Donnai-Barrow syndrome

Mendelian MONDO:0009104 Pathograph 22 Show in embeddings browser hereditary disease

Donnai-Barrow syndrome is a rare LRP2-related autosomal recessive disorder characterized by multiorgan megalin dysfunction with developmental delay, sensorineural hearing impairment, ocular anomalies, and renal tubular proteinuria. Available evidence supports impaired megalin-mediated receptor-mediated endocytosis as the proximal disease mechanism.

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1
Inheritance
1
Pathophys.
13
Phenotypes
22
Pathograph
1
Genes
9
Medical Actions
3
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Donnai-Barrow syndrome is an autosomal recessive disorder caused by biallelic pathogenic variants in LRP2.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome."
This directly supports autosomal recessive inheritance in LRP2-related Donnai-Barrow syndrome.
⚙

Pathophysiology

1
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Donnai-Barrow syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Digestive 1
Omphalocele HP:0001539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Omphalocele (HP:0001539). HP:0001539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews lists omphalocele among common Donnai-Barrow syndrome features.
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome."
This directly supports sensorineural hearing impairment as part of the Donnai-Barrow syndrome phenotype.
Eye 3
Ocular anomalies Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ocular anomalies, annotated with Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome."
This directly supports ocular anomalies as a core feature of Donnai-Barrow syndrome.
High myopia HP:0011003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High myopia (HP:0011003). HP:0011003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss."
GeneReviews directly identifies high myopia as an ocular complication.
Retinal detachment HP:0000541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal detachment (HP:0000541). HP:0000541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss."
GeneReviews directly identifies retinal detachment as an ocular complication.
Genitourinary 1
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome."
This directly supports proteinuria as a core renal manifestation.
Head and Neck 1
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome."
This directly supports a characteristic abnormal facial shape in Donnai-Barrow syndrome.
Musculoskeletal 1
Congenital diaphragmatic hernia HP:0000776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital diaphragmatic hernia (HP:0000776). HP:0000776 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews lists congenital diaphragmatic hernia among common Donnai-Barrow syndrome features.
Nervous System 5
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"We provide a clinical report of two mono-chorionic twins with LRP2-related disease manifesting developmental delay, autistic features, seizures, proteinuria, and sleep disorders."
This directly supports developmental delay as a clinical feature of LRP2-related disease.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"We provide a clinical report of two mono-chorionic twins with LRP2-related disease manifesting developmental delay, autistic features, seizures, proteinuria, and sleep disorders."
This directly supports seizures as a clinical feature of LRP2-related Donnai-Barrow syndrome.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"We provide a clinical report of two mono-chorionic twins with LRP2-related disease manifesting developmental delay, autistic features, seizures, proteinuria, and sleep disorders."
This directly supports autistic behavior as part of the neurobehavioral phenotype.
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews lists corpus callosum agenesis among common Donnai-Barrow syndrome features.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews lists intellectual disability among common Donnai-Barrow syndrome features.
🧬

Genetic Associations

1
LRP2 (Causal biallelic variant)
Gene: LRP2 hgnc:6694 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LRP2 (hgnc:6694). hgnc:6694 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"By sequencing clinical exome, LRP2 candidate rare variants, c.6815G > A, p. (Arg2272His), inherited from the mother and c.12725A > G, p. (Asp4242Gly), inherited from the father, were identified."
This supports LRP2 as the causal gene in molecularly confirmed Donnai-Barrow syndrome.
💊

