CHARGE syndrome

Mendelian MONDO:0008965 Pathograph 4 genetic syndrome hereditary disease

CHARGE syndrome is an autosomal dominant multiple-anomaly disorder caused in the large majority of cases by heterozygous loss-of-function variants in CHD7, which encodes an ATP-dependent chromatin-remodeling enzyme. The acronym CHARGE denotes Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital anomalies, and Ear anomalies, but following discovery of the molecular cause the phenotypic spectrum has expanded to include semicircular canal hypoplasia with vestibular dysfunction, cranial nerve anomalies (notably facial nerve palsy and olfactory/auditory deficits), cleft lip and/or palate, tracheoesophageal anomalies, hypothyroidism, brain anomalies, seizures, renal anomalies, and hypogonadotropic hypogonadism. CHD7 haploinsufficiency disrupts ATP-dependent chromatin remodeling required for the transcriptional programs of multipotent neural crest cells and cranial/otic placodes during early embryogenesis, producing the characteristic multisystem pattern of malformations.

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1
Mappings
1
Inheritance
4
Pathophys.
16
Phenotypes
4
Pathograph
1
Genes
4
Medical Actions
1
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0008965 CHARGE syndrome
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
CHARGE syndrome (CHD7 disorder) is an autosomal dominant disorder typically caused by a de novo pathogenic variant. In rare instances an individual inherits a pathogenic variant from a heterozygous parent, and germline mosaicism has been documented, giving an empiric sibling recurrence risk of approximately 1%-2% when the proband's variant is not detected in either parent.
Autosomal dominant inheritance De novo rate: 90
Show evidence (2 references)
PMID:20301296 SUPPORT Human Clinical
"CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant."
GeneReviews directly states the autosomal dominant inheritance pattern and that most cases arise de novo.
PMID:16155193 SUPPORT Human Clinical
"Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism."
Documents germline mosaicism in CHARGE syndrome, which underlies the empiric recurrence risk for siblings of a proband with apparently de novo variants.
⚙

