👪

Inheritance

1

Autosomal dominant (typically de novo) HP:0000006

YWHAG syndrome is caused by heterozygous pathogenic variants in YWHAG. Reported disease-causing variants are predominantly de novo missense alleles, although familial transmission has also been described in the expanding YWHAG allelic spectrum. Recurrence counseling should include parental testing for the familial variant; if parental blood testing is negative, recurrence risk is low but not zero because parental gonadal mosaicism cannot be fully excluded.

Autosomal dominant inheritance De novo rate: Predominant in reported DEE missense cases; rare familial transmission has also been documented.

Show evidence (2 references)

PMID:28777935 SUPPORT Human Clinical

"We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy"

The original discovery cohort identified de novo heterozygous YWHAG variants as the disease-associated inheritance pattern for early-onset epileptic encephalopathy.

PMID:33767733 SUPPORT Human Clinical

"Two YWHAG mutations were identified in two unrelated families with childhood myoclonic epilepsy and FS, including a familial case with six individuals affected and a sporadic case with de novo mutation."

Supports counseling that the YWHAG allelic spectrum includes both de novo cases and rare familial transmission.

⚙

Pathophysiology

5

Variant-dependent YWHAG / 14-3-3gamma dysfunction

YWHAG encodes the 14-3-3gamma scaffold protein, which coordinates phosphoserine-dependent signaling complexes important for neuronal development. Pathogenic missense variants can perturb the protein through at least two partially distinct mechanisms: recurrent ligand-binding-domain alleles associated with more severe DEE and structural-destabilizing alleles that disrupt the conserved internal hydrophobic core. The recurrent p.Arg132Cys ligand-binding-domain variant provides the best-studied bridge from human genetics to downstream neuronal mechanism.

neuron link cerebral cortex neuron link

Downstream

ROCK-pathway dysregulation and maturation-dependent cytoskeletal remodeling Pathogenic YWHAG dysfunction is linked to altered signaling programs that intersect with ROCK-associated cytoskeletal control in cortical neurons.

Show evidence (3 references)

PMID:28777935 SUPPORT Human Clinical

"We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy"

Establishes YWHAG as the causal disease gene upstream of the downstream neuronal phenotypes represented in this entry.

PMID:38491959 SUPPORT Human Clinical

"A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains"

Supports severity enrichment for ligand-binding-domain missense alleles, including the mechanistically important Arg132 region.

PMID:40152536 SUPPORT Computational

"Our findings suggest that the disruption of the stability of the highly conserved internal core of the YWHAG protein may be one mechanism leading to functional impairment, distinct from the previously proposed pathogenic models of dimer formation defects and/or impaired binding to phosphopeptide ligands."

Supports that pathogenic YWHAG variants can impair function through structural destabilization in addition to altered ligand-binding behavior.

ROCK-pathway dysregulation and maturation-dependent cytoskeletal remodeling

In YWHAG p.Arg132Cys cortical neurons, transcriptomic dysregulation implicates the ROCK pathway and associated modulators, with biphasic maturation-dependent changes in cytoskeletal protein stability and calcium phenotypes. This node is kept distinct from the overt cytoskeletal fragility phenotype because the study suggests a signaling/remodeling layer upstream of the physical instability phenotype.

cerebral cortex neuron link

Rho protein signal transduction link ↕ DYSREGULATED

cerebral cortex link

Downstream

Cytoskeletal instability in cortical neurons Altered ROCK-associated remodeling is positioned upstream of the early cytoskeletal phenotypes and the later fragility/unmasking assays.

Show evidence (1 reference)

DOI:10.64898/2026.04.01.715876 SUPPORT In Vitro

"The widespread alterations in the transcriptome of mutant neurons revealed a biphasic dysregulation in the core genes and modulators associated with the ROCK pathway that resulted in maturation-dependent changes to cytoskeletal protein stability and calcium phenotypes."

Directly supports a ROCK-associated signaling/remodeling layer upstream of the cytoskeletal and calcium phenotypes in the YWHAG p.Arg132Cys cortical neuron model.

Cytoskeletal instability in cortical neurons

YWHAG p.Arg132Cys cortical neurons show early cytoskeletal abnormalities and latent fragility that becomes more evident under Trypsin-EDTA stress. This phenotype is partially ameliorated by lovastatin in the preprint model, supporting cytoskeletal instability as a central disease-relevant mechanism rather than a secondary observation.

cerebral cortex neuron link

cytoskeleton organization link ↕ DYSREGULATED

Downstream

Elevated baseline intracellular calcium Cytoskeletal instability is associated with abnormal calcium baseline and impaired calcium homeostasis.

Reduced calcium signaling and network activity Cytoskeletal instability is also associated with reduced spontaneous calcium-spiking dynamics and lower network activity, consistent with partial decoupling from the baseline-calcium phenotype.

Show evidence (1 reference)

DOI:10.64898/2026.04.01.715876 SUPPORT In Vitro

"Exposure of YWHAG R132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment."

Directly supports latent cytoskeletal fragility in mutant cortical neurons and its partial lovastatin responsiveness.

Elevated baseline intracellular calcium

Mutant cortical neurons exhibit an elevated calcium baseline, indicating altered calcium homeostasis. In the p.Arg132Cys model, this baseline abnormality changes with maturation, is worsened by direct ROCK inhibition with Y27632, and is partially reduced by lovastatin treatment.

cerebral cortex neuron link

calcium ion homeostasis link ↕ DYSREGULATED

Show evidence (1 reference)

DOI:10.64898/2026.04.01.715876 SUPPORT In Vitro

"Direct inhibition of ROCK with Y27632 further increased the calcium baseline compared to the isogenic control. Exposure of YWHAG R132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment. Further, lovastatin partially..."

Directly supports elevated baseline calcium as a distinct homeostatic phenotype that is modified by ROCK inhibition and partially improved by lovastatin.

Reduced calcium signaling and network activity

Despite the elevated baseline calcium phenotype, YWHAG p.Arg132Cys cortical neurons have lower-frequency calcium spikes and reduced network activity. Lovastatin does not rescue calcium spike frequency or amplitude, supporting a partial decoupling between calcium homeostasis and activity-dependent calcium signaling in mutant neurons.

cerebral cortex neuron link

calcium-mediated signaling link ↓ DECREASED chemical synaptic transmission link ↓ DECREASED

Show evidence (2 references)

DOI:10.64898/2026.04.01.715876 SUPPORT In Vitro

"The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal phenotypes, coupled with an elevated calcium baseline, lower frequency of calcium spikes, and reduced network activity."

Directly supports reduced spontaneous calcium signaling and network activity as a phenotype distinct from the elevated baseline-calcium state.

DOI:10.64898/2026.04.01.715876 SUPPORT In Vitro

"Further, lovastatin partially rescued the elevated calcium baseline, but not the frequency or amplitude of calcium spikes."

Directly supports the partial decoupling between baseline calcium homeostasis and activity-dependent calcium signaling in mutant neurons.

⬡

Pathograph

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

●

Phenotypes

13

Nervous System 10

Early-onset seizures VERY_FREQUENT Seizure (HP:0001250)

Show evidence (3 references)

PMID:39413657 SUPPORT Human Clinical

"Developmental and epileptic encephalopathy 56 (DEE-56) is caused by pathogenic variants in YWHAG and is characterized by early-onset epilepsy and neurodevelopmental delay."

Directly supports early-onset epilepsy as a defining clinical feature of DEE56.

PMID:39413657 SUPPORT Human Clinical

"Early-onset seizures, particularly febrile seizures, were common, with various seizure types reported."

Supports the breadth of the seizure phenotype and the prominence of febrile seizures in this syndrome.

PMID:41886798 SUPPORT Human Clinical

"Ninety-five percent presented with seizures, while one patient presented solely with developmental delays."

The 95% seizure frequency falls in the VERY_FREQUENT band and shows that seizures are not strictly obligatory in YWHAG-NDD.

Absence seizures FREQUENT Generalized non-motor (absence) seizure (HP:0002121)

Show evidence (2 references)

PMID:41886798 SUPPORT Human Clinical

"The most commonly reported seizure types included generalized tonic-clonic seizures, myoclonic seizures, and absence seizures."

Author wording "most commonly reported" supports the FREQUENT band under the dismech qualitative frequency mapping.

