🔗

Mappings

MONDO

MONDO:0010010 Schinzel-Giedion syndrome

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Schinzel-Giedion syndrome is typically caused by spontaneous de novo SETBP1 variants.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:38452171 SUPPORT Human Clinical

"Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant."

GeneReviews directly supports dominant inheritance with typically de novo SETBP1 pathogenic variants.

⚙

Pathophysiology

5

Impaired SETBP1 degron-dependent degradation

Classical Schinzel-Giedion syndrome is caused by degron-region SETBP1 variants that disrupt normal protein degradation and produce toxic accumulation.

SETBP1 hgnc:15573

Downstream

Aberrant developmental gene transcription Excess SETBP1 alters transcriptional control over developmental programs

Show evidence (1 reference)

PMID:37872881 SUPPORT Model Organism

"SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS."

This sentence directly states the core degron-disruption mechanism of classical SGS.

Aberrant developmental gene transcription

SETBP1 acts as an epigenetic hub at AT-rich promoter regions to activate developmental genes, and pathogenic variants dysregulate this transcriptional program.

regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Impaired neurogenesis and neuronal migration Dysregulated SETBP1 activity disrupts brain development

Show evidence (2 references)

PMID:29875417 SUPPORT In Vitro

"Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex."

This directly supports SETBP1 as a transcriptional and epigenetic regulator.

PMID:29875417 SUPPORT In Vitro

"Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis."

This links dysregulated SETBP1 targets to the organ-development phenotype of SGS.

Impaired neurogenesis and neuronal migration

Pathogenic SETBP1 activity disrupts neurogenesis, neuronal migration, and cell-type-specific regulatory programs in the brain.

neuron differentiation GO:0030182 ⚠ ABNORMAL

Downstream

Severe neurodevelopmental impairment Impaired neurogenesis leads to profound developmental and cognitive disability

Refractory epilepsy Altered brain development contributes to the syndrome's severe seizure phenotype

Show evidence (1 reference)

PMID:29875417 SUPPORT Model Organism

"In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration."

This directly supports a causal neurodevelopmental mechanism downstream of mutant SETBP1.

Severe neurodevelopmental impairment

Downstream consequences of dysregulated SETBP1 activity include severe global developmental impairment and intellectual disability.

Show evidence (1 reference)

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."

This directly links the disease mechanism to severe human neurodevelopmental impairment.

Refractory epilepsy

Severe epilepsy is a major downstream neurologic consequence of Schinzel- Giedion syndrome.

Show evidence (1 reference)

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."

This directly supports refractory epilepsy as a major downstream clinical outcome.

⬡

Pathograph

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

●

Phenotypes

4

Nervous System 3

Developmental delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:37872881 SUPPORT Model Organism

"The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures."

This mouse-study abstract summarizes the hallmark phenotype background, but is classified as model-organism evidence because of the underlying study design.

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."

This provides direct human clinical support for severe developmental impairment in SGS.

Seizure Seizure HP:0001250

Show evidence (2 references)

PMID:37872881 SUPPORT Model Organism

"The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures."

This mouse-study abstract summarizes the hallmark phenotype background, but is classified as model-organism evidence because of the underlying study design.

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."

This provides direct human clinical support for epilepsy in SGS.

Intellectual disability Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."

GeneReviews directly supports the syndrome's severe intellectual-disability phenotype in humans.

Other 1

Hydronephrosis Hydronephrosis HP:0000126

Show evidence (1 reference)

PMID:38711130 SUPPORT Human Clinical

"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."

This provides direct human clinical support for hydronephrosis as a recognized SGS manifestation.

🧬

Genetic Associations

1

SETBP1 (Degron-region gain-of-stability missense variants)

Gene: SETBP1 hgnc:15573

Show evidence (2 references)

PMID:38452171 SUPPORT Human Clinical

"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot"

This provides direct human clinical support for the characteristic SETBP1 gain-of-function variant class in classical SGS.

CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z SUPPORT Other

ClinGen classifies the SETBP1-Schinzel-Giedion syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

💊

Medical Actions

1

Supportive multidisciplinary care

Action: supportive care MAXO:0000950

Current treatment is supportive and focuses on seizure control, nutritional and developmental support, and surveillance for renal, respiratory, and oncologic complications.

Show evidence (1 reference)

PMID:38452171 SUPPORT Human Clinical

"Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology,..."

GeneReviews directly supports multidisciplinary supportive management as the current standard of care.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Schinzel-Giedion syndrome:

intellectual disability, autosomal dominant 29 MONDO:0014482

Overlapping Features SETBP1 haploinsufficiency disorder overlaps genetically with SGS but is typically milder and lacks the classical degron-mediated toxic accumulation mechanism.

Distinguishing Features

Classical degron-region variants with severe multisystem disease favor Schinzel-Giedion syndrome.
Haploinsufficiency-like speech and developmental phenotypes with less severe congenital involvement favor SETBP1 haploinsufficiency disorder.

Kabuki syndrome MONDO:0016512

Overlapping Features Kabuki syndrome can overlap through developmental delay, seizures, and craniofacial dysmorphism, but differs in its causal genes and typical epigenetic-developmental pattern.

Distinguishing Features

Progressive severe neurologic disease with classical SETBP1 degron variants favors Schinzel-Giedion syndrome.
Persistent fingertip pads and classic Kabuki facial features favor Kabuki syndrome.

📊

Related Datasets

1

Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome. PMID:36147799

Human longitudinal case dataset capturing neonatal presentation, neurodevelopmental progression, seizure onset, and later hydronephrosis in a child with molecularly confirmed Schinzel-Giedion syndrome.

human n=1

Conditions: Schinzel-Giedion syndrome de novo SETBP1 variant

PMID:36147799

Show evidence (1 reference)

PMID:36147799 SUPPORT Human Clinical

"A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up."

This supports the publication as a disease-specific longitudinal clinical dataset for SGS.

