🔗

Mappings

MONDO

MONDO:0018760 DeSanto-Shinawi syndrome

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

DeSanto-Shinawi syndrome is typically caused by heterozygous de novo loss of function variants in WAC.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC."

This directly supports the typical dominant de novo inheritance mechanism.

◆

Subtypes

2

DeSanto-Shinawi syndrome due to WAC point mutation MONDO:0014741

WAC hgnc:17327

The form caused by a heterozygous intragenic WAC sequence variant — in reported series most often de novo nonsense, frameshift, or splice-site changes predicted to cause loss of function, alongside occasional missense variants. MONDO and Orphanet name this branch "point mutation" to contrast it with the contiguous-gene deletion form; the label should be read as "intragenic sequence variant" rather than as a restriction to single nucleotide substitutions. The published pathophysiology and phenotype of this entry are drawn almost entirely from cohorts of this kind.

Show evidence (2 references)

PMID:26264232 SUPPORT Human Clinical

"Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation."

Defines the intragenic-variant form of the syndrome and its variant classes, which is what this MONDO subtype denotes.

PMID:26757981 SUPPORT Human Clinical

"In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID."

A second independent cohort ascertained by sequencing rather than by array, confirming the intragenic-variant form as a recognizable entity.

DeSanto-Shinawi syndrome due to 10p11.21p12.31 microdeletion MONDO:0017283

WAC hgnc:17327

The form caused by an interstitial deletion of 10p spanning WAC, first delineated as the 10p12p11 contiguous gene deletion syndrome. Reported deletions range from about 1 Mb to over 10 Mb, so genes other than WAC are lost in most patients and the phenotype is not necessarily reducible to WAC dosage alone; the smallest region of overlap nonetheless contains WAC, and the intragenic-variant cohorts recapitulate the core neurodevelopmental and craniofacial features. Cardiac malformation was reported in six of seven patients in the defining deletion series, a frequency not established for the intragenic form; it is recorded in this entry's phenotype section scoped to this subtype only.

Show evidence (2 references)

PMID:21522184 SUPPORT Human Clinical

"Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb."

The defining series for the deletion subtype, establishing the interval and its size range.

PMID:26264232 SUPPORT Human Clinical

"Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23."

Argues that WAC haploinsufficiency accounts for most of the deletion phenotype, which is the basis for placing the deletion form under the same disease as the intragenic form rather than curating it separately. Note the claim is "most", not all.

⚙

Pathophysiology

4

WAC haploinsufficiency

DeSanto-Shinawi syndrome results from heterozygous loss-of-function variants in WAC.

WAC hgnc:17327

Downstream

Impaired ULK activation and autophagy Loss of WAC disrupts one of its established cellular functions in autophagy regulation

Ventricular septal defect Congenital cardiac malformation reported with WAC loss of function; the developmental route from WAC dosage to the septal defect is not established.

Bicuspid aortic valve Congenital outflow-tract valve malformation reported with WAC loss of function; the developmental route is not established.

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"WAC-related intellectual disability (ID) is a rare genetic condition characterized by a spectrum of neurodevelopmental disorders of varying severity, including global developmental delay (GDD), ID, and autism spectrum disorder."

This supports WAC-related haploinsufficiency as the basis of the neurodevelopmental syndrome.

Impaired ULK activation and autophagy

WAC regulates starvation-induced autophagy by controlling centrosomal GABARAP trafficking and ULK kinase activation.

autophagy GO:0006914 ↓ DECREASED

Downstream

GABAergic-neuron perturbation WAC loss perturbs inhibitory neuronal development and brain circuitry

Show evidence (2 references)

PMID:26687599 SUPPORT In Vitro

"WAC suppresses GM130 binding to GABARAP, regulating starvation-induced centrosomal GABARAP delivery to the phagophore."

This directly supports a mechanistic role for WAC in autophagosome initiation.

PMID:26687599 SUPPORT In Vitro

"In short, during amino acid starvation WAC promotes ULK1 activation and the initiation of autophagosome formation."

This directly links WAC to ULK1 activation and autophagy initiation.

GABAergic-neuron perturbation

Vertebrate models of Wac loss show direct impacts on GABAergic neurons and altered brain-development programs.

Downstream

Seizure susceptibility and neurobehavioral abnormalities Perturbed inhibitory circuitry contributes to seizure and behavioral phenotypes

Show evidence (1 reference)

PMID:38826421 SUPPORT Model Organism

"In addition, each model revealed impacts to GABAergic neurons"

This directly supports a discrete downstream neuronal-cell-type abnormality in vertebrate Wac models.

Seizure susceptibility and neurobehavioral abnormalities

Wac-deficient vertebrate models show seizure susceptibility, brain-volume changes, and relevant behavioral abnormalities aligned with the human syndrome.

Downstream

Global developmental delay WAC-related neurodevelopmental dysfunction manifests as delayed developmental milestones.

Intellectual disability The same neurodevelopmental circuit disruption contributes to intellectual disability.

Autistic behavior Neurobehavioral abnormalities in WAC-related disease include autistic behavior.

Seizure GABAergic-neuron perturbation lowers seizure threshold in DeSanto-Shinawi syndrome.

Abnormal facial shape Syndromic WAC haploinsufficiency includes a recognizable craniofacial gestalt.