Medical Actions

9
Antiseizure medication therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Antiseizure medications are used for seizure management in affected individuals.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"The patients were under treatment with risperidone, antiseizure medications (ASMs), and supplementation of alpha-lactalbumin for self-injury and sleep disturbance."
This directly supports use of antiseizure medication in Donnai-Barrow syndrome management.
Ophthalmologic surveillance and retinal detachment prevention
Action: eye examinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is eye examination (NCIT:C38060). NCIT:C38060 is a clinical intervention from the NCI Thesaurus. Ontology label: Eye Examination NCIT:C38060
Ophthalmologic monitoring, corrective lenses for myopia, and preventive retinal detachment treatment are key eye-management measures.
Target Phenotypes: High myopia HP:0011003 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets High myopia (HP:0011003). HP:0011003 is a phenotype from the Human Phenotype Ontology. Retinal detachment HP:0000541 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Retinal detachment (HP:0000541). HP:0000541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews recommends corrective lenses and retinal detachment prevention as management.
Hearing rehabilitation
Platform: Device
Hearing aids and cochlear implantation are used for hearing loss management when clinically appropriate.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews supports hearing aids and cochlear implants for hearing loss management.
Cochlear implantation
Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Cochlear implantation may be considered for severe or profound sensorineural hearing loss.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews supports cochlear implants for hearing loss management.
Surgical repair of diaphragmatic hernia or omphalocele
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Structural congenital defects are managed surgically when present.
Target Phenotypes: Congenital diaphragmatic hernia HP:0000776 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congenital diaphragmatic hernia (HP:0000776). HP:0000776 is a phenotype from the Human Phenotype Ontology. Omphalocele HP:0001539 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Omphalocele (HP:0001539). HP:0001539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews recommends surgical repair for diaphragmatic hernia and omphalocele.
Renal and fat-soluble vitamin monitoring
Action: clinical monitoringNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical monitoring, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Kidney function, urinalysis, and serum vitamins A and D should be monitored because megalin dysfunction causes low-molecular-weight proteinuria.
Target Phenotypes: Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Ophthalmologic surveillance to monitor for retinal detachment; serial audiologic examinations; serial measurement of kidney function including blood urea nitrogen and serum creatinine concentrations, urinalysis, and serum vitamin A and D; monitor developmental progress and educational needs."
GeneReviews supports renal, urinalysis, and vitamin surveillance.
Vitamin D supplementation
Action: vitamin D supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vitamin D supplementation, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: vitamin D CHEBI:27300 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vitamin D (CHEBI:27300). CHEBI:27300 is a therapeutic agent from Chemical Entities of Biological Interest.
Vitamin D supplementation is used when serum vitamin D is low.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews supports supplementation for low serum vitamins A and D.
Developmental and educational support
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Developmental monitoring, educational planning, and support should be tailored to intellectual, visual, and hearing abilities.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education..."
GeneReviews recommends education tailored to intellectual, visual, and hearing abilities.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling addresses autosomal recessive recurrence risk, carrier testing, and reproductive options when familial variants are known.
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"When both parents are known to be carriers of a pathogenic variant, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews provides recurrence-risk information that underpins genetic counseling.
🔬

Diagnosis

5
LRP2 molecular genetic testing (Identification of biallelic pathogenic LRP2 variants confirms the diagnosis.)
Molecular confirmation of biallelic pathogenic LRP2 variants establishes the diagnosis.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37810913 SUPPORT Human Clinical
"By sequencing clinical exome, LRP2 candidate rare variants, c.6815G > A, p. (Arg2272His), inherited from the mother and c.12725A > G, p. (Asp4242Gly), inherited from the father, were identified."
This directly supports molecular genetic testing as the confirmatory diagnostic procedure.
Low-molecular-weight proteinuria testing (Low-molecular-weight proteinuria supports the diagnosis in the right clinical context.)
Urine laboratory evaluation for a distinctive low-molecular-weight proteinuria pattern is a key biochemical diagnostic clue.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"The diagnosis of DBS is established in a proband with: the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria; and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing."
GeneReviews identifies low-molecular-weight proteinuria as a diagnostic pattern.
Brain MRI (Corpus callosum agenesis or hypogenesis supports the clinical diagnosis.)
Brain MRI can document agenesis or hypogenesis of the corpus callosum.
MRI of the brain NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews supports corpus callosum agenesis as a common diagnostic feature detectable by brain MRI.
Ophthalmologic examination (High myopia or retinal involvement supports the syndrome diagnosis and guides management.)
Ophthalmologic assessment evaluates high myopia, retinal dystrophy, and retinal detachment risk.
eye examination NCIT:C38060 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss."
GeneReviews supports ophthalmologic evaluation for the characteristic ocular phenotype.
Audiologic evaluation (Sensorineural hearing loss supports the clinical diagnosis and guides hearing rehabilitation.)
Audiologic assessment evaluates sensorineural hearing impairment, often presenting in infancy or childhood.
audiologic evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301732 SUPPORT Human Clinical
"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."
GeneReviews lists sensorineural hearing loss among common Donnai-Barrow syndrome features.
{ }