PMID:31926053 SUPPORT Human Clinical

"Characteristic features included: early-onset seizures, predominantly generalized tonic-clonic and absence type (7/7) with good response to standard anti-epileptic medications"

Supports absence seizures as a characteristic seizure type in an earlier de novo YWHAG missense cohort.

Bilateral tonic-clonic seizures FREQUENT Bilateral tonic-clonic seizure (HP:0002069)

Show evidence (2 references)

PMID:41886798 SUPPORT Human Clinical

"The most commonly reported seizure types included generalized tonic-clonic seizures, myoclonic seizures, and absence seizures."

Author wording "most commonly reported" supports the FREQUENT band under the dismech qualitative frequency mapping.

PMID:31926053 SUPPORT Human Clinical

"Characteristic features included: early-onset seizures, predominantly generalized tonic-clonic and absence type (7/7) with good response to standard anti-epileptic medications"

Supports generalized tonic-clonic seizures as characteristic in an earlier de novo YWHAG missense cohort.

Treatment-resistant epilepsy FREQUENT Seizure (HP:0001250)

Show evidence (1 reference)

PMID:41886798 SUPPORT Human Clinical

"Fifty-five percent of participants reported treatment-resistant epilepsy and 40% reported at least one episode of status epilepticus."

Fifty-five percent falls in the FREQUENT band and supports treatment-resistant epilepsy as a common YWHAG-NDD feature; HP lacks a specific treatment-resistant epilepsy term, so Seizure is used as the closest ontology anchor.

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:41886798 SUPPORT Human Clinical

"Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills."

Supports multidomain developmental delay in YWHAG-NDD.

PMID:31926053 SUPPORT Human Clinical

"Characteristic features included: early-onset seizures, predominantly generalized tonic-clonic and absence type (7/7) with good response to standard anti-epileptic medications; moderate DD; Intellectual Disability (ID) (5/7) and Autism Spectrum Disorder (3/7)."

Supports developmental delay as part of the earlier YWHAG DEE cohort phenotype.

Speech and language delay Delayed speech and language development (HP:0000750)

Show evidence (1 reference)

PMID:41886798 SUPPORT Human Clinical

"Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills."

Supports language delay as a distinct developmental domain affected in YWHAG-NDD.

Motor delay Motor delay (HP:0001270)

Show evidence (1 reference)

PMID:41886798 SUPPORT Human Clinical

"Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills."

Supports motor delay without over-modeling hypotonia, which is not named in the requested natural-history abstract.

Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)

Show evidence (2 references)

PMID:38491959 SUPPORT Human Clinical

"Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common."

Supports intellectual disability as one of the most frequent non-seizure manifestations in reported YWHAG cohorts.

PMID:39413657 SUPPORT Human Clinical

"Individuals with YWHAG variants exhibited variable psychomotor delay, with the majority experiencing mild intellectual disability."

Supports the developmental-delay to mild-intellectual-disability spectrum in the larger pooled cohort.

Behavioral disorders VERY_FREQUENT Atypical behavior (HP:0000708)

Show evidence (2 references)

PMID:38491959 SUPPORT Human Clinical

"Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common."

Supports behavioral abnormality as a very frequent non-seizure feature in the largest dedicated YWHAG cohort.

PMID:39413657 SUPPORT Human Clinical

"Comorbidities such as autism spectrum disorders and attention deficit-hyperreactivity disorder were observed in a proportion of individuals."

Supports the specific spectrum of reported behavioral comorbidities in DEE56.

Ataxia OCCASIONAL Ataxia (HP:0001251)

Show evidence (1 reference)

PMID:39413657 SUPPORT Human Clinical

"Movement disorders were present in a subset of individuals, primarily manifesting as ataxia and tremor."

Supports ataxia as a recurrent but non-obligate neurologic comorbidity.

Other 3

Fever-triggered seizures FREQUENT Seizure precipitated by febrile infection (HP:0032894)

Show evidence (2 references)

PMID:41886798 SUPPORT Human Clinical

"Sixty percent of participants reported seizures in the setting of fever."

Sixty percent falls in the FREQUENT band and directly supports fever-triggered seizures as a common YWHAG-NDD feature.

PMID:33767733 SUPPORT Human Clinical

"This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS."

Supports febrile seizures as part of the milder YWHAG epilepsy spectrum.

Myoclonic seizures FREQUENT Myoclonic seizure (HP:0032794)

Show evidence (2 references)

PMID:41886798 SUPPORT Human Clinical

"The most commonly reported seizure types included generalized tonic-clonic seizures, myoclonic seizures, and absence seizures."

Author wording "most commonly reported" supports the FREQUENT band under the dismech qualitative frequency mapping.

PMID:33767733 SUPPORT Human Clinical

"The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment."

Provides independent clinical evidence that myoclonic seizures can be a core presentation of YWHAG-related epilepsy.

Status epilepticus FREQUENT Status epilepticus (HP:0002133)

Show evidence (1 reference)

PMID:41886798 SUPPORT Human Clinical

"Fifty-five percent of participants reported treatment-resistant epilepsy and 40% reported at least one episode of status epilepticus."

Forty percent falls in the FREQUENT band and directly supports status epilepticus as a common severe seizure manifestation in this cohort.

🧬

Genetic Associations

1

YWHAG variants (Pathogenic mutations)

Show evidence (3 references)

PMID:38491959 SUPPORT Human Clinical

"A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains"

Supports the specific association between ligand-binding-domain missense alleles and the more severe DEE end of the YWHAG spectrum.

PMID:33767733 SUPPORT Human Clinical

"The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic."

Supports truncating haploinsufficiency as a milder familial variant class within the YWHAG allelic spectrum.

PMID:40152536 SUPPORT Computational

"Our findings suggest that the disruption of the stability of the highly conserved internal core of the YWHAG protein may be one mechanism leading to functional impairment"

Supports a second molecular mechanism in which pathogenic alleles impair YWHAG by destabilizing the protein core.

💊

Treatments

6

Antiseizure Pharmacotherapy

Action: pharmacotherapy MAXO:0000058

Agent: valproate ↗

Antiseizure medication management is central to clinical care. Valproate has documented responsiveness in milder YWHAG myoclonic/febrile presentations, while broader YWHAG-NDD treatment response remains variable and should be individualized by epilepsy specialists.

Target Phenotypes: Seizure ↗ Myoclonic seizure ↗

Show evidence (2 references)

PMID:33767733 SUPPORT Human Clinical

"The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment."

Supports valproate responsiveness in the milder YWHAG myoclonic/febrile seizure presentations described in this report.

PMID:39413657 SUPPORT Human Clinical

"Valproic acid has emerged as an effective antiseizure medication."

Supports valproate as a relevant antiseizure medication across the pooled YWHAG literature, while the description preserves the paper's later caveat that response is variable.

Status Epilepticus Action Planning

Action: pharmacotherapy MAXO:0000058

Because status epilepticus is reported in a substantial subset of YWHAG-NDD, care plans should include emergency seizure instructions and access to acute rescue pharmacotherapy according to local epilepsy protocols.

Target Phenotypes: Status epilepticus ↗

Show evidence (1 reference)

PMID:41886798 PARTIAL Human Clinical

"Fifty-five percent of participants reported treatment-resistant epilepsy and 40% reported at least one episode of status epilepticus."

The paper supports the clinical need for status epilepticus preparedness; it does not specify a particular rescue-medication protocol.

Speech-Language Therapy

Action: speech therapy MAXO:0000930

Speech-language therapy should address language delay and communication needs in children with YWHAG-NDD.

Target Phenotypes: Delayed speech and language development ↗

Show evidence (1 reference)

PMID:41886798 PARTIAL Human Clinical

"Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills."

Supports the language target for speech-language therapy, although the abstract does not test therapy efficacy.

Physical Therapy for Motor Delay

Action: physical therapy MAXO:0000011

Physical therapy can support motor-skill acquisition, mobility, balance, and functional participation when motor delay or coordination problems are present.

Target Phenotypes: Motor delay ↗ Ataxia ↗

Show evidence (1 reference)

PMID:41886798 PARTIAL Human Clinical

"Other notable clinical manifestations included mild to moderate delays in language skills, cognition, social skills, and motor skills."

Supports motor delay as a treatment target, although the abstract does not evaluate physical therapy efficacy.