Pathophysiology

4
CHD7 haploinsufficiency and impaired ATP-dependent chromatin remodeling
CHD7 encodes a chromodomain helicase DNA-binding protein that functions as an ATP-dependent chromatin-remodeling enzyme. Heterozygous loss-of-function variants reduce CHD7 dosage (haploinsufficiency), impairing the chromatin-remodeling activity needed to fine-tune transcriptional programs during development. Most pathogenic variants are unique nonsense or frameshift variants scattered throughout the gene, consistent with a loss-of-function mechanism.
ATP-dependent chromatin remodeling GO:0006338 ↓ DECREASED
Downstream
Disrupted neural crest cell development Loss of CHD7 chromatin-remodeling activity disrupts the transcriptional programs of multipotent neural crest cells.
Inappropriate p53 activation CHD7 normally binds the p53 promoter to repress p53; haploinsufficiency releases this repression and causes inappropriate p53 activation.
Impaired cranial and otic placode-derived development Reduced CHD7 dosage impairs the chromatin remodeling required for cranial/otic placode and inner ear development.
Show evidence (2 references)
PMID:15300250 SUPPORT Human Clinical
"Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals."
Original identification of CHD7 (a chromodomain gene family member) as the major cause of CHARGE syndrome.
PMID:33127760 SUPPORT Model Organism
"CHD7 encodes an ATP-dependent chromatin remodeling factor."
Confirms CHD7 functions as an ATP-dependent chromatin remodeling enzyme, the molecular activity reduced by haploinsufficiency.
Disrupted neural crest cell development
CHD7 acts cell-autonomously in multipotent neural crest cells to fine-tune expression of gene networks critical for their development and migration. Conditional deletion of Chd7 in neural crest cells in mice causes severe conotruncal heart defects and perinatal lethality, recapitulating the cardiac neural crest contribution to CHARGE-type malformations. Disrupted neural crest development provides a unifying explanation for the multisystem craniofacial, cardiac, and other anomalies of CHARGE syndrome.
Migratory neural crest cell CL:0000333
Neural crest cell development GO:0014032 ⚠ ABNORMAL Neural crest cell migration GO:0001755 ⚠ ABNORMAL
Show evidence (3 references)
PMID:33127760 SUPPORT Model Organism
"deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development"
Mouse genetic evidence that CHD7 acts cell-autonomously in neural crest cells, linking CHD7 loss to neural crest-derived (conotruncal) defects.
PMID:29179815 SUPPORT In Vitro
"CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo."
Patient iPSC-derived neural crest cells directly demonstrate the defective migration predicted by the neurocristopathy hypothesis for CHARGE syndrome.
PMID:36587182 SUPPORT In Vitro
"CHD7 was strongly associated with active enhancer regions, permitting the expression of hNCC-specific genes to sustain the function of hNCCs."
Provides the molecular basis for CHD7's role in neural crest cells: it acts at active enhancers to drive neural crest-specific gene expression.
Inappropriate p53 activation
CHD7 binds the p53 promoter and negatively regulates p53 expression. Loss of CHD7 in neural crest cells (and in samples from patients with CHARGE syndrome) results in inappropriate p53 activation, and p53 heterozygosity partially rescues Chd7-null mouse phenotypes, indicating that excessive p53 activity contributes to CHARGE-type developmental defects downstream of CHD7 loss.
Signal transduction by p53 class mediator GO:0072331 ↑ INCREASED
Downstream
Disrupted neural crest cell development Inappropriate p53 activation contributes to the neural crest-related phenotypes downstream of CHD7 loss; p53 heterozygosity partially rescues Chd7-null phenotypes.
Show evidence (2 references)
PMID:25119037 SUPPORT Model Organism
"we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation"
Establishes that CHD7 normally represses p53 and that CHD7 loss causes inappropriate p53 activation, a contributing mechanism in CHARGE syndrome.
PMID:25119037 SUPPORT Model Organism
"we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss"
Genetic rescue experiment demonstrating p53 hyperactivation is causally downstream of CHD7 loss in producing CHARGE-like phenotypes.
Impaired cranial and otic placode-derived development
CHD7 is required for normal development of cranial placodes and the inner ear. A consistent and highly specific feature of CHARGE syndrome is hypoplasia of the semicircular canals (derived from the otic placode/otocyst), which produces vestibular dysfunction. Olfactory placode dysfunction contributes to anosmia and to the GnRH-neuron migration defect underlying hypogonadotropic hypogonadism.
Otic placode formation GO:0043049 ⚠ ABNORMAL Inner ear morphogenesis GO:0042472 ⚠ ABNORMAL
Show evidence (2 references)
PMID:16155193 SUPPORT Human Clinical
"A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia."
Semicircular canal hypoplasia is an otic placode/inner ear developmental defect that is a consistent and diagnostically important feature of CHARGE syndrome.
PMID:36396635 SUPPORT In Vitro
"loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors"
Human inner ear organoids show CHD7 is required for otic lineage specification and sensory cell differentiation, mechanistically linking CHD7 loss to the inner ear/hearing phenotype of CHARGE syndrome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CHARGE 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.
●