{ }

Source YAML

click to show

name: Schinzel-Giedion syndrome
creation_date: '2026-04-11T19:38:25Z'
updated_date: '2026-04-12T00:18:00Z'
category: Mendelian
description: >-
  Schinzel-Giedion syndrome is a severe autosomal dominant multisystem
  developmental disorder caused by de novo missense variants in the degron
  region of SETBP1. These variants impair normal SETBP1 protein degradation,
  leading to toxic accumulation of an epigenetic transcriptional regulator.
  Dysregulated SETBP1 activity rewires developmental gene-expression programs,
  impairs neurogenesis and neuronal migration, and underlies the syndrome's
  severe developmental delay, progressive brain disease, seizures, craniofacial
  abnormalities, and visceral malformations.
disease_term:
  preferred_term: Schinzel-Giedion syndrome
  term:
    id: MONDO:0010010
    label: Schinzel-Giedion syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010010
      label: Schinzel-Giedion syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- hereditary disease
- developmental disorder
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Schinzel-Giedion syndrome is typically caused by spontaneous de novo SETBP1
    variants.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant.
    explanation: >-
      GeneReviews directly supports dominant inheritance with typically de novo
      SETBP1 pathogenic variants.
pathophysiology:
- name: Impaired SETBP1 degron-dependent degradation
  description: >-
    Classical Schinzel-Giedion syndrome is caused by degron-region SETBP1
    variants that disrupt normal protein degradation and produce toxic
    accumulation.
  genes:
  - preferred_term: SETBP1
    term:
      id: hgnc:15573
      label: SETBP1
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS.
    explanation: >-
      This sentence directly states the core degron-disruption mechanism of
      classical SGS.
  downstream:
  - target: Aberrant developmental gene transcription
    description: Excess SETBP1 alters transcriptional control over developmental programs
- name: Aberrant developmental gene transcription
  description: >-
    SETBP1 acts as an epigenetic hub at AT-rich promoter regions to activate
    developmental genes, and pathogenic variants dysregulate this transcriptional
    program.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex.
    explanation: >-
      This directly supports SETBP1 as a transcriptional and epigenetic regulator.
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis.
    explanation: >-
      This links dysregulated SETBP1 targets to the organ-development phenotype
      of SGS.
  downstream:
  - target: Impaired neurogenesis and neuronal migration
    description: Dysregulated SETBP1 activity disrupts brain development
- name: Impaired neurogenesis and neuronal migration
  description: >-
    Pathogenic SETBP1 activity disrupts neurogenesis, neuronal migration, and
    cell-type-specific regulatory programs in the brain.
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030182
      label: neuron differentiation
  evidence:
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration.
    explanation: >-
      This directly supports a causal neurodevelopmental mechanism downstream of
      mutant SETBP1.
  downstream:
  - target: Severe neurodevelopmental impairment
    description: Impaired neurogenesis leads to profound developmental and cognitive disability
  - target: Refractory epilepsy
    description: Altered brain development contributes to the syndrome's severe seizure phenotype
- name: Severe neurodevelopmental impairment
  description: >-
    Downstream consequences of dysregulated SETBP1 activity include severe global
    developmental impairment and intellectual disability.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      This directly links the disease mechanism to severe human neurodevelopmental
      impairment.
- name: Refractory epilepsy
  description: >-
    Severe epilepsy is a major downstream neurologic consequence of Schinzel-
    Giedion syndrome.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      This directly supports refractory epilepsy as a major downstream clinical
      outcome.
phenotypes:
- name: Developmental delay
  category: Neurologic
  description: >-
    Severe developmental delay is one of the most recognizable features of
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
    explanation: >-
      This mouse-study abstract summarizes the hallmark phenotype background, but
      is classified as model-organism evidence because of the underlying study
      design.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      This provides direct human clinical support for severe developmental
      impairment in SGS.
- name: Seizure
  category: Neurologic
  description: >-
    Drug-resistant seizures are a prominent neurologic complication of
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
    explanation: >-
      This mouse-study abstract summarizes the hallmark phenotype background, but
      is classified as model-organism evidence because of the underlying study
      design.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      This provides direct human clinical support for epilepsy in SGS.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Schinzel-Giedion syndrome is a severe neurodevelopmental disorder with major
    cognitive impairment.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly supports the syndrome's severe intellectual-disability
      phenotype in humans.
- name: Hydronephrosis
  category: Genitourinary
  description: >-
    Urinary tract and renal malformations are common in Schinzel-Giedion
    syndrome, often including hydronephrosis.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  evidence:
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      This provides direct human clinical support for hydronephrosis as a
      recognized SGS manifestation.
genetic:
- name: SETBP1
  association: Degron-region gain-of-stability missense variants
  gene_term:
    preferred_term: SETBP1
    term:
      id: hgnc:15573
      label: SETBP1
  notes: >-
    Classical Schinzel-Giedion syndrome is caused by de novo missense variants
    in the degron region of SETBP1 that impair protein degradation and increase
    aberrant transcriptional activity.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot
    explanation: >-
      This provides direct human clinical support for the characteristic
      SETBP1 gain-of-function variant class in classical SGS.
  - reference: CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z
    reference_title: "SETBP1 / Schinzel-Giedion syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SETBP1 | HGNC:15573 | Schinzel-Giedion syndrome | MONDO:0010010 | AD | Definitive"
    explanation: ClinGen classifies the SETBP1-Schinzel-Giedion syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Supportive multidisciplinary care
  description: >-
    Current treatment is supportive and focuses on seizure control, nutritional
    and developmental support, and surveillance for renal, respiratory, and
    oncologic complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics.
    explanation: >-
      GeneReviews directly supports multidisciplinary supportive management as
      the current standard of care.
differential_diagnoses:
- name: intellectual disability, autosomal dominant 29
  disease_term:
    preferred_term: intellectual disability, autosomal dominant 29
    term:
      id: MONDO:0014482
      label: intellectual disability, autosomal dominant 29
  description: >-
    SETBP1 haploinsufficiency disorder overlaps genetically with SGS but is
    typically milder and lacks the classical degron-mediated toxic accumulation
    mechanism.
  distinguishing_features:
  - Classical degron-region variants with severe multisystem disease favor Schinzel-Giedion syndrome.
  - Haploinsufficiency-like speech and developmental phenotypes with less severe congenital involvement favor SETBP1 haploinsufficiency disorder.
- name: Kabuki syndrome
  disease_term:
    preferred_term: Kabuki syndrome
    term:
      id: MONDO:0016512
      label: Kabuki syndrome
  description: >-
    Kabuki syndrome can overlap through developmental delay, seizures, and
    craniofacial dysmorphism, but differs in its causal genes and typical
    epigenetic-developmental pattern.
  distinguishing_features:
  - Progressive severe neurologic disease with classical SETBP1 degron variants favors Schinzel-Giedion syndrome.
  - Persistent fingertip pads and classic Kabuki facial features favor Kabuki syndrome.
clinical_trials: []
datasets:
- accession: PMID:36147799
  title: Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome.
  description: >-
    Human longitudinal case dataset capturing neonatal presentation,
    neurodevelopmental progression, seizure onset, and later hydronephrosis in a
    child with molecularly confirmed Schinzel-Giedion syndrome.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 1
  conditions:
  - Schinzel-Giedion syndrome
  - de novo SETBP1 variant
  publication: PMID:36147799
  evidence:
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up.
    explanation: >-
      This supports the publication as a disease-specific longitudinal clinical
      dataset for SGS.
notes: >-
  Asta deep research was run as requested, but final curation relied on direct
  review of PubMed references because the retrieval output was noisy and only
  partially disease-specific.
references:
- reference: PMID:38452171
  title: "Schinzel-Giedion Syndrome."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:38452171