Occupational Therapy and Adaptive Supports

Action: occupational therapy MAXO:0001351

Occupational therapy and adaptive supports should be considered for functional, social, and daily-living needs related to multidomain developmental impairment.

Target Phenotypes: Global developmental delay ↗

Show evidence (1 reference)

PMID:41886798 PARTIAL Human Clinical

"Adaptive function was assessed using the Vineland-3 Adaptive Behavior Scales."

Supports adaptive function as a clinically measured domain relevant to occupational therapy planning, although therapy efficacy was not evaluated.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling should address autosomal dominant inheritance, the high proportion of de novo cases, rare familial transmission, parental testing, variable expressivity, and low but nonzero recurrence risk when parental blood testing is negative.

Show evidence (2 references)

PMID:38491959 SUPPORT Human Clinical

"In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling."

Supports genetic counseling as part of YWHAG-related epilepsy management.

PMID:33767733 SUPPORT Human Clinical

"Two YWHAG mutations were identified in two unrelated families with childhood myoclonic epilepsy and FS, including a familial case with six individuals affected and a sporadic case with de novo mutation."

Supports counseling that YWHAG recurrence risk differs between familial transmission and apparently de novo cases.

🧫

Experimental Models

1

YWHAG p.Arg132Cys isogenic iPSC-derived cortical neuron model IPSC_DERIVED_MODEL

Isogenic human iPSC-derived cortical neurons carrying YWHAG p.Arg132Cys/+ compared with matched isogenic control neurons, used to study cytoskeletal, calcium, transcriptomic, and rescue phenotypes relevant to DEE56.

Organism

human ↗

Tissue

cerebral cortex ↗

Cell source

Isogenic human induced pluripotent stem cells differentiated into cortical neurons

Culture

Two-dimensional iPSC-derived cortical-neuron culture with calcium imaging, transcriptomic, and perturbation/rescue assays

Findings

YWHAG p.Arg132Cys cortical neurons show early cytoskeletal phenotypes with elevated calcium baseline, lower calcium spike frequency, and reduced network activity.

"The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal phenotypes, coupled with an elevated calcium baseline, lower frequency of calcium spikes, and reduced network activity."

Mutant cortical-neuron transcriptomes implicate biphasic ROCK-pathway dysregulation with maturation-dependent changes in cytoskeletal protein stability and calcium phenotypes.

"The widespread alterations in the transcriptome of mutant neurons revealed a biphasic dysregulation in the core genes and modulators associated with the ROCK pathway that resulted in maturation-dependent changes to cytoskeletal protein stability and calcium phenotypes."

ROCK inhibition with Y27632 worsens the calcium-baseline phenotype, whereas lovastatin partially rescues cytoskeletal instability and elevated baseline calcium but not calcium spike frequency or amplitude.

"Direct inhibition of ROCK with Y27632 further increased the calcium baseline compared to the isogenic control. Exposure of YWHAG R132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment. Further, lovastatin partially..."

Source publication is the bioRxiv preprint DOI:10.64898/2026.04.01.715876. This model currently provides the strongest direct mechanistic evidence for YWHAG p.Arg132Cys but remains preprint-stage and allele-specific. Lovastatin rescue is represented only as an in vitro perturbation result, not as a clinical treatment recommendation.