Source YAML

click to show 
name: Donnai-Barrow syndrome
creation_date: "2026-04-15T15:45:03Z"
description: >-
  Donnai-Barrow syndrome is a rare LRP2-related autosomal recessive disorder
  characterized by multiorgan megalin dysfunction with developmental delay,
  sensorineural hearing impairment, ocular anomalies, and renal tubular
  proteinuria. Available evidence supports impaired megalin-mediated
  receptor-mediated endocytosis as the proximal disease mechanism.
category: Mendelian
parents:
- hereditary disease
synonyms:
- FOAR syndrome
disease_term:
  preferred_term: Donnai-Barrow syndrome
  term:
    id: MONDO:0009104
    label: Donnai-Barrow syndrome
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Donnai-Barrow syndrome is an autosomal recessive disorder caused by
    biallelic pathogenic variants in LRP2.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 is implicated in an autosomal recessive disorder characterized by
      dimorphisms, ocular anomalies, sensorineural deafness, proteinuria,
      epilepsy, and intellectual disability: a clinical condition called
      Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR)
      syndrome.
    explanation: This directly supports autosomal recessive inheritance in LRP2-related Donnai-Barrow syndrome.
pathophysiology:
- name: LRP2-related megalin endocytic dysfunction
  description: >-
    Donnai-Barrow syndrome is caused by LRP2 deficiency. Loss of megalin
    disrupts multiligand receptor-mediated endocytosis across affected organs,
    including proximal renal tubule and sensory tissues.
  genes:
  - preferred_term: LRP2
    term:
      id: hgnc:6694
      label: LRP2
  cell_types:
  - preferred_term: proximal tubule epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  molecular_functions:
  - preferred_term: cargo receptor activity
    term:
      id: GO:0038024
      label: cargo receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: receptor-mediated endocytosis
    modifier: ABNORMAL
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  - preferred_term: choroid plexus
    term:
      id: UBERON:0001886
      label: choroid plexus
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: internal ear
    term:
      id: UBERON:0001846
      label: internal ear
  evidence:
  - reference: PMID:38771880
    reference_title: Cryo-EM structures elucidate the multiligand receptor nature of megalin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans.
    explanation: This directly links megalin deficiency to Donnai-Barrow syndrome.
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LRP2 gene encodes megalin (LRP-2/GP330), a large single-spanning
      transmembrane glycoprotein that serves as a multiligand endocytotic
      receptor and mediates the reabsorption of albumin in the proximal renal
      tubule.
    explanation: This supports abnormal megalin-mediated endocytosis as the proximal disease mechanism.
  - reference: PMID:17632512
    reference_title: "Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 encodes megalin, a multiligand uptake receptor that regulates levels
      of diverse circulating compounds.
    explanation: The original molecular report supports LRP2/megalin dysfunction as the disease mechanism.
  downstream:
  - target: Proteinuria
    description: Impaired proximal tubular reabsorption produces characteristic low-molecular-weight proteinuria.
  - target: Sensorineural hearing impairment
    description: Megalin-dependent sensory tissue dysfunction contributes to hearing loss.
  - target: Ocular anomalies
    description: Megalin dysfunction across ocular tissues contributes to characteristic eye abnormalities.
  - target: High myopia
    description: Ocular megalin dysfunction contributes to severe myopia.
  - target: Retinal detachment
    description: High myopia and retinal involvement increase retinal detachment risk.
  - target: Agenesis of corpus callosum
    description: Megalin-dependent developmental signaling disruption contributes to corpus callosum malformation.
  - target: Intellectual disability
    description: Brain developmental effects of LRP2 deficiency contribute to intellectual disability.
  - target: Congenital diaphragmatic hernia
    description: Embryonic megalin pathway disruption contributes to structural congenital malformations.
  - target: Omphalocele
    description: Embryonic megalin pathway disruption contributes to abdominal wall congenital malformations.
  - target: Seizure
    description: Multiorgan developmental dysfunction contributes to epilepsy in Donnai-Barrow syndrome.
  - target: Global developmental delay
    description: Multiorgan developmental dysfunction contributes to neurodevelopmental impairment.
  - target: Autistic behavior
    description: Multiorgan developmental dysfunction can contribute to autistic behavioral features.
  - target: Abnormal facial shape
    description: >
      Embryonic megalin pathway disruption contributes to the facio-oculo-acoustico-renal
      craniofacial presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Global developmental delay
  category: Neurologic
  diagnostic: true
  description: Developmental delay is a recurrent neurodevelopmental manifestation of Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide a clinical report of two mono-chorionic twins with LRP2-related
      disease manifesting developmental delay, autistic features, seizures,
      proteinuria, and sleep disorders.
    explanation: This directly supports developmental delay as a clinical feature of LRP2-related disease.
- name: Sensorineural hearing impairment
  category: Otolaryngologic
  diagnostic: true
  description: Sensorineural hearing impairment is part of the classic clinical syndrome.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 is implicated in an autosomal recessive disorder characterized by
      dimorphisms, ocular anomalies, sensorineural deafness, proteinuria,
      epilepsy, and intellectual disability: a clinical condition called
      Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR)
      syndrome.
    explanation: This directly supports sensorineural hearing impairment as part of the Donnai-Barrow syndrome phenotype.
- name: Ocular anomalies
  category: Ophthalmologic
  diagnostic: true
  description: Ocular anomalies are a defining component of the FOAR syndrome phenotype.
  phenotype_term:
    preferred_term: Ocular anomalies
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 is implicated in an autosomal recessive disorder characterized by