Temporo-occipital epileptiform activity The same inhibitory-circuit perturbation that lowers seizure threshold is recorded interictally as focal epileptiform discharges on EEG.

Behavioral abnormalities Neurobehavioral abnormalities in WAC-related disease include ADHD and behavioral difficulties alongside the autism phenotype.

Show evidence (1 reference)

PMID:38826421 SUPPORT Model Organism

"further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors."

This supports a downstream phenotype-oriented branch linking Wac loss to seizure susceptibility and neurobehavioral abnormalities.

⬡

Pathograph

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

●

Phenotypes

11

Cardiovascular 3

Cardiac malformation Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:21522184 SUPPORT Human Clinical

"All patients also displayed various visual impairments and six out of seven patients had cardiac malformations."

The reported count in the defining deletion series. The general heart-morphology term is used because the abstract names no specific lesion.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:42601842 SUPPORT Human Clinical

"The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome."

Case report documents ventricular septal defect in a patient with DeSanto-Shinawi syndrome due to WAC frameshift variant.

Bicuspid aortic valve HP:0001647

Show evidence (1 reference)

PMID:42601842 SUPPORT Human Clinical

"The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome."

Case report documents bicuspid aortic valve in a patient with DeSanto-Shinawi syndrome due to WAC frameshift variant.

Eye 1

Abnormality of vision HP:0000504

Show evidence (1 reference)

PMID:21522184 SUPPORT Human Clinical

"All patients also displayed various visual impairments and six out of seven patients had cardiac malformations."

Same sentence, recording the visual finding. The broader term is bound because "various visual impairments" does not identify a specific deficit, and a narrower term would assert more than the source does.

Head and Neck 1

Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"All individuals presented with GDD, some degree of ID, and variable dysmorphism."

This directly supports recurring craniofacial dysmorphism in the human clinical series.

Nervous System 6

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"All individuals presented with GDD, some degree of ID, and variable dysmorphism."

This directly supports global developmental delay as a core phenotype.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"All individuals presented with GDD, some degree of ID, and variable dysmorphism."

The clinical series explicitly reports intellectual disability in the affected individuals.

Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:38826421 SUPPORT Model Organism

"Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures."

This disease-focused abstract explicitly lists autism among the recurrent neurobehavioral symptoms.

Seizure HP:0001250

Show evidence (2 references)

PMID:38826421 SUPPORT Model Organism

"Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures."

The syndrome summary directly includes seizures among the recognized features.

PMID:42601842 SUPPORT Human Clinical

"We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies."

Reports epilepsy in an individual with a de novo WAC frameshift variant.

Temporo-occipital epileptiform activity EEG with focal epileptiform discharges HP:0011185

Show evidence (1 reference)

PMID:42601842 SUPPORT Human Clinical

"serial electroencephalography demonstrated persistent epileptiform activity involving the bilateral temporo-occipital regions, with left temporo-occipital persistence on follow-up."

Case report provides detailed electroclinical characterization of temporo-occipital epileptiform activity in DeSanto-Shinawi syndrome.

Behavioral abnormalities Atypical behavior HP:0000708

Show evidence (2 references)

PMID:42601842 SUPPORT Human Clinical

"The clinical spectrum of DESSH continues to expand, whereas detailed electroencephalographic descriptions remain limited. We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies."

Case report explicitly documents behavioral abnormalities as a core feature.

PMID:38826421 SUPPORT Model Organism

"Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures."

Names ADHD and behavioral difficulties among the recurrent neurobehavioral symptoms, which is the part of this phenotype's description the case report alone does not reach.

🧬

Genetic Associations

1

WAC (Loss-of-function)

Gene: WAC hgnc:17327

Show evidence (3 references)

PMID:35018708 SUPPORT Human Clinical

"All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC."

This directly supports the causal gene and variant class.

PMID:42601842 SUPPORT Human Clinical

"Whole-exome sequencing identified a novel heterozygous apparently de novo frameshift variant in WAC (NM_016628.5:c.1793delT; p.Met598Serfs*8), which was classified as pathogenic according to ACMG/AMP criteria."

Case report documents a novel pathogenic frameshift variant expanding the mutational spectrum of WAC-related DeSanto-Shinawi syndrome.

CGGV:assertion_6a1f3c78-d7d2-4a8c-8dbf-ddda78769bd7-2022-11-10T170000.000Z SUPPORT Other

ClinGen classifies the WAC-DeSanto-Shinawi syndrome gene-disease relationship as definitive with autosomal dominant inheritance.

💊

Medical Actions

1

Supportive neurodevelopmental and behavioral care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Management is supportive and typically includes developmental therapies, educational support, and symptom-guided neurologic or behavioral treatment.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from DeSanto-Shinawi syndrome:

Kabuki syndrome MONDO:0016512

Overlapping Features Kabuki syndrome overlaps with DeSanto-Shinawi syndrome through developmental delay, hypotonia, and distinctive facial features, but differs in its characteristic epigenetic gene causes and broader multisystem pattern.

Distinguishing Features

WAC loss-of-function with autism-predominant neurobehavioral features favors DeSanto-Shinawi syndrome.
Persistent fingertip pads and the classic Kabuki craniofacial gestalt favor Kabuki syndrome.

Noonan syndrome MONDO:0018997

Overlapping Features Noonan syndrome may enter the differential because of developmental delay and craniofacial overlap, but it is usually distinguished by congenital heart disease, short stature, and a RASopathy mechanism.