{ }

Source YAML

click to show

name: YWHAG Syndrome
creation_date: "2026-04-05T18:46:08Z"
updated_date: "2026-04-06T15:04:11Z"
category: Mendelian
description: >-
  YWHAG syndrome, also known as developmental and epileptic encephalopathy 56
  (DEE56), is an ultra-rare Mendelian neurodevelopmental disorder caused by
  heterozygous pathogenic variants in YWHAG, which encodes the 14-3-3gamma
  phosphoserine-binding scaffold protein. The clinical spectrum ranges from mild
  developmental delay to developmental and epileptic encephalopathy with
  early-onset seizures, intellectual disability, and variable behavioral,
  developmental, or movement abnormalities. Prospective natural-history data
  show that seizures are very frequent but not universal and include
  generalized tonic-clonic, myoclonic, absence, fever-triggered,
  treatment-resistant, and status epilepticus presentations. Human cohort data
  suggest that missense variants in the ligand-binding domain are enriched among
  the more severe DEE presentations. Emerging human-cell-model work in isogenic
  YWHAG p.Arg132Cys cortical neurons implicates ROCK-associated cytoskeletal
  instability, elevated baseline calcium, reduced calcium signaling, and lower
  network activity, with partial lovastatin rescue of cytoskeletal fragility and
  calcium-baseline abnormalities.
notes: >-
  The most detailed direct mechanistic study currently focuses on the recurrent
  p.Arg132Cys allele in isogenic iPSC-derived cortical neurons. Those findings
  are modeled here as disease-relevant but should not yet be assumed to
  generalize equally to all pathogenic YWHAG variants. Lovastatin and Y27632
  observations remain preclinical in vitro model findings and are not clinical
  treatment recommendations.
disease_term:
  preferred_term: YWHAG syndrome
  term:
    id: MONDO:0033365
    label: developmental and epileptic encephalopathy, 56
parents:
- Genetic Developmental and Epileptic Encephalopathy
- Neurodevelopmental Disorder
synonyms:
- developmental and epileptic encephalopathy 56
- DEE56
- YWHAG-related epilepsy
inheritance:
- name: Autosomal dominant (typically de novo)
  de_novo_rate: >-
    Predominant in reported DEE missense cases; rare familial transmission has
    also been documented.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    YWHAG syndrome is caused by heterozygous pathogenic variants in YWHAG.
    Reported disease-causing variants are predominantly de novo missense alleles,
    although familial transmission has also been described in the expanding
    YWHAG allelic spectrum. Recurrence counseling should include parental testing
    for the familial variant; if parental blood testing is negative, recurrence
    risk is low but not zero because parental gonadal mosaicism cannot be fully
    excluded.
  evidence:
  - reference: PMID:28777935
    reference_title: "De Novo Mutations in YWHAG Cause Early-Onset Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a highly significant enrichment of de novo variants in
      YWHAG, establishing their role in early-onset epilepsy
    explanation: >-
      The original discovery cohort identified de novo heterozygous YWHAG
      variants as the disease-associated inheritance pattern for early-onset
      epileptic encephalopathy.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two YWHAG mutations were identified in two unrelated families with childhood
      myoclonic epilepsy and FS, including a familial case with six individuals
      affected and a sporadic case with de novo mutation.
    explanation: >-
      Supports counseling that the YWHAG allelic spectrum includes both de novo
      cases and rare familial transmission.
prevalence:
- population: Global reported literature
  percentage: Unknown
  notes: >-
    YWHAG syndrome remains ultra-rare. Published clinical experience is still
    limited to a few dozen individuals assembled across case reports and pooled
    cohort studies.
  evidence:
  - reference: PMID:40152536
    reference_title: "A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, fewer than 30 cases of DEE56 have been reported globally,
      and our understanding of YWHAG's function remains limited.
    explanation: >-
      This 2025 case report emphasizes the very small number of reported DEE56
      cases worldwide.
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analyzed data from thirty-nine individuals aged 3-40 years with YWHAG
      variants, including 12 previously unreported individuals
    explanation: >-
      Even one of the largest available pooled studies includes only 39
      individuals, supporting continued classification as ultra-rare.
pathophysiology:
- name: Variant-dependent YWHAG / 14-3-3gamma dysfunction
  description: >-
    YWHAG encodes the 14-3-3gamma scaffold protein, which coordinates
    phosphoserine-dependent signaling complexes important for neuronal
    development. Pathogenic missense variants can perturb the protein through at
    least two partially distinct mechanisms: recurrent ligand-binding-domain
    alleles associated with more severe DEE and structural-destabilizing alleles
    that disrupt the conserved internal hydrophobic core. The recurrent p.Arg132Cys
    ligand-binding-domain variant provides the best-studied bridge from human
    genetics to downstream neuronal mechanism.
  gene:
    preferred_term: YWHAG
    description: >-
      Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein
      gamma, encoding the 14-3-3gamma adaptor/scaffold protein.
    term:
      id: hgnc:12852
      label: YWHAG
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  downstream:
  - target: ROCK-pathway dysregulation and maturation-dependent cytoskeletal remodeling
    description: >-
      Pathogenic YWHAG dysfunction is linked to altered signaling programs that
      intersect with ROCK-associated cytoskeletal control in cortical neurons.
  evidence:
  - reference: PMID:28777935
    reference_title: "De Novo Mutations in YWHAG Cause Early-Onset Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a highly significant enrichment of de novo variants in
      YWHAG, establishing their role in early-onset epilepsy
    explanation: >-
      Establishes YWHAG as the causal disease gene upstream of the downstream
      neuronal phenotypes represented in this entry.
  - reference: PMID:38491959
    reference_title: "Clinical and molecular characterization of patients with YWHAG-related epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genotype-phenotype correlation emerged, as DEE is more represented in
      patients with missense variants located in the ligand-binding domain than
      in those with truncating or missense variants in other domains
    explanation: >-
      Supports severity enrichment for ligand-binding-domain missense alleles,
      including the mechanistically important Arg132 region.
  - reference: PMID:40152536
    reference_title: "A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Our findings suggest that the disruption of the stability of the highly
      conserved internal core of the YWHAG protein may be one mechanism leading
      to functional impairment, distinct from the previously proposed pathogenic
      models of dimer formation defects and/or impaired binding to phosphopeptide
      ligands.
    explanation: >-
      Supports that pathogenic YWHAG variants can impair function through
      structural destabilization in addition to altered ligand-binding behavior.
- name: ROCK-pathway dysregulation and maturation-dependent cytoskeletal remodeling
  description: >-
    In YWHAG p.Arg132Cys cortical neurons, transcriptomic dysregulation
    implicates the ROCK pathway and associated modulators, with biphasic
    maturation-dependent changes in cytoskeletal protein stability and calcium
    phenotypes. This node is kept distinct from the overt cytoskeletal fragility
    phenotype because the study suggests a signaling/remodeling layer upstream of
    the physical instability phenotype.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: Rho protein signal transduction
    term:
      id: GO:0007266
      label: Rho protein signal transduction
    modifier: DYSREGULATED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  downstream:
  - target: Cytoskeletal instability in cortical neurons
    description: >-
      Altered ROCK-associated remodeling is positioned upstream of the early
      cytoskeletal phenotypes and the later fragility/unmasking assays.
  evidence:
  - reference: DOI:10.64898/2026.04.01.715876
    reference_title: "Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The widespread alterations in the transcriptome of mutant neurons revealed
      a biphasic dysregulation in the core genes and modulators associated with
      the ROCK pathway that resulted in maturation-dependent changes to
      cytoskeletal protein stability and calcium phenotypes.
    explanation: >-
      Directly supports a ROCK-associated signaling/remodeling layer upstream of
      the cytoskeletal and calcium phenotypes in the YWHAG p.Arg132Cys cortical
      neuron model.
- name: Cytoskeletal instability in cortical neurons
  description: >-
    YWHAG p.Arg132Cys cortical neurons show early cytoskeletal abnormalities and
    latent fragility that becomes more evident under Trypsin-EDTA stress. This
    phenotype is partially ameliorated by lovastatin in the preprint model,
    supporting cytoskeletal instability as a central disease-relevant mechanism
    rather than a secondary observation.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: cytoskeleton organization
    term:
      id: GO:0007010
      label: cytoskeleton organization
    modifier: DYSREGULATED
  downstream:
  - target: Elevated baseline intracellular calcium
    description: >-
      Cytoskeletal instability is associated with abnormal calcium baseline and
      impaired calcium homeostasis.
  - target: Reduced calcium signaling and network activity
    description: >-
      Cytoskeletal instability is also associated with reduced spontaneous
      calcium-spiking dynamics and lower network activity, consistent with
      partial decoupling from the baseline-calcium phenotype.
  evidence:
  - reference: DOI:10.64898/2026.04.01.715876
    reference_title: "Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Exposure of YWHAG R132C/+ neurons to Trypsin-EDTA revealed underlying
      cytoskeletal instability, which was partially reversed by lovastatin
      treatment.
    explanation: >-
      Directly supports latent cytoskeletal fragility in mutant cortical neurons
      and its partial lovastatin responsiveness.
- name: Elevated baseline intracellular calcium
  description: >-
    Mutant cortical neurons exhibit an elevated calcium baseline, indicating
    altered calcium homeostasis. In the p.Arg132Cys model, this baseline
    abnormality changes with maturation, is worsened by direct ROCK inhibition
    with Y27632, and is partially reduced by lovastatin treatment.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.64898/2026.04.01.715876
    reference_title: "Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Direct inhibition of ROCK with Y27632 further increased the calcium
      baseline compared to the isogenic control. Exposure of YWHAG R132C/+
      neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which
      was partially reversed by lovastatin treatment. Further, lovastatin
      partially rescued the elevated calcium baseline, but not the frequency or
      amplitude of calcium spikes.
    explanation: >-
      Directly supports elevated baseline calcium as a distinct homeostatic
      phenotype that is modified by ROCK inhibition and partially improved by
      lovastatin.
- name: Reduced calcium signaling and network activity
  description: >-
    Despite the elevated baseline calcium phenotype, YWHAG p.Arg132Cys cortical
    neurons have lower-frequency calcium spikes and reduced network activity.
    Lovastatin does not rescue calcium spike frequency or amplitude, supporting
    a partial decoupling between calcium homeostasis and activity-dependent
    calcium signaling in mutant neurons.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: calcium-mediated signaling
    term:
      id: GO:0019722
      label: calcium-mediated signaling
    modifier: DECREASED
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  evidence:
  - reference: DOI:10.64898/2026.04.01.715876
    reference_title: "Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal
      phenotypes, coupled with an elevated calcium baseline, lower frequency of
      calcium spikes, and reduced network activity.
    explanation: >-
      Directly supports reduced spontaneous calcium signaling and network
      activity as a phenotype distinct from the elevated baseline-calcium state.
  - reference: DOI:10.64898/2026.04.01.715876
    reference_title: "Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Further, lovastatin partially rescued the elevated calcium baseline, but
      not the frequency or amplitude of calcium spikes.
    explanation: >-
      Directly supports the partial decoupling between baseline calcium
      homeostasis and activity-dependent calcium signaling in mutant neurons.