      dimorphisms, ocular anomalies, sensorineural deafness, proteinuria,
      epilepsy, and intellectual disability: a clinical condition called
      Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR)
      syndrome.
    explanation: This directly supports ocular anomalies as a core feature of Donnai-Barrow syndrome.
- name: Seizure
  category: Neurologic
  description: Seizures are part of the neurologic phenotype in Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide a clinical report of two mono-chorionic twins with LRP2-related
      disease manifesting developmental delay, autistic features, seizures,
      proteinuria, and sleep disorders.
    explanation: This directly supports seizures as a clinical feature of LRP2-related Donnai-Barrow syndrome.
- name: Autistic behavior
  category: Neurologic
  description: Autistic features are reported in affected individuals with Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide a clinical report of two mono-chorionic twins with LRP2-related
      disease manifesting developmental delay, autistic features, seizures,
      proteinuria, and sleep disorders.
    explanation: This directly supports autistic behavior as part of the neurobehavioral phenotype.
- name: Abnormal facial shape
  category: Morphological
  description: Facial dysmorphism is part of the classic facio-oculo-acoustico-renal syndrome presentation.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 is implicated in an autosomal recessive disorder characterized by
      dimorphisms, ocular anomalies, sensorineural deafness, proteinuria,
      epilepsy, and intellectual disability: a clinical condition called
      Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR)
      syndrome.
    explanation: This directly supports a characteristic abnormal facial shape in Donnai-Barrow syndrome.
- name: Proteinuria
  category: Renal
  diagnostic: true
  description: Persistent tubular proteinuria is a characteristic renal feature of Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LRP2 is implicated in an autosomal recessive disorder characterized by
      dimorphisms, ocular anomalies, sensorineural deafness, proteinuria,
      epilepsy, and intellectual disability: a clinical condition called
      Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR)
      syndrome.
    explanation: This directly supports proteinuria as a core renal manifestation.
- name: Agenesis of corpus callosum
  category: Neurologic
  diagnostic: true
  description: Agenesis or hypogenesis of the corpus callosum is a common structural brain feature.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews lists corpus callosum agenesis among common Donnai-Barrow syndrome features.
- name: High myopia
  category: Ophthalmologic
  diagnostic: true
  description: Severe myopia is a characteristic ocular complication of Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ocular complications include high myopia, retinal detachment, retinal
      dystrophy, and progressive vision loss.
    explanation: GeneReviews directly identifies high myopia as an ocular complication.
- name: Retinal detachment
  category: Ophthalmologic
  description: Retinal detachment is a clinically important ocular complication and surveillance target.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ocular complications include high myopia, retinal detachment, retinal
      dystrophy, and progressive vision loss.
    explanation: GeneReviews directly identifies retinal detachment as an ocular complication.
- name: Intellectual disability
  category: Neurologic
  diagnostic: true
  description: Intellectual disability is part of the neurodevelopmental phenotype, distinct from early developmental delay.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews lists intellectual disability among common Donnai-Barrow syndrome features.
- name: Congenital diaphragmatic hernia
  category: Morphological
  description: Congenital diaphragmatic hernia is a recurrent structural malformation in Donnai-Barrow syndrome.
  phenotype_term:
    preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews lists congenital diaphragmatic hernia among common Donnai-Barrow syndrome features.
- name: Omphalocele
  category: Morphological
  description: Omphalocele or related umbilical hernia is a recurrent abdominal wall malformation.
  phenotype_term:
    preferred_term: Omphalocele
    term:
      id: HP:0001539
      label: Omphalocele
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews lists omphalocele among common Donnai-Barrow syndrome features.
biochemical: []
genetic:
- name: LRP2
  association: Causal biallelic variant
  gene_term:
    preferred_term: LRP2
    term:
      id: hgnc:6694
      label: LRP2
  notes: >-
    Donnai-Barrow syndrome is caused by pathogenic LRP2 variants affecting the
    multiligand receptor megalin.
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By sequencing clinical exome, LRP2 candidate rare variants, c.6815G > A,
      p. (Arg2272His), inherited from the mother and c.12725A > G, p.
      (Asp4242Gly), inherited from the father, were identified.
    explanation: This supports LRP2 as the causal gene in molecularly confirmed Donnai-Barrow syndrome.
environmental: []
treatments:
- name: Antiseizure medication therapy
  description: Antiseizure medications are used for seizure management in affected individuals.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients were under treatment with risperidone, antiseizure medications (ASMs), and supplementation of alpha-lactalbumin for self-injury and sleep disturbance.
    explanation: This directly supports use of antiseizure medication in Donnai-Barrow syndrome management.
- name: Ophthalmologic surveillance and retinal detachment prevention
  description: >-
    Ophthalmologic monitoring, corrective lenses for myopia, and preventive
    retinal detachment treatment are key eye-management measures.
  treatment_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  target_phenotypes:
  - preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  - preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews recommends corrective lenses and retinal detachment prevention as management.
- name: Hearing rehabilitation
  description: Hearing aids and cochlear implantation are used for hearing loss management when clinically appropriate.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid usage
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews supports hearing aids and cochlear implants for hearing loss management.
- name: Cochlear implantation