Schinzel-Giedion Syndrome.

No top-level findings curated for this source.

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schinzel-Giedion syndrome. Core disease mechanisms, molecular and cellular...

Asta Scientific Corpus Retrieval 20 citations 2026-04-11T16:00:29.721430

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schinzel-Giedion syndrome. Core disease mechanisms, molecular and cellular...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] 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: 0.384) > : 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.

[2] 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: 0.382) > 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

[3] 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: 0.377) > 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.

[4] 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: 0.377) > 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.

[5] 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: 0.377) > 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.

[6] 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: 0.373) > 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.

[7] Chemotherapy and Mechanisms of Resistance in Breast Cancer

Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
Year: 2012
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
DOI: 10.5772/24629
Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
Evidence snippets:
Snippet 1 (score: 0.370) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[8] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
Year: 2021
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
DOI: 10.1002/mgg3.1809
PMID: 34519438
PMCID: 8580094
Citations: 12
Influential citations: 2
Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
Evidence snippets:
Snippet 1 (score: 0.369) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[9] 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: 0.368) > 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.

[10] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

Authors: M. Saporta
Year: 2015
Venue: Neural Regeneration Research
URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
DOI: 10.4103/1673-5374.158345
PMID: 26199602
PMCID: 4498347
Citations: 4
Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
Evidence snippets:
Snippet 1 (score: 0.368) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
Year: 2025
Venue: Pathophysiology
URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
DOI: 10.3390/pathophysiology32010009
PMID: 39982365
PMCID: 12077258
Citations: 23
Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
Evidence snippets:
Snippet 1 (score: 0.364) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[12] Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