phenotypes:
- category: NEUROLOGICAL
  name: Early-onset seizures
  description: >-
    Seizures are the predominant neurologic feature of DEE56 and typically begin
    in infancy or early childhood, but natural-history data show that a minority
    of affected children may present with developmental delay without seizures.
    Febrile, myoclonic, absence, tonic-clonic, treatment-resistant, and status
    epilepticus presentations occur within the broader seizure spectrum.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental and epileptic encephalopathy 56 (DEE-56) is caused by
      pathogenic variants in YWHAG and is characterized by early-onset epilepsy
      and neurodevelopmental delay.
    explanation: >-
      Directly supports early-onset epilepsy as a defining clinical feature of
      DEE56.
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early-onset seizures, particularly febrile seizures, were common, with
      various seizure types reported.
    explanation: >-
      Supports the breadth of the seizure phenotype and the prominence of febrile
      seizures in this syndrome.
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ninety-five percent presented with seizures, while one patient presented
      solely with developmental delays.
    explanation: >-
      The 95% seizure frequency falls in the VERY_FREQUENT band and shows that
      seizures are not strictly obligatory in YWHAG-NDD.
- category: NEUROLOGICAL
  name: Fever-triggered seizures
  description: >-
    Fever-triggered seizures are a common seizure precipitant in YWHAG-NDD and
    help connect the DEE presentation with milder febrile-seizure-plus family
    presentations.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fever-triggered seizures
    term:
      id: HP:0032894
      label: Seizure precipitated by febrile infection
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sixty percent of participants reported seizures in the setting of fever.
    explanation: >-
      Sixty percent falls in the FREQUENT band and directly supports
      fever-triggered seizures as a common YWHAG-NDD feature.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study suggests that YWHAG is potentially a candidate pathogenic gene
      of childhood myoclonic epilepsy and FS.
    explanation: >-
      Supports febrile seizures as part of the milder YWHAG epilepsy spectrum.
- category: NEUROLOGICAL
  name: Myoclonic seizures
  description: >-
    Myoclonic seizures are among the most commonly reported YWHAG-NDD seizure
    types and are prominent in milder familial febrile-seizure-plus
    presentations.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly reported seizure types included generalized
      tonic-clonic seizures, myoclonic seizures, and absence seizures.
    explanation: >-
      Author wording "most commonly reported" supports the FREQUENT band under
      the dismech qualitative frequency mapping.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two probands experienced daily myoclonic seizures that were recorded
      with ictal generalized polyspike-slow waves, but became seizure-free with
      simple valproate treatment.
    explanation: >-
      Provides independent clinical evidence that myoclonic seizures can be a
      core presentation of YWHAG-related epilepsy.
- category: NEUROLOGICAL
  name: Absence seizures
  description: >-
    Absence seizures occur among the common YWHAG-NDD seizure types and can
    coexist with generalized tonic-clonic and myoclonic seizures.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absence seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly reported seizure types included generalized
      tonic-clonic seizures, myoclonic seizures, and absence seizures.
    explanation: >-
      Author wording "most commonly reported" supports the FREQUENT band under
      the dismech qualitative frequency mapping.
  - reference: PMID:31926053
    reference_title: "Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic features included: early-onset seizures, predominantly
      generalized tonic-clonic and absence type (7/7) with good response to
      standard anti-epileptic medications
    explanation: >-
      Supports absence seizures as a characteristic seizure type in an earlier
      de novo YWHAG missense cohort.
- category: NEUROLOGICAL
  name: Bilateral tonic-clonic seizures
  description: >-
    Generalized or bilateral tonic-clonic seizures are among the common seizure
    types in YWHAG-NDD.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Generalized tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most commonly reported seizure types included generalized
      tonic-clonic seizures, myoclonic seizures, and absence seizures.
    explanation: >-
      Author wording "most commonly reported" supports the FREQUENT band under
      the dismech qualitative frequency mapping.
  - reference: PMID:31926053
    reference_title: "Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic features included: early-onset seizures, predominantly
      generalized tonic-clonic and absence type (7/7) with good response to
      standard anti-epileptic medications
    explanation: >-
      Supports generalized tonic-clonic seizures as characteristic in an earlier
      de novo YWHAG missense cohort.
- category: NEUROLOGICAL
  name: Treatment-resistant epilepsy
  description: >-
    More than half of participants in the prospective natural-history cohort
    had treatment-resistant epilepsy, indicating that seizure management can be
    difficult despite valproate-responsive milder presentations in some families.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Treatment-resistant epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-five percent of participants reported treatment-resistant epilepsy
      and 40% reported at least one episode of status epilepticus.
    explanation: >-
      Fifty-five percent falls in the FREQUENT band and supports
      treatment-resistant epilepsy as a common YWHAG-NDD feature; HP lacks a
      specific treatment-resistant epilepsy term, so Seizure is used as the
      closest ontology anchor.
- category: NEUROLOGICAL
  name: Status epilepticus
  description: >-
    Status epilepticus is a recurrent severe seizure outcome in YWHAG-NDD and
    should drive seizure action planning and emergency care preparation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-five percent of participants reported treatment-resistant epilepsy
      and 40% reported at least one episode of status epilepticus.
    explanation: >-
      Forty percent falls in the FREQUENT band and directly supports status
      epilepticus as a common severe seizure manifestation in this cohort.
- category: NEUROLOGICAL
  name: Global developmental delay
  description: >-
    YWHAG-NDD affects multiple developmental domains, including language,
    cognition, social skills, and motor skills, and developmental delay may be
    the sole presenting feature in a minority of children.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports multidomain developmental delay in YWHAG-NDD.
  - reference: PMID:31926053
    reference_title: "Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic features included: early-onset seizures, predominantly
      generalized tonic-clonic and absence type (7/7) with good response to
      standard anti-epileptic medications; moderate DD; Intellectual Disability
      (ID) (5/7) and Autism Spectrum Disorder (3/7).
    explanation: >-
      Supports developmental delay as part of the earlier YWHAG DEE cohort
      phenotype.
- category: NEUROLOGICAL
  name: Speech and language delay
  description: >-
    Language delay is part of the multidomain developmental impairment in
    YWHAG-NDD and should be evaluated separately from later intellectual
    disability.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports language delay as a distinct developmental domain affected in
      YWHAG-NDD.
- category: NEUROLOGICAL
  name: Motor delay
  description: >-
    Motor-skill delay is part of the multidomain developmental impairment
    reported in YWHAG-NDD natural-history data.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports motor delay without over-modeling hypotonia, which is not named
      in the requested natural-history abstract.
- category: NEUROLOGICAL
  name: Intellectual disability
  description: >-
    Neurodevelopmental involvement is common across the YWHAG spectrum and often
    includes global developmental delay with later intellectual disability. Many
    reported individuals have mild intellectual disability, although severity is
    variable.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38491959
    reference_title: "Clinical and molecular characterization of patients with YWHAG-related epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%),
      neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common.
    explanation: >-
      Supports intellectual disability as one of the most frequent non-seizure
      manifestations in reported YWHAG cohorts.
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with YWHAG variants exhibited variable psychomotor delay, with
      the majority experiencing mild intellectual disability.
    explanation: >-
      Supports the developmental-delay to mild-intellectual-disability spectrum
      in the larger pooled cohort.
- category: NEUROLOGICAL
  name: Behavioral disorders
  description: >-
    Behavioral comorbidities are common in YWHAG syndrome and include autism
    spectrum disorder, attention deficit-hyperreactivity disorder, and broader
    behavioral dysregulation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:38491959
    reference_title: "Clinical and molecular characterization of patients with YWHAG-related epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%),
      neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common.
    explanation: >-
      Supports behavioral abnormality as a very frequent non-seizure feature in
      the largest dedicated YWHAG cohort.
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comorbidities such as autism spectrum disorders and attention
      deficit-hyperreactivity disorder were observed in a proportion of
      individuals.
    explanation: >-
      Supports the specific spectrum of reported behavioral comorbidities in
      DEE56.
- category: NEUROLOGICAL
  name: Ataxia
  description: >-
    Movement abnormalities occur in a subset of affected individuals, most often
    as ataxia or tremor.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Movement disorders were present in a subset of individuals, primarily
      manifesting as ataxia and tremor.
    explanation: >-
      Supports ataxia as a recurrent but non-obligate neurologic comorbidity.
diagnosis:
- name: YWHAG Molecular Genetic Testing
  description: >-
    Molecular diagnosis is made by identifying a pathogenic or likely pathogenic
    heterozygous YWHAG variant, most often through clinical exome sequencing or
    comparable epilepsy/neurodevelopmental sequencing workflows with parental
    testing when possible.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: MAXO:0009004
      label: clinical whole-exome sequencing
  evidence:
  - reference: PMID:31926053
    reference_title: "Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES was performed in five patients via Deciphering Developmental Disorders
      Study and the remaining two were identified via Genematcher and AnnEX
      databases.
    explanation: >-
      Supports exome-based molecular ascertainment for YWHAG DEE cases.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we performed trios-based whole exome sequencing approach in a cohort
      of patients with FS plus.
    explanation: >-
      Supports trio exome sequencing in milder familial and sporadic
      YWHAG-associated epilepsy presentations.
- name: Electroencephalography
  description: >-
    EEG is part of the epilepsy evaluation for seizure classification,
    epileptiform activity assessment, and follow-up of children with
    YWHAG-associated seizures.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: MAXO:0000932
      label: electroencephalography
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants were assessed using standardized assessments via video visits,
      review of medical records, neuroimaging, and electroencephalograms.
    explanation: >-
      Supports inclusion of EEG review in the natural-history clinical
      characterization of YWHAG-NDD.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term Video- electroencephalography (EEG) monitoring records that
      included hyperventilation, intermittent photic stimulation, open-close eyes
      test, and sleeping recording were obtained.
    explanation: >-
      Supports long-term video EEG as part of YWHAG epilepsy characterization.
- name: Neurodevelopmental Assessment
  description: >-
    Formal neurodevelopmental and adaptive-function assessment should evaluate
    language, cognition, social skills, motor skills, and adaptive supports.
  diagnosis_term:
    preferred_term: neurodevelopmental assessment