  description: Cochlear implantation may be considered for severe or profound sensorineural hearing loss.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews supports cochlear implants for hearing loss management.
- name: Surgical repair of diaphragmatic hernia or omphalocele
  description: Structural congenital defects are managed surgically when present.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  - preferred_term: Omphalocele
    term:
      id: HP:0001539
      label: Omphalocele
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews recommends surgical repair for diaphragmatic hernia and omphalocele.
- name: Renal and fat-soluble vitamin monitoring
  description: >-
    Kidney function, urinalysis, and serum vitamins A and D should be monitored
    because megalin dysfunction causes low-molecular-weight proteinuria.
  treatment_term:
    preferred_term: clinical monitoring
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic surveillance to monitor for retinal detachment; serial
      audiologic examinations; serial measurement of kidney function including
      blood urea nitrogen and serum creatinine concentrations, urinalysis, and
      serum vitamin A and D; monitor developmental progress and educational
      needs.
    explanation: GeneReviews supports renal, urinalysis, and vitamin surveillance.
- name: Vitamin D supplementation
  description: Vitamin D supplementation is used when serum vitamin D is low.
  treatment_term:
    preferred_term: vitamin D supplementation
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vitamin D
      term:
        id: CHEBI:27300
        label: vitamin D
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews supports supplementation for low serum vitamins A and D.
- name: Developmental and educational support
  description: >-
    Developmental monitoring, educational planning, and support should be
    tailored to intellectual, visual, and hearing abilities.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical repair of diaphragmatic hernia and/or omphalocele; corrective
      lenses for myopia; preventive treatments for retinal detachment; hearing
      aids and/or cochlear implants for hearing loss; antiepileptic drugs for
      seizures; supplementation as needed for low serum vitamins A and D;
      education tailored to degree of intellectual, visual, and hearing
      abilities.
    explanation: GeneReviews recommends education tailored to intellectual, visual, and hearing abilities.
- name: Genetic counseling
  description: >-
    Counseling addresses autosomal recessive recurrence risk, carrier testing,
    and reproductive options when familial variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When both parents are known to be carriers of a pathogenic variant, each
      sib of an affected individual has a 25% chance of being affected, a 50%
      chance of being an asymptomatic carrier, and a 25% chance of being
      unaffected and not a carrier.
    explanation: GeneReviews provides recurrence-risk information that underpins genetic counseling.
diagnosis:
- name: LRP2 molecular genetic testing
  description: Molecular confirmation of biallelic pathogenic LRP2 variants establishes the diagnosis.
  presence: Identification of biallelic pathogenic LRP2 variants confirms the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: LRP2
        term:
          id: hgnc:6694
          label: LRP2
  evidence:
  - reference: PMID:37810913
    reference_title: >-
      Behavioral Phenotype, Electroclinical Features, and Treatment Options in
      Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By sequencing clinical exome, LRP2 candidate rare variants, c.6815G > A,
      p. (Arg2272His), inherited from the mother and c.12725A > G, p.
      (Asp4242Gly), inherited from the father, were identified.
    explanation: This directly supports molecular genetic testing as the confirmatory diagnostic procedure.
- name: Low-molecular-weight proteinuria testing
  description: >-
    Urine laboratory evaluation for a distinctive low-molecular-weight proteinuria
    pattern is a key biochemical diagnostic clue.
  presence: Low-molecular-weight proteinuria supports the diagnosis in the right clinical context.
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of DBS is established in a proband with: the characteristic
      clinical features and a distinctive pattern of low-molecular-weight
      proteinuria; and/or biallelic pathogenic variants in LRP2 identified by
      molecular genetic testing.
    explanation: GeneReviews identifies low-molecular-weight proteinuria as a diagnostic pattern.
- name: Brain MRI
  description: Brain MRI can document agenesis or hypogenesis of the corpus callosum.
  presence: Corpus callosum agenesis or hypogenesis supports the clinical diagnosis.
  diagnosis_term:
    preferred_term: MRI of the brain
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews supports corpus callosum agenesis as a common diagnostic feature detectable by brain MRI.
- name: Ophthalmologic examination
  description: Ophthalmologic assessment evaluates high myopia, retinal dystrophy, and retinal detachment risk.
  presence: High myopia or retinal involvement supports the syndrome diagnosis and guides management.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ocular complications include high myopia, retinal detachment, retinal
      dystrophy, and progressive vision loss.
    explanation: GeneReviews supports ophthalmologic evaluation for the characteristic ocular phenotype.
- name: Audiologic evaluation
  description: Audiologic assessment evaluates sensorineural hearing impairment, often presenting in infancy or childhood.
  presence: Sensorineural hearing loss supports the clinical diagnosis and guides hearing rehabilitation.
  diagnosis_term:
    preferred_term: audiologic evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: GeneReviews lists sensorineural hearing loss among common Donnai-Barrow syndrome features.
differential_diagnoses: []
clinical_trials: []
references:
- reference: PMID:20301732
  title: "Donnai-Barrow Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1878/
  title: "Donnai-Barrow Syndrome - GeneReviews® - NCBI Bookshelf"
  tags:
  - GeneReviews
  findings: []
- reference: PMID:17632512
  title: "Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes."
  findings: []
datasets: []
notes: >-
  Asta deep research was completed for this disorder. Final curation prioritized
  disease-specific LRP2 case and megalin mechanism papers with exact cached
  abstract support.
📚