Distinguishing Features

Autism and seizure-associated WAC-related neurodevelopmental findings favor DeSanto-Shinawi syndrome.
Pulmonary valve stenosis, lymphatic findings, and RASopathy facies favor Noonan syndrome.

📊

Related Datasets

1

Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant. PMID:35018708

Human clinical-genetic case series of five individuals with WAC-related neurodevelopmental disorder, including phenotype expansion and splicing validation for a recurrent pathogenic variant.

human n=5

Conditions: DeSanto-Shinawi syndrome WAC loss-of-function variants

PMID:35018708

Show evidence (1 reference)

PMID:35018708 SUPPORT Human Clinical

"Here, we describe five affected individuals, age range 9-20 years, and provide proof of pathogenicity of a novel splicing variant."

This defines a disease-specific human case-series dataset for WAC-related disorder phenotyping and variant interpretation.

{ }

Source YAML

click to show

name: DeSanto-Shinawi syndrome
creation_date: '2026-04-11T19:38:25Z'
category: Mendelian
description: >-
  DeSanto-Shinawi syndrome is an autosomal dominant neurodevelopmental disorder
  caused by heterozygous loss-of-function variants in WAC. WAC participates in
  transcription-coupled chromatin regulation and in starvation-induced
  autophagy, where it regulates centrosomal GABARAP trafficking and ULK kinase
  activation. Loss of WAC function disrupts these cellular processes and is
  associated with developmental delay or intellectual disability, autism and
  behavioral symptoms, seizures in a subset of individuals, and characteristic
  craniofacial findings.
disease_term:
  preferred_term: DeSanto-Shinawi syndrome
  term:
    id: MONDO:0018760
    label: DeSanto-Shinawi syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018760
      label: DeSanto-Shinawi syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- syndromic intellectual disability
- hereditary disease
has_subtypes:
- name: WAC point mutation
  display_name: DeSanto-Shinawi syndrome due to WAC point mutation
  description: >-
    The form caused by a heterozygous intragenic WAC sequence variant — in
    reported series most often de novo nonsense, frameshift, or splice-site
    changes predicted to cause loss of function, alongside occasional missense
    variants. MONDO and Orphanet name this branch "point mutation" to contrast
    it with the contiguous-gene deletion form; the label should be read as
    "intragenic sequence variant" rather than as a restriction to single
    nucleotide substitutions. The published pathophysiology and phenotype of
    this entry are drawn almost entirely from cohorts of this kind.
  subtype_term:
    preferred_term: DeSanto-Shinawi syndrome due to WAC point mutation
    term:
      id: MONDO:0014741
      label: DeSanto-Shinawi syndrome due to WAC point mutation
  genes:
  - preferred_term: WAC
    term:
      id: hgnc:17327
      label: WAC
  evidence:
  - reference: PMID:26264232
    reference_title: "WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation.
    explanation: >-
      Defines the intragenic-variant form of the syndrome and its variant
      classes, which is what this MONDO subtype denotes.
  - reference: PMID:26757981
    reference_title: "De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID.
    explanation: >-
      A second independent cohort ascertained by sequencing rather than by array,
      confirming the intragenic-variant form as a recognizable entity.
- name: 10p11.21p12.31 microdeletion
  display_name: DeSanto-Shinawi syndrome due to 10p11.21p12.31 microdeletion
  description: >-
    The form caused by an interstitial deletion of 10p spanning WAC, first
    delineated as the 10p12p11 contiguous gene deletion syndrome. Reported
    deletions range from about 1 Mb to over 10 Mb, so genes other than WAC are
    lost in most patients and the phenotype is not necessarily reducible to WAC
    dosage alone; the smallest region of overlap nonetheless contains WAC, and
    the intragenic-variant cohorts recapitulate the core neurodevelopmental and
    craniofacial features. Cardiac malformation was reported in six of seven
    patients in the defining deletion series, a frequency not established for
    the intragenic form; it is recorded in this entry's phenotype section scoped
    to this subtype only.
  subtype_term:
    preferred_term: DeSanto-Shinawi syndrome due to 10p11.21p12.31 microdeletion
    term:
      id: MONDO:0017283
      label: DeSanto-Shinawi Syndrome due to 10p11.21p12.31 microdeletion
  genes:
  - preferred_term: WAC
    term:
      id: hgnc:17327
      label: WAC
  evidence:
  - reference: PMID:21522184
    reference_title: "Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb.
    explanation: >-
      The defining series for the deletion subtype, establishing the interval and
      its size range.
  - reference: PMID:26264232
    reference_title: "WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.
    explanation: >-
      Argues that WAC haploinsufficiency accounts for most of the deletion
      phenotype, which is the basis for placing the deletion form under the same
      disease as the intragenic form rather than curating it separately. Note the
      claim is "most", not all.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    DeSanto-Shinawi syndrome is typically caused by heterozygous de novo loss of
    function variants in WAC.
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC.
    explanation: >-
      This directly supports the typical dominant de novo inheritance mechanism.
pathophysiology:
- name: WAC haploinsufficiency
  description: >-
    DeSanto-Shinawi syndrome results from heterozygous loss-of-function variants
    in WAC.
  genes:
  - preferred_term: WAC
    term:
      id: hgnc:17327
      label: WAC
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WAC-related intellectual disability (ID) is a rare genetic condition characterized by a spectrum of neurodevelopmental disorders of varying severity, including global developmental delay (GDD), ID, and autism spectrum disorder.
    explanation: >-
      This supports WAC-related haploinsufficiency as the basis of the
      neurodevelopmental syndrome.
  downstream:
  - target: Impaired ULK activation and autophagy
    description: Loss of WAC disrupts one of its established cellular functions in autophagy regulation
  - target: Ventricular septal defect
    description: >-
      Congenital cardiac malformation reported with WAC loss of function; the
      developmental route from WAC dosage to the septal defect is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Bicuspid aortic valve
    description: >-
      Congenital outflow-tract valve malformation reported with WAC loss of
      function; the developmental route is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired ULK activation and autophagy
  description: >-
    WAC regulates starvation-induced autophagy by controlling centrosomal
    GABARAP trafficking and ULK kinase activation.
  biological_processes:
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:26687599
    reference_title: "Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      WAC suppresses GM130 binding to GABARAP, regulating starvation-induced centrosomal GABARAP delivery to the phagophore.
    explanation: >-