Phenotypes

16
Cardiovascular 1
Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627
Show evidence (2 references)
PMID:33127760 SUPPORT Model Organism
"in which conotruncal anomalies are the most prevalent form of heart defects"
Identifies conotruncal anomalies as the most prevalent heart defect in CHARGE syndrome, supporting congenital heart disease as a core feature.
PMID:37675914 SUPPORT Human Clinical
"The prevalence of CHDs was 76.6%, patent ductus arteriosus 26%, ventricular 21%, atrial septal defects 18%, tetralogy of Fallot 11%, and aortic abnormalities 24%."
Systematic review of 943 CHARGE patients reporting a 76.6% prevalence of congenital heart defects, supporting both the association and the FREQUENT frequency band.
Digestive 2
Feeding difficulties Feeding difficulties HP:0011968
Show evidence (1 reference)
PMID:37675914 SUPPORT Human Clinical
"CHDs and feeding disorders associated with CS may have a substantial impact on prognosis."
Identifies feeding disorders as a clinically significant feature of CHARGE syndrome that substantially affects prognosis.
Tracheoesophageal fistula Tracheoesophageal fistula HP:0002575
Show evidence (1 reference)
PMID:16155193 SUPPORT Human Clinical
"Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula."
Documents tracheo-oesophageal fistula as a commonly associated congenital anomaly in CHARGE syndrome.
Ear 1
Hearing impairment Sensorineural hearing impairment HP:0000407
Show evidence (2 references)
PMID:20301296 SUPPORT Human Clinical
"ear anomalies (including deafness)"
Ear anomalies including deafness are a defining CHARGE feature per GeneReviews.
PMID:36396635 SUPPORT In Vitro
"Results from transcriptome profiling of hair cells reveal disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss."
Identifies disrupted deafness-gene expression in CHD7-deficient hair cells as a mechanism for sensorineural hearing loss in CHARGE syndrome.
Endocrine 2
Hypogonadotropic hypogonadism Hypogonadotropic hypogonadism HP:0000044
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)"
Genital hypoplasia (with underlying hypogonadotropic hypogonadism) is part of the core CHARGE phenotype described in GeneReviews.
Hypothyroidism Hypothyroidism HP:0000821
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies"
GeneReviews lists hypothyroidism among the expanded CHARGE phenotype.
Eye 1
Coloboma Coloboma HP:0000589
Show evidence (1 reference)
PMID:20186815 SUPPORT Human Clinical
"We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals."
Large clinical cohort showing ocular coloboma is a core feature enriched in CHD7 mutation-positive CHARGE patients.
Genitourinary 1
Renal anomalies Abnormality of the kidney HP:0000077
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies"
GeneReviews lists renal anomalies among the expanded CHARGE phenotype.
Head and Neck 3
Choanal atresia Choanal atresia HP:0000453
Show evidence (1 reference)
PMID:16155193 SUPPORT Human Clinical
"CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness."
Choanal atresia is one of the cardinal congenital anomalies defining CHARGE syndrome.
Facial palsy Facial palsy HP:0010628
Show evidence (1 reference)
PMID:20186815 SUPPORT Human Clinical
"We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals."
Facial nerve paralysis is enriched in CHD7 mutation-positive CHARGE patients in a large cohort.
Cleft lip and/or palate Cleft palate HP:0000175
Show evidence (1 reference)
PMID:16155193 SUPPORT Human Clinical
"Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula."
Identifies cleft lip/palate as a commonly associated anomaly in CHARGE syndrome.
Nervous System 3
Cranial nerve dysfunction Cranial nerve paralysis HP:0006824
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies"
GeneReviews lists cranial nerve anomalies among the expanded CHARGE phenotype.
Growth and developmental delay Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)"
Retarded growth and development is part of the core CHARGE acronym and phenotype.
Seizures Seizure HP:0001250
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies"
GeneReviews lists seizures among the expanded CHARGE phenotype.
Other 2
Semicircular canal hypoplasia Hypoplasia of the semicircular canal HP:0011382
Show evidence (1 reference)
PMID:16155193 SUPPORT Human Clinical
"A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia."
Directly documents semicircular canal hypoplasia as a consistent feature of CHARGE syndrome.
Brain anomalies Abnormal brain morphology HP:0012443
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies"
GeneReviews lists brain anomalies among the expanded CHARGE phenotype.
🧬

Genetic Associations

1
CHD7 (causative)
Gene: CHD7 hgnc:20626 relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:16155193 SUPPORT Human Clinical
"CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation."
Establishes CHD7 as the causative gene in most CHARGE cases with broad clinical variability and no genotype-phenotype correlation.
PMID:15300250 SUPPORT Human Clinical
"We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome."
Documents 8q12 microdeletion as a less common mechanism of CHARGE syndrome involving CHD7.
💊