Authors: Ester Di Muro, P. Palumbo, Mario Benvenuto, M. Accadia, M. D. Di Giacomo et al.
Year: 2021
Venue: Genes
URL: https://www.semanticscholar.org/paper/5645cba84a9fd5bc5561d2c0a4217b57929d4b68
DOI: 10.3390/genes12081116
PMID: 34440290
PMCID: 8392311
Citations: 14
Influential citations: 2
Summary: A 5 year old female patient with neurodevelopmental delay, mild intellectual disability, dysmorphic features and congenital anomalies is described, in which next generation sequencing analysis allowed us to identify a novel pathogenic variation c.2769_2770del p.(Ile924Serfs*8) in STAG1 gene, which result to be de novo.
Evidence snippets:
Snippet 1 (score: 0.362) > Obviously, more patients and genotype-phenotype correlation studies are needed to corroborate these data and to better delineate the clinical spectrum of this rare cohesinopathy. > From a molecular point of view, the variant c.2769_2770del p.(Ile924Serfs*8) detected in our patient was never reported before in medical literature, is absent in public databases, and is thus useful to expand the molecular spectrum of pathogenic alterations of STAG1. > Furthermore, a careful observation of the clinical and molecular features documented in the affected individuals, including ours, suggests that the etiopathogenetic mechanism may be the same, namely STAG1 haploinsufficiency. In fact, although to date very heterogeneous patients from a genetic point of view (carriers of STAG1 deletions, frameshift variants, missense) have been identified, and there does not seem to be a mutational hot spot for the STAG1 gene which has instead emerged for other clinical conditions such as Schinzel-Giedion syndrome (SGS, OMIM 269150) [18], all the patients described share specific clinical features. Therefore, in agreement with other authors [8], we suggest that the clinical manifestations and severity of the STAG1-syndrome does not depend on the nature/type of the gene variant but arises through transcriptional dysregulation due to depletion/defects of cohesin complex. Further functional studies on cellular and/or animal models, and analysis of gene expression profiles are needed to reinforce this emerging evidence on the etiopathogenetic mechanisms and to delineate the key events responsible for the onset of this rare cohesinopaty.

[13] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

Authors: Michael Harris, K. Bhuvaneshwar, Thanemozhi Natarajan, L. Sheahan, Difei Wang et al.
Year: 2013
Venue: Pharmacogenetics and Genomics
URL: https://www.semanticscholar.org/paper/1382ddf84b87736a73c2f2f81164ca876c29f4c4
DOI: 10.1097/FPC.0000000000000015
PMID: 24401833
PMCID: 3888473
Citations: 16
Summary: This in-silico study identified gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic and gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews.
Evidence snippets:
Snippet 1 (score: 0.360) > Understanding the genetic and molecular mechanisms underlying complex diseases such as cancer is extremely challenging. Genome-wide association studies (GWAS) have been extensively used in the past decade to discover important genetic variants. However, the identified SNPs explain only a small proportion of the phenotypic variation, and the predictive power of these SNPs remains low for many complex diseases [10]. To fully elucidate genetic underpinnings of disease a systems biology approach is necessary to characterize variants, mRNA, copy number, proteins, and metabolites, as well as their cellular interactions [11]. Gene set and pathway association analyses are playing an increasingly important role in explaining disease mechanisms through the identification of functional genetic interactions [12]. Many gene-disease association analyses are based on SNP genotype profiling or gene expression studies. However, SNPs can influence many downstream processes including the expression levels of multiple genes and/or protein levels, and variations in expression levels can directly or indirectly impact disease progression and even drug response [13]. An integrative approach combining multiple data types can more accurately capture pathway associations [12] for discovery of clinically actionable variants. > Statistical approaches commonly used to associate variants with disease and/or drug response Fisher's exact test (FET) is commonly used in the association of germline polymorphisms with drug response [14]. The use of probabilistic networks in conjunction with traditional statistical models for mining relationships and associations from genotype-phenotype data is well established [15]. Probabilistic network methods for pharmacogenomics and newer methods such as the Markov Blanket concept may be helpful to better analyze these complex genotype-phenotype associations [16]. Considering the complexity of both cancer prognosis and individual drug response to chemotherapeutics, application of these association methods in conjunction with novel informatics and data integration approaches is necessary to identify clinically relevant variants for validation studies and ultimately testing in the clinic for pharmacogenomics applications.

[14] 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: 0.359) > 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].

[15] 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: 0.359) > 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.