      This directly supports a mechanistic role for WAC in autophagosome
      initiation.
  - reference: PMID:26687599
    reference_title: "Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In short, during amino acid starvation WAC promotes ULK1 activation and the initiation of autophagosome formation.
    explanation: >-
      This directly links WAC to ULK1 activation and autophagy initiation.
  downstream:
  - target: GABAergic-neuron perturbation
    description: WAC loss perturbs inhibitory neuronal development and brain circuitry
- name: GABAergic-neuron perturbation
  description: >-
    Vertebrate models of Wac loss show direct impacts on GABAergic neurons and
    altered brain-development programs.
  evidence:
  - reference: PMID:38826421
    reference_title: "Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, each model revealed impacts to GABAergic neurons
    explanation: >-
      This directly supports a discrete downstream neuronal-cell-type abnormality
      in vertebrate Wac models.
  downstream:
  - target: Seizure susceptibility and neurobehavioral abnormalities
    description: Perturbed inhibitory circuitry contributes to seizure and behavioral phenotypes
- name: Seizure susceptibility and neurobehavioral abnormalities
  description: >-
    Wac-deficient vertebrate models show seizure susceptibility, brain-volume
    changes, and relevant behavioral abnormalities aligned with the human
    syndrome.
  evidence:
  - reference: PMID:38826421
    reference_title: "Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors.
    explanation: >-
      This supports a downstream phenotype-oriented branch linking Wac loss to
      seizure susceptibility and neurobehavioral abnormalities.
  downstream:
  - target: Global developmental delay
    description: WAC-related neurodevelopmental dysfunction manifests as delayed developmental milestones.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GABAergic-neuron perturbation
    - brain-volume and behavior abnormalities
  - target: Intellectual disability
    description: The same neurodevelopmental circuit disruption contributes to intellectual disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GABAergic-neuron perturbation
    - impaired neurodevelopmental program
  - target: Autistic behavior
    description: Neurobehavioral abnormalities in WAC-related disease include autistic behavior.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GABAergic-neuron perturbation
    - neurobehavioral circuit dysfunction
  - target: Seizure
    description: GABAergic-neuron perturbation lowers seizure threshold in DeSanto-Shinawi syndrome.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - inhibitory-circuit perturbation
  - target: Abnormal facial shape
    description: Syndromic WAC haploinsufficiency includes a recognizable craniofacial gestalt.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Temporo-occipital epileptiform activity
    description: >-
      The same inhibitory-circuit perturbation that lowers seizure threshold is
      recorded interictally as focal epileptiform discharges on EEG.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - inhibitory-circuit perturbation
  - target: Behavioral abnormalities
    description: >-
      Neurobehavioral abnormalities in WAC-related disease include ADHD and
      behavioral difficulties alongside the autism phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GABAergic-neuron perturbation
    - neurobehavioral circuit dysfunction
phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay is a central and recurring feature of DeSanto-Shinawi
    syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals presented with GDD, some degree of ID, and variable dysmorphism.
    explanation: >-
      This directly supports global developmental delay as a core phenotype.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is common, although severity varies across the
    syndrome spectrum.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals presented with GDD, some degree of ID, and variable dysmorphism.
    explanation: >-
      The clinical series explicitly reports intellectual disability in the
      affected individuals.
- name: Autistic behavior
  category: Behavioral
  description: >-
    Autism spectrum symptoms are part of the recurrent neurobehavioral profile
    of DeSanto-Shinawi syndrome.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:38826421
    reference_title: "Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures.
    explanation: >-
      This disease-focused abstract explicitly lists autism among the recurrent
      neurobehavioral symptoms.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures affect a subset of individuals with DeSanto-Shinawi syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38826421
    reference_title: "Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures.
    explanation: >-
      The syndrome summary directly includes seizures among the recognized
      features.
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies.
    explanation: >-
      Reports epilepsy in an individual with a de novo WAC frameshift variant.
- name: Temporo-occipital epileptiform activity
  category: Neurologic
  description: >-
    Detailed electroclinical characterization reveals bilateral temporo-occipital
    epileptiform activity, with persistent left-sided focus on follow-up EEG, in
    some individuals with WAC-related seizures.
  phenotype_term:
    preferred_term: Bilateral temporo-occipital epileptiform discharges
    term:
      id: HP:0011185
      label: EEG with focal epileptiform discharges
  evidence:
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      serial electroencephalography demonstrated persistent epileptiform activity involving the bilateral temporo-occipital regions, with left temporo-occipital persistence on follow-up.
    explanation: >-
      Case report provides detailed electroclinical characterization of temporo-occipital
      epileptiform activity in DeSanto-Shinawi syndrome.
- name: Cardiac malformation
  category: Cardiovascular
  subtype: 10p11.21p12.31 microdeletion
  description: >-
    Cardiac malformation was reported in six of seven patients in the series that
    defined the 10p12p11 deletion syndrome. It is scoped to the deletion subtype:
    the intragenic-variant series did not report cardiac malformation, and no
    frequency for the intragenic form has been established, so this phenotype
    makes no claim about that subtype. Whether the cardiac finding is attributable
    to WAC dosage or to neighbouring genes lost in the larger deletions is not
    settled.
  phenotype_term:
    preferred_term: Cardiac malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:21522184
    reference_title: "Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients also displayed various visual impairments and six out of seven patients had cardiac malformations.
    explanation: >-
      The reported count in the defining deletion series. The general
      heart-morphology term is used because the abstract names no specific lesion.
- name: Abnormality of vision
  category: Ophthalmologic
  subtype: 10p11.21p12.31 microdeletion
  description: >-
    Visual impairment was reported in all seven patients in the defining deletion