    term:
      id: MAXO:0035041
      label: neurodevelopmental assessment
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adaptive function was assessed using the Vineland-3 Adaptive Behavior
      Scales.
    explanation: >-
      Supports structured adaptive-function assessment in YWHAG-NDD.
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports assessment across the affected developmental domains.
treatments:
- name: Antiseizure Pharmacotherapy
  description: >-
    Antiseizure medication management is central to clinical care. Valproate has
    documented responsiveness in milder YWHAG myoclonic/febrile presentations,
    while broader YWHAG-NDD treatment response remains variable and should be
    individualized by epilepsy specialists.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproate
      term:
        id: CHEBI:60654
        label: valproate
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two probands experienced daily myoclonic seizures that were recorded
      with ictal generalized polyspike-slow waves, but became seizure-free with
      simple valproate treatment.
    explanation: >-
      Supports valproate responsiveness in the milder YWHAG myoclonic/febrile
      seizure presentations described in this report.
  - reference: PMID:39413657
    reference_title: "Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Valproic acid has emerged as an effective antiseizure medication.
    explanation: >-
      Supports valproate as a relevant antiseizure medication across the pooled
      YWHAG literature, while the description preserves the paper's later caveat
      that response is variable.
- name: Status Epilepticus Action Planning
  description: >-
    Because status epilepticus is reported in a substantial subset of
    YWHAG-NDD, care plans should include emergency seizure instructions and
    access to acute rescue pharmacotherapy according to local epilepsy protocols.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  target_phenotypes:
  - preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-five percent of participants reported treatment-resistant epilepsy
      and 40% reported at least one episode of status epilepticus.
    explanation: >-
      The paper supports the clinical need for status epilepticus preparedness;
      it does not specify a particular rescue-medication protocol.
- name: Speech-Language Therapy
  description: >-
    Speech-language therapy should address language delay and communication
    needs in children with YWHAG-NDD.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports the language target for speech-language therapy, although the
      abstract does not test therapy efficacy.
- name: Physical Therapy for Motor Delay
  description: >-
    Physical therapy can support motor-skill acquisition, mobility, balance, and
    functional participation when motor delay or coordination problems are
    present.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable clinical manifestations included mild to moderate delays in
      language skills, cognition, social skills, and motor skills.
    explanation: >-
      Supports motor delay as a treatment target, although the abstract does not
      evaluate physical therapy efficacy.
- name: Occupational Therapy and Adaptive Supports
  description: >-
    Occupational therapy and adaptive supports should be considered for
    functional, social, and daily-living needs related to multidomain
    developmental impairment.
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: MAXO:0001351
      label: occupational therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41886798
    reference_title: "Natural History of YWHAG-Associated Neurodevelopmental Disorder."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adaptive function was assessed using the Vineland-3 Adaptive Behavior
      Scales.
    explanation: >-
      Supports adaptive function as a clinically measured domain relevant to
      occupational therapy planning, although therapy efficacy was not evaluated.
- name: Genetic Counseling
  description: >-
    Genetic counseling should address autosomal dominant inheritance, the high
    proportion of de novo cases, rare familial transmission, parental testing,
    variable expressivity, and low but nonzero recurrence risk when parental
    blood testing is negative.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:38491959
    reference_title: "Clinical and molecular characterization of patients with YWHAG-related epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this allelic series, a genotype-phenotype correlation begins to emerge,
      potentially providing prognostic information for clinical management and
      genetic counseling.
    explanation: >-
      Supports genetic counseling as part of YWHAG-related epilepsy management.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two YWHAG mutations were identified in two unrelated families with childhood
      myoclonic epilepsy and FS, including a familial case with six individuals
      affected and a sporadic case with de novo mutation.
    explanation: >-
      Supports counseling that YWHAG recurrence risk differs between familial
      transmission and apparently de novo cases.
genetic:
- name: YWHAG variants
  gene_term:
    preferred_term: YWHAG
    term:
      id: hgnc:12852
      label: YWHAG
  association: Pathogenic mutations
  presence: Positive
  notes: >-
    Reported disease-causing alleles include predominantly heterozygous missense
    variants, with ligand-binding-domain variants enriched in severe DEE, and
    rare truncating haploinsufficiency variants associated with milder familial
    myoclonic/febrile seizure presentations.
  variants:
  - name: Ligand-binding domain missense variants
    description: >-
      Missense variants in the phosphopeptide ligand-binding region are enriched
      among patients with the more severe DEE presentation.
    clinical_significance: PATHOGENIC
  - name: Truncating haploinsufficiency variants
    description: >-
      Truncating YWHAG variants can segregate with a milder familial phenotype
      dominated by febrile seizures or myoclonic epilepsy, consistent with
      haploinsufficiency being less severe than many ligand-binding-domain
      missense alleles.
    clinical_significance: PATHOGENIC
  - name: Internal-core destabilizing missense variants
    description: >-
      Variants such as p.Leu173Ser may impair YWHAG function by destabilizing
      the conserved internal hydrophobic core rather than primarily affecting the
      ligand-binding groove.
    clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:38491959
    reference_title: "Clinical and molecular characterization of patients with YWHAG-related epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A genotype-phenotype correlation emerged, as DEE is more represented in
      patients with missense variants located in the ligand-binding domain than
      in those with truncating or missense variants in other domains
    explanation: >-
      Supports the specific association between ligand-binding-domain missense
      alleles and the more severe DEE end of the YWHAG spectrum.
  - reference: PMID:33767733
    reference_title: "YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The truncating mutation was identified in the family with six individuals
      of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency
      are relatively less pathogenic.
    explanation: >-
      Supports truncating haploinsufficiency as a milder familial variant class
      within the YWHAG allelic spectrum.
  - reference: PMID:40152536
    reference_title: "A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Our findings suggest that the disruption of the stability of the highly
      conserved internal core of the YWHAG protein may be one mechanism leading
      to functional impairment
    explanation: >-
      Supports a second molecular mechanism in which pathogenic alleles impair
      YWHAG by destabilizing the protein core.
variants:
- name: p.Arg132Cys
  description: >-
    Recurrent pathogenic YWHAG missense variant in the ligand-binding domain and
    the allele modeled in the current isogenic iPSC-derived cortical-neuron
    preprint.
  gene:
    preferred_term: YWHAG
    term:
      id: hgnc:12852
      label: YWHAG
  clinical_significance: PATHOGENIC
  type: single_nucleotide_variant
  sequence_length: 1
  synonyms:
  - R132C
  - c.394C>T
  evidence:
  - reference: PMID:28777935
    reference_title: "De Novo Mutations in YWHAG Cause Early-Onset Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      YWHAG (aka 14-3-3γ) (c.394C>T
    explanation: >-
      Uses the discovery-paper abstract text that explicitly names
      c.394C>T/p.Arg132Cys rather than relying on a gene-level YWHAG statement.
experimental_models:
- name: YWHAG p.Arg132Cys isogenic iPSC-derived cortical neuron model
  description: >-
    Isogenic human iPSC-derived cortical neurons carrying YWHAG p.Arg132Cys/+
    compared with matched isogenic control neurons, used to study cytoskeletal,
    calcium, transcriptomic, and rescue phenotypes relevant to DEE56.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  conditions:
  - YWHAG syndrome
  - YWHAG p.Arg132Cys/+
  - isogenic control
  - cortical neuron differentiation
  cell_source: Isogenic human induced pluripotent stem cells differentiated into cortical neurons
  culture_system: Two-dimensional iPSC-derived cortical-neuron culture with calcium imaging, transcriptomic, and perturbation/rescue assays
  findings:
  - statement: YWHAG p.Arg132Cys cortical neurons show early cytoskeletal phenotypes with elevated calcium baseline, lower calcium spike frequency, and reduced network activity.
    supporting_text: >-
      The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal
      phenotypes, coupled with an elevated calcium baseline, lower frequency of
      calcium spikes, and reduced network activity.
  - statement: Mutant cortical-neuron transcriptomes implicate biphasic ROCK-pathway dysregulation with maturation-dependent changes in cytoskeletal protein stability and calcium phenotypes.
    supporting_text: >-
      The widespread alterations in the transcriptome of mutant neurons revealed
      a biphasic dysregulation in the core genes and modulators associated with
      the ROCK pathway that resulted in maturation-dependent changes to
      cytoskeletal protein stability and calcium phenotypes.
  - statement: ROCK inhibition with Y27632 worsens the calcium-baseline phenotype, whereas lovastatin partially rescues cytoskeletal instability and elevated baseline calcium but not calcium spike frequency or amplitude.
    supporting_text: >-
      Direct inhibition of ROCK with Y27632 further increased the calcium
      baseline compared to the isogenic control. Exposure of YWHAG R132C/+
      neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which
      was partially reversed by lovastatin treatment. Further, lovastatin
      partially rescued the elevated calcium baseline, but not the frequency or
      amplitude of calcium spikes.
  notes: >-
    Source publication is the bioRxiv preprint DOI:10.64898/2026.04.01.715876.
    This model currently provides the strongest direct mechanistic evidence for
    YWHAG p.Arg132Cys but remains preprint-stage and allele-specific.
    Lovastatin rescue is represented only as an in vitro perturbation result,
    not as a clinical treatment recommendation.
references:
- reference: DOI:10.64898/2026.04.01.715876
  title: Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons
  findings:
  - statement: YWHAG p.Arg132Cys cortical neurons show early cytoskeletal abnormalities together with elevated baseline calcium, lower calcium-spike frequency, and reduced network activity.
    supporting_text: >-
      The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal
      phenotypes, coupled with an elevated calcium baseline, lower frequency of
      calcium spikes, and reduced network activity.
  - statement: Transcriptomic changes implicate biphasic dysregulation of ROCK-pathway genes and modulators with maturation-dependent changes in cytoskeletal protein stability and calcium phenotypes.
    supporting_text: >-
      The widespread alterations in the transcriptome of mutant neurons revealed
      a biphasic dysregulation in the core genes and modulators associated with
      the ROCK pathway that resulted in maturation-dependent changes to
      cytoskeletal protein stability and calcium phenotypes.
  - statement: Y27632 worsens baseline calcium, Trypsin-EDTA unmasks cytoskeletal fragility, and lovastatin partially rescues cytoskeletal instability and baseline calcium without rescuing spike frequency or amplitude.
    supporting_text: >-
      Direct inhibition of ROCK with Y27632 further increased the calcium
      baseline compared to the isogenic control. Exposure of YWHAG R132C/+
      neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which
      was partially reversed by lovastatin treatment. Further, lovastatin
      partially rescued the elevated calcium baseline, but not the frequency or
      amplitude of calcium spikes.

