the severe combined immunodeficiency (SCID) syndrome, allogenic hematopoietic stem cell transplantation (HSCT) (or autologous HSC-gene therapy) is the only curative therapy (6,7). However, HSCT always lurks the risk of immunological rejection or development of graft versus host disease with devastating consequences for the patient, pointing towards the need of suitable alternatives. > For these reasons, more targeted therapeutic approaches, which can directly modulate specific cell types or intracellular pathways, are preferred. These approaches include the use of specific inhibitors or biologics (antibodies or recombinant proteins). For the safe use of these emerging therapeutic agents, a detailed study of the pathophysiological mechanisms of the diseases is necessary. Given the rarity of IEI and the technical difficulties (obtaining sufficient samples from children or the low number of affected cells), the study of IEI-related diseases remains challenging. Thus, the development of novel systems to unravel the cellular and molecular mechanisms involved in the pathophysiology of the various IEI is of great importance.

[12] Phenotypic drug discovery: a case for thymosin alpha-1

Authors: Enrico Garaci, Maurizio Paci, C. Matteucci, C. Costantini, P. Puccetti et al.
Year: 2024
Venue: Frontiers in Medicine
URL: https://www.semanticscholar.org/paper/84001176cd8c6059e1ee06845db21c61c9fd9d27
DOI: 10.3389/fmed.2024.1388959
PMID: 38903817
PMCID: 11187271
Citations: 4
Summary: The experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings are explored and how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework is discussed.
Evidence snippets:
Snippet 1 (score: 0.353) > This approach focuses on identifying and understanding the specific molecular targets that drugs interact with, and the subsequent biochemical and physiological changes that occur as a result of drug-target interactions.At the molecular level, researchers investigate how drugs bind to specific proteins, receptors, enzymes, or other molecules involved in biological processes.They analyze the structureactivity relationship to determine how the drug's chemical structure influences its interaction with the target, and how this interaction leads to molecular changes.Once the specific target or targets are identified, the reductionistic approach is applied at the cellular level.Researchers examine how the drug affects cellular signaling pathways, gene expression, protein synthesis, or other cellular processes.Understanding these cellular-level interactions helps elucidate how drugs modulate specific cell functions and influence overall physiological responses.At the physiological level, researchers investigate the effects of drugs on organ systems, whole organisms, and clinical outcomes.This includes studying how drugs affect organ function, systemic processes, and the overall disease state.By examining the drug's impact on the entire organism, researchers gain insights into the broader therapeutic effects and potential side effects of the drug.Therefore, the reductionistic approach in mechanisms of action of drugs involves studying drugs at different levels of complexity, from the molecular to the physiological, to understand how they interact with biological systems.Yet, it almost exclusively focuses on modulating specific molecular targets of interest, namely, the qualitative and quantitative description of the drug/receptor interaction (11).As a matter of fact, currently, target-based drug discovery heavily dominates drug discovery approaches in both academia and the pharmaceutical industry.Little emphasis is placed on realistic disease conditions whereby the local tissue microenvironment and/or specific environmental factors might flexibly modulate a patient's response.Indeed, due to the complexity of multifactorial diseases, drug intervention based on single-target drugs with high affinity, high selectivity, and strong potency may not fit well and does not always exhibit satisfactory efficacy with the network-based, inter-balanced regulation mode of the smart biological system (12,13).Many "targetbased" drugs have indeed numerous "off-target" therapeutic mechanisms (14).