    series. The abstract does not specify the kind of impairment, so the binding
    is deliberately left at the general vision-abnormality term rather than
    narrowed. Note the intragenic-variant series separately reported eye
    abnormalities in five of six patients, but under different wording and
    ascertainment, so the two are not pooled here.
  phenotype_term:
    preferred_term: Various visual impairments
    term:
      id: HP:0000504
      label: Abnormality of vision
  evidence:
  - reference: PMID:21522184
    reference_title: "Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients also displayed various visual impairments and six out of seven patients had cardiac malformations.
    explanation: >-
      Same sentence, recording the visual finding. The broader term is bound
      because "various visual impairments" does not identify a specific deficit,
      and a narrower term would assert more than the source does.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    A recognizable craniofacial gestalt is a recurrent component of
    DeSanto-Shinawi syndrome.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals presented with GDD, some degree of ID, and variable dysmorphism.
    explanation: >-
      This directly supports recurring craniofacial dysmorphism in the human
      clinical series.
- name: Behavioral abnormalities
  category: Behavioral
  description: >-
    Behavioral abnormalities including ADHD and behavioral difficulties are
    recurrent features of DeSanto-Shinawi syndrome, distinct from autism but
    part of the broader neurobehavioral spectrum.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical spectrum of DESSH continues to expand, whereas detailed electroencephalographic descriptions remain limited. We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies.
    explanation: >-
      Case report explicitly documents behavioral abnormalities as a core feature.
  - reference: PMID:38826421
    reference_title: "Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures.
    explanation: >-
      Names ADHD and behavioral difficulties among the recurrent neurobehavioral
      symptoms, which is the part of this phenotype's description the case report
      alone does not reach.
- name: Ventricular septal defect
  category: Cardiac
  description: >-
    Ventricular septal defect reported in an individual with a de novo WAC
    frameshift variant, co-occurring with bicuspid aortic valve. Cardiac
    malformation is separately established for the 10p11.21p12.31 microdeletion
    subtype; this is the intragenic-variant counterpart and rests on a single
    case, so it carries no frequency claim.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome.
    explanation: >-
      Case report documents ventricular septal defect in a patient with DeSanto-Shinawi syndrome due to WAC frameshift variant.
- name: Bicuspid aortic valve
  category: Cardiac
  description: >-
    Bicuspid aortic valve reported in an individual with a de novo WAC
    frameshift variant, co-occurring with ventricular septal defect. Rests on a
    single case, so it carries no frequency claim.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome.
    explanation: >-
      Case report documents bicuspid aortic valve in a patient with DeSanto-Shinawi syndrome due to WAC frameshift variant.
genetic:
- name: WAC
  association: Loss-of-function
  gene_term:
    preferred_term: WAC
    term:
      id: hgnc:17327
      label: WAC
  notes: >-
    Most reported individuals carry heterozygous de novo truncating, splice, or
    other loss-of-function variants in WAC. Examples include frameshift variants
    such as c.1793delT (p.Met598Serfs*8), which are classified as pathogenic by
    ACMG/AMP criteria.
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals were heterozygous for de novo, previously unreported, loss of function variants in WAC.
    explanation: >-
      This directly supports the causal gene and variant class.
  - reference: PMID:42601842
    reference_title: "A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a novel heterozygous apparently de novo frameshift variant in WAC (NM_016628.5:c.1793delT; p.Met598Serfs*8), which was classified as pathogenic according to ACMG/AMP criteria.
    explanation: >-
      Case report documents a novel pathogenic frameshift variant expanding the mutational spectrum of WAC-related DeSanto-Shinawi syndrome.
  - reference: CGGV:assertion_6a1f3c78-d7d2-4a8c-8dbf-ddda78769bd7-2022-11-10T170000.000Z
    reference_title: "WAC / DeSanto-Shinawi syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "WAC | HGNC:17327 | DeSanto-Shinawi syndrome | MONDO:0018760 | AD | Definitive"
    explanation: ClinGen classifies the WAC-DeSanto-Shinawi syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Supportive neurodevelopmental and behavioral care
  description: >-
    Management is supportive and typically includes developmental therapies,
    educational support, and symptom-guided neurologic or behavioral treatment.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
differential_diagnoses:
- name: Kabuki syndrome
  disease_term:
    preferred_term: Kabuki syndrome
    term:
      id: MONDO:0016512
      label: Kabuki syndrome
  description: >-
    Kabuki syndrome overlaps with DeSanto-Shinawi syndrome through developmental
    delay, hypotonia, and distinctive facial features, but differs in its
    characteristic epigenetic gene causes and broader multisystem pattern.
  distinguishing_features:
  - WAC loss-of-function with autism-predominant neurobehavioral features favors DeSanto-Shinawi syndrome.
  - Persistent fingertip pads and the classic Kabuki craniofacial gestalt favor Kabuki syndrome.
- name: Noonan syndrome
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  description: >-
    Noonan syndrome may enter the differential because of developmental delay
    and craniofacial overlap, but it is usually distinguished by congenital
    heart disease, short stature, and a RASopathy mechanism.
  distinguishing_features:
  - Autism and seizure-associated WAC-related neurodevelopmental findings favor DeSanto-Shinawi syndrome.
  - Pulmonary valve stenosis, lymphatic findings, and RASopathy facies favor Noonan syndrome.
clinical_trials: []
datasets:
- accession: PMID:35018708
  title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
  description: >-
    Human clinical-genetic case series of five individuals with WAC-related
    neurodevelopmental disorder, including phenotype expansion and splicing
    validation for a recurrent pathogenic variant.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 5
  conditions:
  - DeSanto-Shinawi syndrome
  - WAC loss-of-function variants
  publication: PMID:35018708
  evidence:
  - reference: PMID:35018708
    reference_title: "Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe five affected individuals, age range 9-20 years, and provide proof of pathogenicity of a novel splicing variant.
    explanation: >-
      This defines a disease-specific human case-series dataset for WAC-related
      disorder phenotyping and variant interpretation.
notes: >-
  Asta deep research was run as requested, but final curation relied on direct
  PubMed review because the retrieval output was noisy and only partially
  disease-specific.