📚

References & Deep Research

References

1

DOI:10.64898/2026.04.01.715876

Decoupled calcium homeostasis and signaling associated with cytoskeletal instability in YWHAG R132C induced pluripotent stem cell-derived cortical neurons

3 findings

YWHAG p.Arg132Cys cortical neurons show early cytoskeletal abnormalities together with elevated baseline calcium, lower calcium-spike frequency, and reduced network activity.

"The YWHAG R132C/+ iPSC-derived neurons exhibited early cytoskeletal phenotypes, coupled with an elevated calcium baseline, lower frequency of calcium spikes, and reduced network activity."

Transcriptomic changes implicate biphasic dysregulation of ROCK-pathway genes and modulators with maturation-dependent changes in cytoskeletal protein stability and calcium phenotypes.

"The widespread alterations in the transcriptome of mutant neurons revealed a biphasic dysregulation in the core genes and modulators associated with the ROCK pathway that resulted in maturation-dependent changes to cytoskeletal protein stability and calcium phenotypes."

Y27632 worsens baseline calcium, Trypsin-EDTA unmasks cytoskeletal fragility, and lovastatin partially rescues cytoskeletal instability and baseline calcium without rescuing spike frequency or amplitude.

"Direct inhibition of ROCK with Y27632 further increased the calcium baseline compared to the isogenic control. Exposure of YWHAG R132C/+ neurons to Trypsin-EDTA revealed underlying cytoskeletal instability, which was partially reversed by lovastatin treatment. Further, lovastatin partially..."

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of YWHAG Syndrome. Core disease mechanisms, molecular and cellular pathways,...

Asta Scientific Corpus Retrieval 20 citations 2026-04-05T11:53:44.128392

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of YWHAG Syndrome. Core disease mechanisms, molecular and cellular pathways,...

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

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

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

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.410) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

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

Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
Year: 2025
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
DOI: 10.1038/s41598-025-97642-8
PMID: 40229542
PMCID: 11997208
Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
Evidence snippets:
Snippet 1 (score: 0.399) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

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

Authors: Debopam Samanta
Year: 2025
Venue: Children
URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
DOI: 10.3390/children12040481
PMID: 40310132
PMCID: 12025602
Citations: 19
Influential citations: 1
Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
Evidence snippets:
Snippet 1 (score: 0.390) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[4] Molecular insights into the premature aging disease progeria

Authors: Sandra Vidak, R. Foisner
Year: 2016
Venue: Histochemistry and Cell Biology
URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
DOI: 10.1007/s00418-016-1411-1
PMID: 26847180
PMCID: 4796323
Citations: 105
Influential citations: 3
Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
Evidence snippets:
Snippet 1 (score: 0.388) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[5] 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.

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

Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
Year: 2023
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
DOI: 10.3389/fphar.2023.1290253
PMID: 38026943
PMCID: 10662320
Citations: 3
Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
Evidence snippets:
Snippet 1 (score: 0.384) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

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

Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
Year: 2026
Venue: Nucleus
URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
DOI: 10.1080/19491034.2025.2611484
PMID: 41489464
PMCID: 12773485
Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
Evidence snippets:
Snippet 1 (score: 0.383) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[8] Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

Authors: C. Çubuk, F. Can, M. Peña-Chilet, J. Dopazo
Year: 2020
Venue: Cells
URL: https://www.semanticscholar.org/paper/e40f7a3b8f72ba01374ba00fbf308a47a3fa5dd4
DOI: 10.3390/cells9071579
PMID: 32610626
PMCID: 7408716
Citations: 9
Summary: Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-s...
Evidence snippets:
Snippet 1 (score: 0.371) > Therefore, a proper interpretation of the effect that differences in gene expression have over phenotypes, such as drug response or disease progression, involves understanding the mechanisms of the disease or the mode of action of drugs, which can be interpreted through mechanistic models of cell signaling [12] or cell metabolism [13]. Mechanistic models have helped to understand the disease mechanisms behind different cancers [14,15], including neuroblastoma [16,17], breast cancer [18], rare diseases [19], complex diseases [20], the mechanisms of action of drugs [21,22], and other biologically interesting scenarios such as the molecular mechanisms that explain how stress-induced activation of brown adipose tissue prevents obesity [23] or the molecular mechanisms of death and the post-mortem ischemia of a tissue [24]. Among the few available proposals of mechanistic modeling algorithms that model different aspects of signaling pathway activity, Hipathia has demonstrated having superior sensitivity and specificity [12]. > Here, we propose the use of mechanistic models [13,14] of signaling activity related with cancer hallmarks [25], other cancer-related signaling pathways, and some extra relevant cellular functions to understand the functional consequences of the gender bias in gene expression. Such mechanistic models use gene expression data to produce an estimation of profiles of signaling or metabolic circuit activity within pathways [13,14]. An interesting property of mechanistic models is that they can be used not only to understand molecular mechanisms of disease or of drug action but also to predict the potential consequences of gene perturbations over the circuit activity in a given condition [26]. Actually, in a recent work, our group has successfully predicted therapeutic targets in cancer cell lines with a precision over 60% [15]. Therefore, we will use this mechanistic framework to understand what is the molecular basis of the different effects of cancer drugs by directly simulating their effect in the patients. This approach has recently been used by us to understand the generation of resistances in cancer at the single cell level in glioblastoma [27].