References & Deep Research

References

3
PMID:20301732
Donnai-Barrow Syndrome.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/books/NBK1878/
Donnai-Barrow Syndrome - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:17632512
Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Asta deep research was completed for this disorder. Final curation prioritized disease-specific LRP2 case and megalin mechanism papers with exact cached abstract support.

Review: Donnai-Barrow syndrome (Changes required) · 2026-05-30T02:55:01Z · View source

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3416 Issue state: OPEN Issue created: 2026-05-30T02:55:01Z Issue updated: 2026-05-30T02:58:00Z Issue closed: not closed Review decision: Changes required Labels: curation, medium_effort, review ## Completed curation review - Disease: **Donnai-Barrow syndrome** - Entry: `kb/disorders/Donnai-Barrow_syndrome.yaml` - Selection basis: #29 of 50 least-recently edited Mendelian entries - Review decision: **Changes required** - Validation stance: assumes schema/term/reference validation passes; this is a biological and clinical-content review. ## Findings 1. **GeneReviews exists and should be tagged/used.** Donnai-Barrow syndrome GeneReviews is available and should be the baseline. The current entry has no indication of GeneReviews consumption. Source: https://www.ncbi.nlm.nih.gov/books/NBK1878/ 2. **Clinical phenotype coverage is incomplete.** The YAML lists developmental delay, sensorineural hearing impairment, ocular anomalies, seizures, autistic behavior, facial shape, and proteinuria. GeneReviews emphasizes agenesis/hypogenesis of the corpus callosum, diaphragmatic hernia and/or omphalocele, high myopia/retinal detachment risk, sensorineural hearing loss, distinctive facial features, intellectual disability, and low-molecular-weight proteinuria. 3. **Diagnosis should include the biochemical clue.** The YAML has `LRP2 molecular genetic testing` but not the characteristic low-molecular-weight proteinuria diagnostic pattern that GeneReviews highlights. 4. **Management is too narrow.** Only antiseizure medication therapy is listed. Donnai-Barrow care should include ophthalmologic surveillance for high myopia/retinal detachment, audiology, renal/proteinuria monitoring, developmental therapies, congenital diaphragmatic/abdominal-wall management when present, and genetic counseling. 5. **Pathophysiology is too compressed.** `LRP2-related megalin endocytic dysfunction` is the correct anchor, but the entry should connect megalin-mediated endocytosis to renal tubular proteinuria, eye/brain development, and congenital malformation phenotypes. ## Research-artifact cross-check Checked `research/Donnai-Barrow_syndrome-deep-research-asta.md` and `.citations.md`. Because it is an Asta artifact, GeneReviews should anchor phenotype, diagnostic, and management updates. ## Content-completeness summary - **Phenotypes:** major gaps relative to GeneReviews: corpus callosum, diaphragmatic hernia/omphalocele, high myopia/retinal detachment, renal tubular proteinuria details. - **Subtype/lumping:** appropriate as LRP2-related Donnai-Barrow/FOAR syndrome. - **Pathophysiology:** deepen megalin endocytosis-to-organ phenotype links. - **Management/diagnosis:** major gap beyond antiseizure therapy and molecular testing. - **References:** add/tag GeneReviews if updating YAML. ## Suggested remediation Use GeneReviews as baseline, add low-molecular-weight proteinuria diagnosis, expand phenotypes, and add ophthalmic/audiologic/renal/developmental management. ## Sources used - GeneReviews, Donnai-Barrow Syndrome: https://www.ncbi.nlm.nih.gov/books/NBK1878/ - MedlinePlus Donnai-Barrow syndrome: https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ No YAML files or `references_cache/*.md` files were edited.

Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Donnai-Barrow syndrome. Core disease mechanisms, molecular and cellular pa...
Asta Scientific Corpus Retrieval 20 citations 2026-04-15T11:53:15.976369

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Donnai-Barrow syndrome. Core disease mechanisms, molecular and cellular pa...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] 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: 0.417) > 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.

[2] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[3] 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: 0.392) > 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.

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

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

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

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 3
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

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

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 25
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[7] 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: 0.374) > 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.