[16] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.358) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[17] Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

Authors: Jing-wen Li, Xinjie Zhang, Jianfeng Guo, Chen Yu, Jun Yang
Year: 2022
Venue: Frontiers in Genetics
URL: https://www.semanticscholar.org/paper/d53bdf5f73f54a6d5a8be8777d23c465a13e9185
DOI: 10.3389/fgene.2021.777926
PMID: 35047005
PMCID: 8762052
Citations: 15
Influential citations: 2
Summary: Some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus are elicited, and knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.
Evidence snippets:
Snippet 1 (score: 0.355) > Cwh43 modifies the glycosylphosphatidylinositol-anchored proteins on the ependymal cells, and the mutant Cwh43 is related to iNPH in both humans and mice. The clinical features manifest as late-onset communicating hydrocephalus with symptoms of gait and balance dysfunction (Yang et al., 2021a). > The clinical manifestation and progression, as well as experimental investigations, indicate that hydrocephalus is a complex disease with polygenic involvement, rather than a simple CSF accumulation disorder. Although the current studies have revealed that some genetic mutations are involved in the pathogenesis of hydrocephalus, how these mutations are associated with the disorder of CSF circulation and their pathogenic roles in the pathological progression of hydrocephalus still remain largely unknown. Previous studies indicated that a lot of genetic mutations were relevant to the disorders of ciliary and/or centrosome, resulting in the dysfunction of the glymphatic system. However, how these mutations and their interactions contribute to the pathogenesis of hydrocephalus needs to be further elucidated. Moreover, there is still a lack of basic knowledge on the mechanisms underlying the cognitive functional impairment of hydrocephalus. Therefore, further extensive studies should be conducted to explore the underlying molecular mechanisms of identified and/or unidentified genes in the pathophysiology of hydrocephalus. Based on our knowledge, we propose that the genetic mutations relevant to ciliary and centrosomal proteins and the interaction between glymphatic system and ciliary/ centrosomal structures/functions may be a critical molecular mechanism in the pathophysiology of hydrocephalus. In addition, based on these fundamental molecular mechanisms, it is noteworthy that environmental and other acquired risks or etiological factors are also involved in the facilitation of ventricular enlargement.

[18] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
Year: 2023
Venue: Genes
URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
DOI: 10.3390/genes14091734
PMID: 37761876
PMCID: 10531442
Citations: 11
Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
Evidence snippets:
Snippet 1 (score: 0.353) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[19] Single-nucleus multi-omics identifies shared and distinct pathways in Pick’s and Alzheimer’s disease

Authors: Zechuan Shi, Sudeshna Das, S. Morabito, Jennifer T. Stocksdale, Emily Miyoshi et al.
Year: 2024
Venue: bioRxiv
URL: https://www.semanticscholar.org/paper/ca1fba4e0f132d9a309b13c1dc393873bf0de2ad
DOI: 10.1101/2024.09.06.611761
PMID: 39282421
PMCID: 11398495
Citations: 3
Summary: Comparative studies in AD and PiD reveal critical regulatory changes driving disease progression and identify risk gene associations for PiD, and validated the findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks.
Evidence snippets:
Snippet 1 (score: 0.352) > Our differential analyses highlight the utility of our identified promoter-enhancer links in elucidating regulatory mechanisms, and revealed widespread chromatin accessibility and gene expression changes linked to PiD and AD pathology across major cell types. Some of these changes, including the increased chromatin accessibility and dysregulated gene expression involved in synap- tic signaling, apoptotic process, regulation of neuronal activity, cellular response to stress, and cell communication, may represent an attempt of neurons and oligodendrocytes interaction to reestablish homeostasis through necessary attempts to different genes. Some promoter-enhancer connections facilitated increased chromatin accessibility, potentially serving as a compensatory mechanism to mitigate the dysregulation of target genes. Other alterations, including positive regulation of endocytosis, genes responsible for cellular metabolic process, and genes encoding cellular response to unfolded/misfolded protein in astrocytes and microglia, may contribute to glial cell differentiation or immune activation in PiD and AD. Disruptions in the metabolic processes and cellular stress response compromise the balance in the cellular microenvironment and consequently contribute to the progression of PiD and AD. > While the causative molecular mechanisms of PiD remain unknown, our work offers new insights that assist in unraveling the nature of gene regulation in PiD, especially regarding genomic loci with well-described heritable disease risk. We capitalized on the AD and FTD GWAS data to identify genes associated with phenotypic variability between PiD and AD because of similar pathological and clinical traits, such as tauopathies and cognitive decline. GWASs have been widely used to enhance our understanding of polygenic human traits and to reveal clinically relevant risk variants for neurodegeneration. Notably, we identified genetic risk variants that overlapped with specific cell types to narrow down the potential non-coding variants underlying disease susceptibility. Furthermore, our analysis revealed that AD GWAS genes showed a highly significant overlap with differentially expressed genes in PiD cases, suggesting that these associations are not random. This highlights the potential convergent regulatory mechanisms that may be shared between PiD and AD, despite the distinct clinical manifestations.