Medical Actions

4
Multidisciplinary supportive management
Action: supportive care MAXO:0000950
Management of CHARGE syndrome is complex and requires a multidisciplinary approach involving clinicians, therapists, and educators, with treatment directed at the individual's specific manifestations (cardiac surgery, choanal atresia repair, feeding/airway support, hearing and vision rehabilitation, endocrine management, and developmental/educational support).
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"Management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators."
GeneReviews describes multidisciplinary supportive management as the mainstay of CHARGE care.
Anesthesia precautions for airway complications
Action: supportive care MAXO:0000950
Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible. This is a documented "agents/circumstances to avoid" safety consideration in CHARGE syndrome.
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible."
GeneReviews "Agents/circumstances to avoid" warning on anesthesia-related airway complications in CHARGE syndrome.
Cardiac surgery
Action: cardiac surgical procedure Ontology label: surgical procedure MAXO:0000004
Surgical correction of congenital heart defects is required in a large proportion of individuals with CHARGE syndrome, reflecting the high prevalence and complexity of cardiac malformations in the disorder.
Show evidence (1 reference)
PMID:37675914 SUPPORT Human Clinical
"Cardiac surgery was performed in more than half of CS patients (150/242, 62%)."
Systematic review reporting that cardiac surgery was performed in the majority of CHARGE syndrome patients with congenital heart defects.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is recommended for families given the autosomal dominant inheritance and the empiric sibling recurrence risk of approximately 1%-2% arising from documented germline mosaicism, with discussion of prenatal and preimplantation genetic testing options.
Show evidence (1 reference)
PMID:20301296 SUPPORT Human Clinical
"CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant."
The autosomal dominant inheritance with de novo and germline-mosaic recurrence risk documented in GeneReviews is the basis for genetic counseling in CHARGE syndrome.
{ }