[13] The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

Authors: S. Silva, G. Arno, A. Robson, A. Fakin, Nikolas Pontikos et al.
Year: 2020
Venue: Progress in retinal and eye research
URL: https://www.semanticscholar.org/paper/0002f4d18faa348181db81ac27fed490c9ddb569
DOI: 10.1016/j.preteyeres.2020.100898
PMID: 32860923
Citations: 127
Influential citations: 7
Summary: An algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy is presented, current experimental therapeutic approaches are summarised, and questions for future research are considered.
Evidence snippets:
Snippet 1 (score: 0.352) > Inherited retinal diseases are a frequent cause of blindness in paediatric and working age populations in many countries Rahman et al., 2020;Solebo and Rahi, 2014;Solebo et al., 2017). > The X-linked retinopathies represent an important, diverse subgroup, including both progressive and stationary conditions, and disorders with and without syndromic features. They display a number of different pathogenic mechanisms, thereby yielding important and wide-ranging insights into key aspects of retinal physiology and pathophysiology. A significant number are also the subject of novel therapeutic trials. > Pathogenic variants usually cause disease by loss of protein function; hence these conditions are particularly attractive for gene-replacement strategies. There is a carrier phenotype in several of these conditions, which can help clinicians narrow the differential diagnosis and thereby mode of inheritance, and which may also reveal valuable information regarding patterns of X inactivation, normal retinal cellular development and migration, and mechanisms of disease. Carrier females are often asymptomatic, but may infrequently be as severely affected as males, which may result in inheritance being incorrectly classified as autosomal dominant. Some of the disorders also illustrate ways in which variants in the same gene can generate a number of phenotypes, and potential limitations in current genetic sequencing methods; awareness of the latter is particularly relevant as we enter the era of widely available whole genome sequencing and gene therapy. > In this article, X-inactivation and patterns of X-linked inheritance will be reviewed briefly. We then explore the burden of disease attributable to X-linked genes in a large clinically and genetically characterised inherited retinal disease cohort, highlighting the most frequently implicated genes, and investigating correlation between gene transcript length and numbers of affected families. Subsequently, we provide a list of X-linked genes involved in a number of non-syndromic and syndromic retinopathies, together with key clinical features, and a schematic showing sites of expression or impairment in the retina. We then discuss several genes in more detail as specified in the abstract. For several conditions, disease mechanisms, clinical features, carrier phenotypes, electrophysiological findings, and novel experimental therapies, where applicable, are considered. A comprehensive, detailed discussion of

[14] Molecular insights into the premature aging disease progeria

Authors: Sandra Vidak, R. Foisner
Year: 2016
Venue: Histochemistry and Cell Biology
URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
DOI: 10.1007/s00418-016-1411-1
PMID: 26847180
PMCID: 4796323
Citations: 105
Influential citations: 3
Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
Evidence snippets:
Snippet 1 (score: 0.352) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[15] Renal ciliopathies: promising drug targets and prospects for clinical trials

Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
Year: 2023
Venue: Expert Opinion on Therapeutic Targets
URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
DOI: 10.1080/14728222.2023.2218616
PMID: 37243567
Citations: 10
Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
Evidence snippets:
Snippet 1 (score: 0.352) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[16] Chromatin modifiers in neurodevelopment

Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
Year: 2025
Venue: Frontiers in Molecular Neuroscience
URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
DOI: 10.3389/fnmol.2025.1551107
PMID: 40469903
PMCID: 12133960
Citations: 2
Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
Evidence snippets:
Snippet 1 (score: 0.351) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[17] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
Year: 2025
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
DOI: 10.3389/fendo.2025.1501305
PMID: 40070584
PMCID: 11893406
Citations: 11
Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
Evidence snippets:
Snippet 1 (score: 0.351) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[18] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
Year: 2024
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
DOI: 10.3389/fphar.2024.1397864
PMID: 38846086
PMCID: 11154008
Citations: 3
Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
Evidence snippets:
Snippet 1 (score: 0.350) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[19] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

Authors: Debopam Samanta
Year: 2025
Venue: Children
URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
DOI: 10.3390/children12040481
PMID: 40310132
PMCID: 12025602
Citations: 19
Influential citations: 1
Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
Evidence snippets:
Snippet 1 (score: 0.348) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[20] Therapies for Mitochondrial Disease: Past, Present, and Future

Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
Year: 2025
Venue: Journal of Inherited Metabolic Disease
URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
DOI: 10.1002/jimd.70065
PMID: 40714961
PMCID: 12301291
Citations: 3
Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
Evidence snippets:
Snippet 1 (score: 0.348) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

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Pilarowski-Bjornsson syndrome

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Pilarowski-Bjornsson syndrome. Core disease mechanisms, molecular and cell...

Relevant Papers

[1] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

[2] New therapeutic targets in rare genetic skeletal diseases

[3] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

[4] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

[5] Role of Transcriptomics in Precision Oncology

[6] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

[7] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

[8] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

[9] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

[10] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

[11] In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

[12] Phenotypic drug discovery: a case for thymosin alpha-1

[13] The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

[14] Molecular insights into the premature aging disease progeria

[15] Renal ciliopathies: promising drug targets and prospects for clinical trials

[16] Chromatin modifiers in neurodevelopment

[17] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

[18] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

[19] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

[20] Therapies for Mitochondrial Disease: Past, Present, and Future

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