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

  • Authors: W. Tulalamba, T. Janvilisri
  • Year: 2012
  • Venue: International Journal of Cell Biology
  • URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
  • DOI: 10.1155/2012/594681
  • PMID: 22500174
  • PMCID: 3303613
  • Citations: 93
  • Influential citations: 5
  • Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[9] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 9
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[10] 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: 0.373) > : 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.

[11] Cardiac Phenotype and Gene Mutations in RASopathies

  • Authors: M. Faienza, G. Meliota, D. Mentino, R. Ficarella, Mattia Gentile et al.
  • Year: 2024
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/a4087d3b73d20a6e2f46b7fb87eed4017ec9a9be
  • DOI: 10.3390/genes15081015
  • PMID: 39202376
  • PMCID: 11353738
  • Citations: 9
  • Influential citations: 1
  • Summary: The molecular mechanisms underlying the development of cardiac diseases associated particularly with NS are clarified, and the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype–cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype–phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype–phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

[12] 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: 0.370) > 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.

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

  • Authors: Jing-wen Li, Xinjie Zhang, Jianfeng Guo, Chen Yu, Jun Yang
  • Year: 2022
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/d53bdf5f73f54a6d5a8be8777d23c465a13e9185
  • DOI: 10.3389/fgene.2021.777926
  • PMID: 35047005
  • PMCID: 8762052
  • Citations: 15
  • Influential citations: 2
  • Summary: Some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus are elicited, and knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > Cwh43 modifies the glycosylphosphatidylinositol-anchored proteins on the ependymal cells, and the mutant Cwh43 is related to iNPH in both humans and mice. The clinical features manifest as late-onset communicating hydrocephalus with symptoms of gait and balance dysfunction (Yang et al., 2021a). > The clinical manifestation and progression, as well as experimental investigations, indicate that hydrocephalus is a complex disease with polygenic involvement, rather than a simple CSF accumulation disorder. Although the current studies have revealed that some genetic mutations are involved in the pathogenesis of hydrocephalus, how these mutations are associated with the disorder of CSF circulation and their pathogenic roles in the pathological progression of hydrocephalus still remain largely unknown. Previous studies indicated that a lot of genetic mutations were relevant to the disorders of ciliary and/or centrosome, resulting in the dysfunction of the glymphatic system. However, how these mutations and their interactions contribute to the pathogenesis of hydrocephalus needs to be further elucidated. Moreover, there is still a lack of basic knowledge on the mechanisms underlying the cognitive functional impairment of hydrocephalus. Therefore, further extensive studies should be conducted to explore the underlying molecular mechanisms of identified and/or unidentified genes in the pathophysiology of hydrocephalus. Based on our knowledge, we propose that the genetic mutations relevant to ciliary and centrosomal proteins and the interaction between glymphatic system and ciliary/ centrosomal structures/functions may be a critical molecular mechanism in the pathophysiology of hydrocephalus. In addition, based on these fundamental molecular mechanisms, it is noteworthy that environmental and other acquired risks or etiological factors are also involved in the facilitation of ventricular enlargement.

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

  • Authors: I. Condò
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
  • DOI: 10.3390/ijms23126525
  • PMID: 35742964
  • PMCID: 9223693
  • Citations: 15
  • Influential citations: 2
  • Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[15] Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants

  • Authors: N. Kawashima, Usua Oyarbide, M. Cipolli, V. Bezzerri, S. Corey
  • Year: 2023
  • Venue: Haematologica
  • URL: https://www.semanticscholar.org/paper/3562173b36d169a99527f5cb0492a27530eacb6c
  • DOI: 10.3324/haematol.2023.282949
  • PMID: 37226705
  • PMCID: 10543188
  • Citations: 34
  • Summary: Four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Similar to dyskeratosis congenita in its restriction to a particular physiologic process is Fanconi anemia, which is due to one of 23 genes involved in different steps to detect and repair DNA interstrand crosslink damage. Defying thematic unity in its pathophysiology, severe congenital neutropenia is due to a number of genes that vary in their biochemical and cellular function. 89 BDS, EFL1, DNAJC21, and SRP54 encode proteins involved in ribosome assembly and nascent polypeptide synthesis. SDS has been viewed as a ribosomopathy. 90 This term has been applied to diverse diseases with germline or somatic mutations, such as Treacher Collins syndrome, Diamond-Blackfan anemia, cartilage hair hypoplasia, and del(5q) MDS. 91 We suggest using the term Shwachman-Diamond syndromes or Shwachman-Diamond-like syndrome to denote disorders that may involve blood and/or pancreatic abnormalities, and which result from germline variants that encode proteins affecting ribosome biogenesis and early protein synthesis. The term Diamond-Blackfan anemia should be reserved for those with congenital hypoplastic anemia. > Limitations of this analysis for human phenotypes of SDS due to DNAJC21, EFL1, or SRP54 variants include missing data from patients in the literature and the nature of the descriptive research that did not provide an adequate sample size for statistical analyses to be performed. To date, there have been few organismal models to characterize phenotypes that copy human SDS. The molecular pathways underlying these entities have fallen short on identifying precise mechanisms for developing BMF and pancreatic insufficiency. In addition, even though embryonic lethality was avoided, neoplastic transformation (the major concern for SDS patients in late adolescence-early adulthood) has not been modeled in mice or zebrafish. > Comparison of phenotypes should promote a better understanding of the disease entities covered by the term SDS.