Source YAML

click to show 
name: CHARGE syndrome
creation_date: '2026-06-03T00:00:00Z'
category: Mendelian
description: >-
  CHARGE syndrome is an autosomal dominant multiple-anomaly disorder caused in
  the large majority of cases by heterozygous loss-of-function variants in CHD7,
  which encodes an ATP-dependent chromatin-remodeling enzyme. The acronym CHARGE
  denotes Coloboma, Heart defects, Atresia of the choanae, Retardation of growth
  and development, Genital anomalies, and Ear anomalies, but following discovery
  of the molecular cause the phenotypic spectrum has expanded to include
  semicircular canal hypoplasia with vestibular dysfunction, cranial nerve
  anomalies (notably facial nerve palsy and olfactory/auditory deficits), cleft
  lip and/or palate, tracheoesophageal anomalies, hypothyroidism, brain
  anomalies, seizures, renal anomalies, and hypogonadotropic hypogonadism. CHD7
  haploinsufficiency disrupts ATP-dependent chromatin remodeling required for the
  transcriptional programs of multipotent neural crest cells and cranial/otic
  placodes during early embryogenesis, producing the characteristic multisystem
  pattern of malformations.
disease_term:
  preferred_term: CHARGE syndrome
  term:
    id: MONDO:0008965
    label: CHARGE syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008965
      label: CHARGE syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- genetic syndrome
- hereditary disease
synonyms:
- CHD7 disorder
- coloboma, heart defect, atresia choanae, retarded growth and development, genital
  abnormality, and ear abnormality syndrome
references:
- reference: PMID:20301296
  title: "CHD7 Disorder."
  tags:
  - GeneReviews
prevalence:
- population: General population (birth prevalence)
  notes: >-
    Estimated birth prevalence of CHARGE syndrome is approximately 1 in
    8,500 to 1 in 17,000 live births across cohort and review estimates.
  evidence:
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHARGE syndrome (CS) is a rare genetic disease that affects many areas of the body.
    explanation: >-
      Confirms CHARGE syndrome is a rare multisystem genetic disorder.
progression:
- phase: Early life
  notes: >-
    Major early-life morbidity and mortality are driven by complex congenital
    heart defects and by airway/feeding problems; aspiration related to feeding
    difficulties is a leading cause of non-cardiovascular death.
  evidence:
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHDs and feeding disorders associated with CS may have a substantial impact on prognosis.
    explanation: >-
      Systematic review concluding that congenital heart defects and feeding
      disorders substantially affect prognosis in CHARGE syndrome.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: "90"
  description: >-
    CHARGE syndrome (CHD7 disorder) is an autosomal dominant disorder typically
    caused by a de novo pathogenic variant. In rare instances an individual
    inherits a pathogenic variant from a heterozygous parent, and germline
    mosaicism has been documented, giving an empiric sibling recurrence risk of
    approximately 1%-2% when the proband's variant is not detected in either
    parent.
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.
    explanation: >-
      GeneReviews directly states the autosomal dominant inheritance pattern and
      that most cases arise de novo.
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism.
    explanation: >-
      Documents germline mosaicism in CHARGE syndrome, which underlies the
      empiric recurrence risk for siblings of a proband with apparently de novo
      variants.
pathophysiology:
- name: CHD7 haploinsufficiency and impaired ATP-dependent chromatin remodeling
  description: >-
    CHD7 encodes a chromodomain helicase DNA-binding protein that functions as an
    ATP-dependent chromatin-remodeling enzyme. Heterozygous loss-of-function
    variants reduce CHD7 dosage (haploinsufficiency), impairing the
    chromatin-remodeling activity needed to fine-tune transcriptional programs
    during development. Most pathogenic variants are unique nonsense or frameshift
    variants scattered throughout the gene, consistent with a loss-of-function
    mechanism.
  biological_processes:
  - preferred_term: ATP-dependent chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: DECREASED
  downstream:
  - target: Disrupted neural crest cell development
    description: >-
      Loss of CHD7 chromatin-remodeling activity disrupts the transcriptional
      programs of multipotent neural crest cells.
  - target: Inappropriate p53 activation
    description: >-
      CHD7 normally binds the p53 promoter to repress p53; haploinsufficiency
      releases this repression and causes inappropriate p53 activation.
  - target: Impaired cranial and otic placode-derived development
    description: >-
      Reduced CHD7 dosage impairs the chromatin remodeling required for
      cranial/otic placode and inner ear development.
  evidence:
  - reference: PMID:15300250
    reference_title: "Mutations in a new member of the chromodomain gene family cause CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.
    explanation: >-
      Original identification of CHD7 (a chromodomain gene family member) as the
      major cause of CHARGE syndrome.
  - reference: PMID:33127760