📚

References & Deep Research

Deep Research

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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 (1)

Record notes

Asta deep research was run as requested, but final curation relied on direct PubMed review because the retrieval output was noisy and only partially disease-specific.

Asta ▸

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

Asta Scientific Corpus Retrieval 20 citations 2026-04-11T16:00:20.198191

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of DeSanto-Shinawi 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] Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing

Authors: Jiahe Wang, Yi Fan, Guowen Luo, L. Xiong, Lijie Wang et al.
Year: 2025
Venue: Advanced Science
URL: https://www.semanticscholar.org/paper/a9cdd48066fec3e65a3fc68c0d9a984d39a4bbe3
DOI: 10.1002/advs.202406759
PMID: 39840526
PMCID: 11904943
Citations: 4
Influential citations: 1
Summary: The findings reveal a previously unrecognized mechanism for the nuclear regulation of mitochondrial function through liquid–liquid phase separation (LLPS) and provide insights into the pathogenesis of WAC‐related disorders.
Evidence snippets:
Snippet 1 (score: 0.427) > This insight into the role of WAC in RNA biogenesis, particularly within nuclear speckles, opens new avenues for understanding the multifaceted mechanisms governing gene expression. > In eukaryotes, the regulation of gene expression is a multistep and highly complex process that is meticulously balanced to maintain physiological equilibrium. Disruptions in this balance, especially through aberrant AS, can lead to a wide range of diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Our findings not only reveal that the WAC protein forms a scaffold within nuclear speckles by recruiting client proteins to specific condensates through its multivalent domain but also highlight the role of condensate absence in generating BECN1-S, thereby impacting mitochondrial autophagy. The connection between the regulation of AS and mitochondrial autophagy by WAC condensates underscores a novel pathway that could contribute to the pathogenesis of diseases related to WAC dysfunction or imbalances in mitochondrial autophagy homeostasis, offering new insights into the cellular and molecular mechanisms driving disease progression. > Patients with loss-of-function mutations in WAC were first identified as having Desanto-Shinawi syndrome in 2015, which is characterized by a neurocognitive phenotype and fa-cial dysmorphism. [16] Interestingly, all patients with Desanto-Shinawi syndrome and loss-of-function mutations in WAC appear to have lost the CC domain of WAC, [30] which strengthens our hypothesis that phase-separated characteristics play an important role in nuclear biological functions. These findings will contribute to our understanding of biomolecular condensates and the potential pathogenesis through which improperly regulated AS leads to Desanto-Shinawi syndrome.