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

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.369) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[10] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
Year: 2025
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
DOI: 10.3390/ijms26062571
PMID: 40141213
PMCID: 11942187
Citations: 4
Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
Evidence snippets:
Snippet 1 (score: 0.369) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[11] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
DOI: 10.3390/ijms22083930
PMID: 33920294
PMCID: 8069124
Citations: 6
Influential citations: 1
Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
Evidence snippets:
Snippet 1 (score: 0.369) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

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

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.367) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[13] A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure

Authors: Yuan Jin, Qian Niu, Shannon N Liang, M. Luo, X. Su et al.
Year: 2025
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/3cafb0ee2e4b243aa1ddbc8582132bc2bb87d038
DOI: 10.1002/mgg3.70079
PMID: 40152536
PMCID: 11951171
Summary: Developmental epileptic encephalopathy 56 (DEE56) is a monogenic DEE type caused by heterozygous mutations in YWHAG, and understanding of YWHAG's function remains limited.
Evidence snippets:
Snippet 1 (score: 0.365) > DEEs encompass a spectrum of clinical phenotypes overlapping with other developmental disorders, including psychomotor developmental delay, intellectual disability, impaired or absent speech development, behavioral abnormalities, hypotonia, movement disorders, seizures, microcephaly, and dysmorphic facial features (Guerrini et al. 2023). Therefore, diagnosis based solely on clinical phenotypes is challenging, with the primary diagnostic focus being on the early onset of epilepsy, typically in infancy, and the varying types and severity of seizures. Before the identification of the YWHAG-related DEE type (MIM:#194050), YWHAG was implicated in the rare phenotype of epilepsy and severe psychomotor developmental delay associated with Williams-Beuren syndrome or the 7q11.23 deletion syndrome (Morimoto et al. 2003). Subsequent discoveries of single-gene DEE56 cases exhibited more consistent DEE phenotypic features (Guella et al. 2017), aligning with the patient's presentation in this study. > YWHAG, also known as 14-3-3γ, is highly expressed in the mammalian brain, and its primary known function is binding to target proteins, thereby altering their activity, modification, and intracellular localization (Bridges and Moorhead 2004;Jin et al. 2004;Obsilova et al. 2008;Lundby et al. 2012). This was demonstrated in the study published by Guella et al. (2017). > Through the investigation of the YWHAG R132C and E15A variants, the authors proposed that the pathogenic mechanism of YWHAG variants involves disrupting dimerization and/or phosphopeptide ligand binding (Guella et al. 2017), which our analysis corroborates (Figure 3D). Furthermore, we found that the five previously reported missense mutation sites, E15, R57, D129, R132, and Y133, collectively form a loose, hydrophilic surface structure for phosphopeptide ligand binding, consistent with Guella et al.'s (2017) speculation but differing from our findings.

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

Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
Year: 2016
Venue: Molecular Psychiatry
URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
DOI: 10.1038/mp.2016.89
PMID: 27240529
PMCID: 4995546
Citations: 77
Influential citations: 2
Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
Evidence snippets:
Snippet 1 (score: 0.365) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[15] 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: 0.364) > : 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.

[16] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
Year: 2015
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
DOI: 10.1186/s13023-015-0242-9
PMID: 25874378
PMCID: 4358699
Citations: 92
Influential citations: 5
Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Evidence snippets:
Snippet 1 (score: 0.362) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[17] Network Based Integrated Analysis of Phenotype-Genotype Data for Prioritization of Candidate Symptom Genes

Authors: Xing Li, Xuezhong Zhou, Yonghong Peng, Baoyan Liu, Runshun Zhang et al.
Year: 2014
Venue: BioMed Research International
URL: https://www.semanticscholar.org/paper/c7596cd5f26d3c88666ffc5e4ab658efea644c4b
DOI: 10.1155/2014/435853
PMID: 24991551
PMCID: 4060751
Citations: 13
Summary: A network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms provided an effective approach to identify candidate genes of symptoms.
Evidence snippets:
Snippet 1 (score: 0.361) > Using network-based approaches to gain insights into human disease has found multiple potential biological and clinical applications [13]. Further understanding of the effects of cellular interconnectedness on disease progression leads to the identification of disease biomarker genes and the pathways causing the associated diseases [14], which, in turn, offer effective targets for new drug development. Many human genetic diseases are caused by multiple genes. For genes that are associated with the same or similar phenotypes, the genes are likely to be functionally related. Such relations can be exploited to aid in searching for novel disease genes. Computational approaches have recently been proposed to predict associations between genes and diseases [15][16][17]. Vanunu et al. developed a network-based approach, which is known as PRINCE algorithm, for predicting causal genes and protein complexes involved in a disease of interest [18]. The availability of large-scale data of phenotype-genotype associations like OMIM, CTD [19], and PharmGKB [20] provides valuable resources for studying disease-gene associations. > Recently increasing interest on the study of molecular mechanism of symptoms was found. The underlying molecular mechanisms of several symptoms, such as depression, pain, and high blood pressure, have been discussed previously [21][22][23]. However, no work has been done to investigate systematically the mechanism of symptoms in the literature. Until recently, Zhou et al. used large-scale biomedical literature database to construct a symptom-based human disease network and investigate the associations between clinical manifestations of diseases and the underlying molecular interactions [24]. Their results showed that symptom-based similarity of diseases correlates strongly with the number of shared genetic associations and the extent to which their associated proteins interact. This indicates that symptoms would have their underlying molecular mechanisms needed to be further explored. In this paper, we attempt to develop a new data mining framework to explore the relationships between symptoms and genes, which may provide scientific evidences to traditional Chinese medicine in individualized diagnosis and treatment because symptoms are the main clinical manifestations captured by TCM physicians for both diagnosis and treatment.

[18] 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: 0.360) > 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].

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

Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
Year: 2024
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
DOI: 10.3389/fphar.2024.1397864
PMID: 38846086
PMCID: 11154008
Citations: 2
Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
Evidence snippets:
Snippet 1 (score: 0.359) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

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

Authors: Enrico Garaci, Maurizio Paci, C. Matteucci, C. Costantini, P. Puccetti et al.
Year: 2024
Venue: Frontiers in Medicine
URL: https://www.semanticscholar.org/paper/84001176cd8c6059e1ee06845db21c61c9fd9d27
DOI: 10.3389/fmed.2024.1388959
PMID: 38903817
PMCID: 11187271
Citations: 4
Summary: The experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings are explored and how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework is discussed.
Evidence snippets:
Snippet 1 (score: 0.359) > This approach focuses on identifying and understanding the specific molecular targets that drugs interact with, and the subsequent biochemical and physiological changes that occur as a result of drug-target interactions.At the molecular level, researchers investigate how drugs bind to specific proteins, receptors, enzymes, or other molecules involved in biological processes.They analyze the structureactivity relationship to determine how the drug's chemical structure influences its interaction with the target, and how this interaction leads to molecular changes.Once the specific target or targets are identified, the reductionistic approach is applied at the cellular level.Researchers examine how the drug affects cellular signaling pathways, gene expression, protein synthesis, or other cellular processes.Understanding these cellular-level interactions helps elucidate how drugs modulate specific cell functions and influence overall physiological responses.At the physiological level, researchers investigate the effects of drugs on organ systems, whole organisms, and clinical outcomes.This includes studying how drugs affect organ function, systemic processes, and the overall disease state.By examining the drug's impact on the entire organism, researchers gain insights into the broader therapeutic effects and potential side effects of the drug.Therefore, the reductionistic approach in mechanisms of action of drugs involves studying drugs at different levels of complexity, from the molecular to the physiological, to understand how they interact with biological systems.Yet, it almost exclusively focuses on modulating specific molecular targets of interest, namely, the qualitative and quantitative description of the drug/receptor interaction (11).As a matter of fact, currently, target-based drug discovery heavily dominates drug discovery approaches in both academia and the pharmaceutical industry.Little emphasis is placed on realistic disease conditions whereby the local tissue microenvironment and/or specific environmental factors might flexibly modulate a patient's response.Indeed, due to the complexity of multifactorial diseases, drug intervention based on single-target drugs with high affinity, high selectivity, and strong potency may not fit well and does not always exhibit satisfactory efficacy with the network-based, inter-balanced regulation mode of the smart biological system (12,13).Many "targetbased" drugs have indeed numerous "off-target" therapeutic mechanisms (14).

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No synthesis or second-stage model call is performed.

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Relevant Papers

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

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

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

[4] Molecular insights into the premature aging disease progeria

[5] New therapeutic targets in rare genetic skeletal diseases

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

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

[8] Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

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

[10] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

[11] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

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

[13] A Novel YWHAG Variant L173S Causes Developmental and Epileptic Encephalopathy by Disrupting the Hydrophobic Internal Protein Structure

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

[15] Role of Transcriptomics in Precision Oncology

[16] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

[17] Network Based Integrated Analysis of Phenotype-Genotype Data for Prioritization of Candidate Symptom Genes

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

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

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

Notes