[20] Can network biology unravel the aetiology of congenital hyperinsulinism?

Authors: A. Stevens, K. Cosgrove, R. Padidela, M. Skae, P. Clayton et al.
Year: 2013
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/474ed97fdbb2a604459faa0b626a8b7d20ed6bf4
DOI: 10.1186/1750-1172-8-21
PMID: 23394473
PMCID: 3599136
Citations: 9
Influential citations: 1
Summary: A rational argument for the use of computational biology as a valuable resource for identifying new candidate genes which may cause disease and for understanding the complex mechanisms which define the pathophysiology of this rare disease is presented.
Evidence snippets:
Snippet 1 (score: 0.352) > Congenital Hyperinsulinism (CHI) is a rare disease, but is the most common cause of recurrent hypoglycaemia in infancy [1]. The treatment of CHI can be difficult and involves drugs which may not be successful and often are poorly tolerated. As a potentially life-threatening condition, CHI is associated with lifelong sequelae -including critical brain damage (epilepsy, cerebral palsy and neurological impairment) in up to 40% of cases. To date, nine candidate genes associate with CHI, but for the majority of patientsestimated to be approximately 65%, both the aetiology of the CHI and the mechanisms of disease are unknown. > Our current approach to the classification and treatment of CHI is based largely upon observational correlations between the pathological analysis of candidate gene defects and clinical symptoms of hypoglycaemia [1][2][3]. In this respect, there are similarities between CHI and many other diseases in which numerous mutations in different genes give rise to clinical phenotypes that are essentially indistinguishable from one another. However, under normal physiological conditions, cells function correctly because there is a high degree of interdependency between individual biochemical components (DNA, RNA, proteins and metabolites) and their complex interactions (DNA-protein interactions, protein-protein interactions, metabolic and biochemical pathways, etc.), and tissues function in a co-ordinated manner because there is interplay between different cell types. Diseases rarely result from an abnormality in a single gene, but are in fact the manifestation of disturbances in the multiple networks that integrate cellular processes, and those that link cells with tissues, and tissues with organ systems. As a result, current approaches to molecular diagnosis, however valuable, have shortcomings. These include a lack of sensitivity in identifying preclinical disease, a poor ability to predict prognosis, and ambiguity in defining and resolving a condition where several clinical phenotypes can be observed. All of these inadequacies are evident in CHI, with our current understanding of the causes of disease failing to distinguish transient from persistent disease at the point of presentation and to determine accurately the severity of disease.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schinzel-Giedion syndrome. Core disease mechanisms, molecular and cellular...

Relevant Papers

[1] Role of Transcriptomics in Precision Oncology

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[7] Chemotherapy and Mechanisms of Resistance in Breast Cancer

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[9] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

[10] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

[12] Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

[13] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

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

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

[16] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

[17] Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

[18] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

[19] Single-nucleus multi-omics identifies shared and distinct pathways in Pick’s and Alzheimer’s disease

[20] Can network biology unravel the aetiology of congenital hyperinsulinism?

Notes