[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: 0.386) > 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] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Authors: Kyung-Yil Lee
Year: 2022
Venue: Cell & Bioscience
URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
DOI: 10.1186/s13578-022-00920-5
PMID: 36384812
PMCID: 9668226
Citations: 9
Influential citations: 1
Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
Evidence snippets:
Snippet 1 (score: 0.368) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[4] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

Authors: A. W. Rachfal, S. Grant, S. Schwartz
Year: 2021
Venue: International Journal of General Medicine
URL: https://www.semanticscholar.org/paper/4c088a6a8b613c15e817f7491d24022497b7f5c4
DOI: 10.2147/IJGM.S305156
PMID: 33776471
PMCID: 7987256
Citations: 6
Summary: The “Diabetes Syndrome”, an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions.
Evidence snippets:
Snippet 1 (score: 0.367) > Although many pathways lead to hyperglycemia in diabetes -the so-called "Egregious Eleven" (Listed in Table 1) -β-cell dysfunction is the core defect. 1,2 Four basic pathophysiologic mechanisms damage the β-cell, namely, genes and epigenetic changes, inflammation, an abnormal environment [especially fuel excess], and insulin resistance (IR). 1,2 2][3] The interplay between these pathophysiologic mechanisms influences the specific risk of development and progression of complications in an individual patient. [6][7][8][9][10][11][12][13][14][15] In clinical practice we often encounter these common diseases, frequently within one individual patient and they are treated as independent conditions. However, we believe their epidemiologic associations is, in part, due to the same underlying pathophysiologies driving β-cell damage and diabetic complications. That is, the same pathophysiologic mechanisms that damage the β-cell and promote diabetesspecific complications also have key roles in the pathogenesis of these diseases. ][9][10][11][12][13][14][15] However, we propose these connections go beyond mere epidemiologic links due to overlapping pathophysiology. In fact, these conditions occur together in enough frequency and have common overlapping pathophysiologic drivers that we have created a conceptual framework called "The Diabetes Syndrome". The name is inspired by the Greek meaning of syndromē (sun-[together] + dramein [to run]) as the conditions, indeed, run together (Figure 1). This article will describe the shared pathophysiologic and etiologic factors across these prevalent and related diseases within the Diabetes Syndrome conceptual framework discussed within the context of the 4 basic pathophysiologic mechanisms -genes and epigenetic changes, abnormal environment, inflammation, and IR -with a focus on commonalities between these diseases and DM. In brief, genetics can mediate susceptibility to damage from abnormal external and internal environmental factors, including inflammation and IR. All these mechanisms can promote epigenetic changes.

[5] 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: 0.366) > 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.

[6] 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: 0.357) > 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.

[7] 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: 2
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: 0.353) > 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.

[8] 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: 0.351) > 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.

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.351) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[10] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

Authors: K. Lourida, G. Louridas
Year: 2022
Venue: Cardiogenetics
URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
DOI: 10.3390/cardiogenetics12020015
Citations: 4
Influential citations: 1
Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
Evidence snippets:
Snippet 1 (score: 0.350) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[11] 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: 0.350) > 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

[12] Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development

Authors: Huifang Peng, Wenyuan Peng, Jiali Chen, Keyan Hu, Yingyu Zhang et al.
Year: 2025
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/ff11ed0f8a3776fc0ef16b1d0673cc0735fc84a2
DOI: 10.3389/fendo.2025.1507749
PMID: 40026690
PMCID: 11867910
Citations: 1
Summary: Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected.
Evidence snippets:
Snippet 1 (score: 0.348) > The RNA helicase DHX37 gene is involved in ribosomal biological processes, and linked to human genetic diseases associated with 46,XY disorders of sex development (46,XY DSD) or neurodevelopment. Recently, relevant reports have primarily focused on 46,XY DSD. However, there is still a lack of overall understanding of the genetic characteristics, phenotype, etc. of the DHX37 gene in human genetic diseases, and its molecular mechanism is not fully understood. We searched literature databases and summarized and analyzed all the literature related to DHX37 to date, including case reports, cohort studies, and molecular mechanism studies, to comprehensively demonstrate the role of DHX37 in human genetic diseases. Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively. In DSD cohorts, DHX37 gene mutations have different detection frequencies (0.77%–45.45%), whereas in testicular regression syndrome and 46,XY gonadal dysgenesis cohorts, they have a high detection rate. The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY). The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown. Although the molecular mechanism of DHX37 mutation related 46,XY DSD is unclear, ribosome synthesis, cell cycle regulation, and the NF-κB and Wnt pathways may be affected. This review summarizes the profile of DHX37 defects in human genetic diseases.

[13] Novel Approaches to Studying SLC13A5 Disease

Authors: Adriana S. Beltran
Year: 2024
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
DOI: 10.3390/metabo14020084
PMID: 38392976
PMCID: 10890222
Citations: 2
Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
Evidence snippets:
Snippet 1 (score: 0.348) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[14] 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: 0.348) > : 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.

[15] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

Authors: Tian-Guang Zhang, Chaoyu Miao
Year: 2022
Venue: Acta Pharmaceutica Sinica. B
URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
DOI: 10.1016/j.apsb.2022.10.008
PMID: 36970208
PMCID: 10031255
Citations: 83
Influential citations: 1
Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
Evidence snippets:
Snippet 1 (score: 0.347) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[16] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Authors: Christine Péladeau, J. Sandhu
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
DOI: 10.3390/ijms22116068
PMID: 34199845
PMCID: 8200055
Citations: 17
Influential citations: 1
Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
Evidence snippets:
Snippet 1 (score: 0.343) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[17] LifeTime and improving European healthcare through cell-based interceptive medicine