[16] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

  • Authors: Jakub Szyller, I. Bil-Lula
  • Year: 2021
  • Venue: Oxidative Medicine and Cellular Longevity
  • URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
  • DOI: 10.1155/2021/6678457
  • PMID: 33603951
  • PMCID: 7868165
  • Citations: 112
  • Influential citations: 2
  • Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[17] 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: 0.362) > A key advantage of disease-modifying therapies is their potential to target pathogenic mechanisms early in the disease course, potentially preventing the progression of some infantile epileptic encephalopathies to LGS. > This narrative review explores precision therapeutic strategies based on specific monogenic causes and disease mechanisms relevant to LGS. A comprehensive literature search (PubMed, MEDLINE, ClinicalTrials.gov, conference abstracts from the American Academy of Neurology and American Epilepsy Society, and gray literature) was conducted through 19 February 2025 to identify established ASMs, repurposed and novel drugs, as well as various gene therapy approaches with potential relevance to LGS. Given that over 900 monogenic causes of DEEs have been identified-implicating diverse cellular components such as ion channels, receptors, synaptic proteins, signaling pathways, metabolic processes, and epigenetic regulators-this review discusses current and emerging precision therapeutics based on shared molecular mechanisms and the pathophysiology of select genes associated with LGS [17] (Table 1).

[18] Синдром Донна–Барроу в практике нефролога

  • Authors: М. Е. Аксенова, Н. М. Зайкова, Т. В. Лепаева, В. В. Длин
  • Year: 2021
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/9eb7eac9aa318f351162bc3a0276b3ea5c578a65
  • DOI: 10.21508/1027-4065-2021-66-1-106-112
  • Citations: 1
  • Summary: Clinical cases of children with different phenotypes of the Donnai-Barrow syndrome, including different renal disorders are described, one patient had isolated low-molecular-weight proteinuria, another patient suffered fromproteinuria, hypercalciuria, nephrocalcinosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Donnai–Barrow syndrome is a multi-system disorder characterized by a variable combination of congenital anomalies, progressive myopia, sensorineural hearing loss, intellectual disability and renal disease. The article describes clinical cases of children with different phenotypes of the syndrome, including different renal disorders. One patient had isolated low-molecular-weight proteinuria, another patient suffered from proteinuria, hypercalciuria, nephrocalcinosis. Disruption of megaline-mediated endocytosis, retrograde endosomal transport of ligands, mitochondrial dysfunction, stress of the endoplasmic reticulum can lead to a different spectrum and various degrees of severity of tubular dysfunction in Donnai-Barrow syndrome. A variety of clinical manifestations of the disease can lead to a low diagnosis of Donnai-Barrow syndrome and inadequate patient management.

[19] Donnai–Barrow syndrome in nephrology practice

  • Authors: M. Aksenova, N. Zaikova, T. Lepaeva, V. Dlin
  • Year: Unknown
  • Venue: Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)
  • URL: https://www.semanticscholar.org/paper/4c39c603b69bb195f4e6ba31a6faeb9259548a8e
  • DOI: 10.21508/1027-4065-2021-66-1-106-112
  • Summary: Clinical cases of children with different phenotypes of the Donnai-Barrow syndrome, including different renal disorders are described, one patient had isolated low-molecular-weight proteinuria, another patient suffered fromproteinuria, hypercalciuria, nephrocalcinosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Donnai–Barrow syndrome is a multi-system disorder characterized by a variable combination of congenital anomalies, progressive myopia, sensorineural hearing loss, intellectual disability and renal disease. The article describes clinical cases of children with different phenotypes of the syndrome, including different renal disorders. One patient had isolated low-molecular-weight proteinuria, another patient suffered from proteinuria, hypercalciuria, nephrocalcinosis. Disruption of megaline-mediated endocytosis, retrograde endosomal transport of ligands, mitochondrial dysfunction, stress of the endoplasmic reticulum can lead to a different spectrum and various degrees of severity of tubular dysfunction in Donnai-Barrow syndrome. A variety of clinical manifestations of the disease can lead to a low diagnosis of Donnai-Barrow syndrome and inadequate patient management.

[20] 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: 0.356) > 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

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.