    reference_title: "CHD7 regulates cardiovascular development through ATP-dependent and -independent activities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CHD7 encodes an ATP-dependent chromatin remodeling factor.
    explanation: >-
      Confirms CHD7 functions as an ATP-dependent chromatin remodeling enzyme,
      the molecular activity reduced by haploinsufficiency.
- name: Disrupted neural crest cell development
  description: >-
    CHD7 acts cell-autonomously in multipotent neural crest cells to fine-tune
    expression of gene networks critical for their development and migration.
    Conditional deletion of Chd7 in neural crest cells in mice causes severe
    conotruncal heart defects and perinatal lethality, recapitulating the
    cardiac neural crest contribution to CHARGE-type malformations. Disrupted
    neural crest development provides a unifying explanation for the multisystem
    craniofacial, cardiac, and other anomalies of CHARGE syndrome.
  cell_types:
  - preferred_term: Migratory neural crest cell
    term:
      id: CL:0000333
      label: migratory neural crest cell
  biological_processes:
  - preferred_term: Neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: ABNORMAL
  - preferred_term: Neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33127760
    reference_title: "CHD7 regulates cardiovascular development through ATP-dependent and -independent activities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development
    explanation: >-
      Mouse genetic evidence that CHD7 acts cell-autonomously in neural crest
      cells, linking CHD7 loss to neural crest-derived (conotruncal) defects.
  - reference: PMID:29179815
    reference_title: "CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo.
    explanation: >-
      Patient iPSC-derived neural crest cells directly demonstrate the defective
      migration predicted by the neurocristopathy hypothesis for CHARGE syndrome.
  - reference: PMID:36587182
    reference_title: "Chromatin remodeler CHD7 targets active enhancer region to regulate cell type-specific gene expression in human neural crest cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CHD7 was strongly associated with active enhancer regions, permitting the expression of hNCC-specific genes to sustain the function of hNCCs.
    explanation: >-
      Provides the molecular basis for CHD7's role in neural crest cells: it acts
      at active enhancers to drive neural crest-specific gene expression.
- name: Inappropriate p53 activation
  description: >-
    CHD7 binds the p53 promoter and negatively regulates p53 expression. Loss of
    CHD7 in neural crest cells (and in samples from patients with CHARGE syndrome)
    results in inappropriate p53 activation, and p53 heterozygosity partially
    rescues Chd7-null mouse phenotypes, indicating that excessive p53 activity
    contributes to CHARGE-type developmental defects downstream of CHD7 loss.
  biological_processes:
  - preferred_term: Signal transduction by p53 class mediator
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
    modifier: INCREASED
  downstream:
  - target: Disrupted neural crest cell development
    description: >-
      Inappropriate p53 activation contributes to the neural crest-related
      phenotypes downstream of CHD7 loss; p53 heterozygosity partially rescues
      Chd7-null phenotypes.
  evidence:
  - reference: PMID:25119037
    reference_title: "Inappropriate p53 activation during development induces features of CHARGE syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation
    explanation: >-
      Establishes that CHD7 normally represses p53 and that CHD7 loss causes
      inappropriate p53 activation, a contributing mechanism in CHARGE syndrome.
  - reference: PMID:25119037
    reference_title: "Inappropriate p53 activation during development induces features of CHARGE syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss
    explanation: >-
      Genetic rescue experiment demonstrating p53 hyperactivation is causally
      downstream of CHD7 loss in producing CHARGE-like phenotypes.
- name: Impaired cranial and otic placode-derived development
  description: >-
    CHD7 is required for normal development of cranial placodes and the inner ear.
    A consistent and highly specific feature of CHARGE syndrome is hypoplasia of
    the semicircular canals (derived from the otic placode/otocyst), which
    produces vestibular dysfunction. Olfactory placode dysfunction contributes to
    anosmia and to the GnRH-neuron migration defect underlying hypogonadotropic
    hypogonadism.
  biological_processes:
  - preferred_term: Otic placode formation
    term:
      id: GO:0043049
      label: otic placode formation
    modifier: ABNORMAL
  - preferred_term: Inner ear morphogenesis
    term:
      id: GO:0042472
      label: inner ear morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia.
    explanation: >-
      Semicircular canal hypoplasia is an otic placode/inner ear developmental
      defect that is a consistent and diagnostically important feature of CHARGE
      syndrome.
  - reference: PMID:36396635
    reference_title: "CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors
    explanation: >-
      Human inner ear organoids show CHD7 is required for otic lineage
      specification and sensory cell differentiation, mechanistically linking