Authors: N. Rajewsky, G. Almouzni, S. Gorski, S. Aerts, I. Amit et al.
Year: 2020
Venue: Nature
URL: https://www.semanticscholar.org/paper/d626a4acb560c1ef16ea394cb4dccf277882d119
DOI: 10.1038/s41586-020-2715-9
PMID: 32894860
PMCID: 7656507
Citations: 138
Influential citations: 2
Summary: The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe over the next decade.
Evidence snippets:
Snippet 1 (score: 0.343) > , a major challenge is a lack of understanding of the early events in disease onset to enable the development of disease-modifying therapies. The lack of access to longitudinal samples from patients necessitates the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. The discovery of pathways and biomarkers that will allow the stratification of patients on the basis of the cellular mechanisms that drive a disease will make it possible to design new clinical trials to reevaluate drugs that were previously tested without such stratification, and to broaden the drug target portfolio. > As seen during the coronavirus disease 2019 (COVID-19) pandemic, it is important to be able to understand infection mechanisms and the host response in order to rapidly identify the most likely effective treatment for an infection. At the same time, the continuous rise of antimicrobial resistance requires the discovery of new therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and to develop precision, immune-based therapeutic strategies to combat infections. > Chronic inflammatory diseases impose a high burden owing to their long-term debilitating consequences, which result from the structural destruction of affected organs or tissues. Current therapies treat the symptoms but do not cure or fully control the chronic inflammatory pathophysiology. While different targeted therapies exist, they are expensive and their success is limited by high rates of non-response to treatment. Consequently, there is an urgent need to explore and understand how cellular heterogeneity contributes to the pathology of inflammatory diseases 61 and how this relates to the predicted course of disease and the response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies owing to a lack of knowledge of their underlying causes and the link between abnormal cardiac cell structure or function and pathophysiology. The identified medical priority is to understand the cellular and molecular mechanisms involved, in order to enable early diagnosis and the design of new mechanism-based therapies for precise clinical treatment. > The LifeTime disease roadmaps can be divided broadly into three phases 7 : first, immediate research into the identified medical challenges using established, scaled single-cell technologies, computational tools and disease models; second, the development of new technologies that are required

[18] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

Authors: A. Morsy, Angelica V Carmona, P. Trippier
Year: 2021
Venue: Molecules
URL: https://www.semanticscholar.org/paper/d510bd31c2c0312641423e0a06892605943439bc
DOI: 10.3390/molecules26206235
PMID: 34684815
PMCID: 8538546
Citations: 10
Influential citations: 2
Summary: An overview of available iPSC models for a number of different NCLs is provided and findings in these models that may spur target identification and drug development are highlighted.
Evidence snippets:
Snippet 1 (score: 0.342) > The NCLs encompasses a group of rare, fatal, pediatric neurodegenerative lysosomal storage disorders.Several gene mutations (CLN1-CLN8, CLN10-CLN14) can lead to NCL; however, a partial understanding of the function of the disease-associated proteins has hindered therapy development.Current treatment options are only symptomatic and focus on delaying progression.To date, there are only two clinically approved drugs, Brineuria, for the treatment of CLN2 disease, and Neurogene's recently approved gene therapy to treat CLN5 disease.Different organism models have become available for NCL disease research which have provided a myriad of important information about the protein function or dysfunction for each of the associated genes, possible disease mechanisms, and have enabled detailed preclinical studies and in a small number of cases, clinical trials. > Herein, we have highlighted the contributions of different disease models to NCL research, focusing on the established patient-derived iPSC phenotypic screening models.The ability of iPSCs to encompass the precise pattern of genetic variants, along with acquiring disease pathogenesis and phenotype makes them a more translational model compared to mice and eliminates the problem of species difference.However, compared to animal models, fewer iPSC models currently exist. > The brain is a complex network of many different cellular phenotypes and screening compounds in just one phenotype, i.e., neurons, is not a complete representation of the environment in the brain.While most studies in NCL patient-derived iPSCs employ either NPCs or neurons there are emerging studies looking at biochemical and pathophysiology effects of NCL on other cell phenotypes, one such example is the use of BMECs to model the blood-brain barrier that identified an impaired barrier phenotype in CLN3.Differentiation of iPSCs into other phenotypes including oligodendrocytes, astrocytes, microglia etc. is ongoing and results are expected in due course.These cell types will allow the construction of increasingly complex co-culture models that more readily represent the human brain and thus allow a greater understanding of the disease.

[19] 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: 0.342) > 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.

[20] Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

Authors: F. Bellomo, Ester De Leo, A. Taranta, L. Giaquinto, G. di Giovamberardino et al.
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/5e45caf9d574a1dc3ebf53a7fcb57c10bb2373f8
DOI: 10.3390/ijms222312829
PMID: 34884638
PMCID: 8657658
Citations: 18
Summary: A drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases is shown, combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels.
Evidence snippets:
Snippet 1 (score: 0.342) > Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

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No synthesis or second-stage model call is performed.

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Relevant Papers

[1] Nuclear Condensates of WW Domain‐Containing Adaptor With Coiled‐Coil Regulate Mitophagy via Alternative Splicing

[2] New therapeutic targets in rare genetic skeletal diseases

[3] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

[4] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

[5] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

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

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

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

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

[10] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

[11] Chemotherapy and Mechanisms of Resistance in Breast Cancer

[12] Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development

[13] Novel Approaches to Studying SLC13A5 Disease

[14] Role of Transcriptomics in Precision Oncology

[15] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

[16] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

[17] LifeTime and improving European healthcare through cell-based interceptive medicine

[18] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

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

[20] Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

Notes