      CHD7 loss to the inner ear/hearing phenotype of CHARGE syndrome.
phenotypes:
- name: Coloboma
  category: Phenotypic
  description: >-
    Ocular coloboma (of the iris, retina, choroid, or optic disc) is a cardinal
    feature of CHARGE syndrome and is more frequent in CHD7 mutation-positive
    individuals.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals.
    explanation: >-
      Large clinical cohort showing ocular coloboma is a core feature
      enriched in CHD7 mutation-positive CHARGE patients.
- name: Choanal atresia
  category: Phenotypic
  description: >-
    Atresia (or stenosis) of the choanae, the bony or membranous narrowing of the
    posterior nasal passages, is one of the defining CHARGE anomalies.
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness.
    explanation: >-
      Choanal atresia is one of the cardinal congenital anomalies defining
      CHARGE syndrome.
- name: Congenital heart defect
  category: Phenotypic
  frequency: FREQUENT
  description: >-
    Congenital heart defects are common in CHARGE syndrome; conotruncal anomalies
    are among the most prevalent forms and reflect the cardiac neural crest
    contribution to the disorder. Complex heart defects are a major contributor
    to early mortality.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:33127760
    reference_title: "CHD7 regulates cardiovascular development through ATP-dependent and -independent activities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in which conotruncal anomalies are the most prevalent form of heart defects
    explanation: >-
      Identifies conotruncal anomalies as the most prevalent heart defect in
      CHARGE syndrome, supporting congenital heart disease as a core feature.
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of CHDs was 76.6%, patent ductus arteriosus 26%, ventricular 21%, atrial septal defects 18%, tetralogy of Fallot 11%, and aortic abnormalities 24%.
    explanation: >-
      Systematic review of 943 CHARGE patients reporting a 76.6% prevalence of
      congenital heart defects, supporting both the association and the FREQUENT
      frequency band.
- name: Feeding difficulties
  category: Phenotypic
  description: >-
    Feeding difficulties (including dysphagia from cranial nerve dysfunction)
    are very common in CHARGE syndrome, often necessitating tube feeding, and
    associated aspiration is a leading cause of non-cardiovascular death.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHDs and feeding disorders associated with CS may have a substantial impact on prognosis.
    explanation: >-
      Identifies feeding disorders as a clinically significant feature of CHARGE
      syndrome that substantially affects prognosis.
- name: Semicircular canal hypoplasia
  category: Phenotypic
  description: >-
    Hypoplasia (or aplasia) of the semicircular canals is a consistent and
    highly specific radiologic feature of CHARGE syndrome, resulting in
    vestibular areflexia and balance problems. It is one of the major diagnostic
    criteria.
  phenotype_term:
    preferred_term: Semicircular canal hypoplasia
    term:
      id: HP:0011382
      label: Hypoplasia of the semicircular canal
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia.
    explanation: >-
      Directly documents semicircular canal hypoplasia as a consistent feature
      of CHARGE syndrome.
- name: Facial palsy
  category: Phenotypic
  description: >-
    Facial nerve (cranial nerve VII) palsy is a frequent cranial nerve anomaly in
    CHARGE syndrome and is more common in CHD7 mutation-positive individuals.
  phenotype_term:
    preferred_term: Facial nerve palsy
    term:
      id: HP:0010628
      label: Facial palsy
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals.
    explanation: >-
      Facial nerve paralysis is enriched in CHD7 mutation-positive CHARGE
      patients in a large cohort.
- name: Cranial nerve dysfunction
  category: Phenotypic
  description: >-
    Cranial nerve anomalies are part of the expanded CHARGE phenotype recognized
    after identification of the genetic cause, and include facial nerve palsy,
    olfactory dysfunction, and impaired swallowing from lower cranial nerve
    involvement.
  phenotype_term:
    preferred_term: Cranial nerve paralysis
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies
    explanation: >-
      GeneReviews lists cranial nerve anomalies among the expanded CHARGE
      phenotype.
- name: Cleft lip and/or palate
  category: Phenotypic
  description: >-
    Cleft lip and/or cleft palate are commonly associated orofacial anomalies in
    CHARGE syndrome.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula.
    explanation: >-
      Identifies cleft lip/palate as a commonly associated anomaly in CHARGE
      syndrome.
- name: Tracheoesophageal fistula
  category: Phenotypic
  description: >-
    Tracheoesophageal and esophageal anomalies, including tracheo-oesophageal
    fistula, occur in a subset of individuals with CHARGE syndrome.
  phenotype_term:
    preferred_term: Tracheoesophageal fistula
    term:
      id: HP:0002575
      label: Tracheoesophageal fistula
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula.
    explanation: >-
      Documents tracheo-oesophageal fistula as a commonly associated congenital
      anomaly in CHARGE syndrome.
- name: Hypogonadotropic hypogonadism
  category: Phenotypic
  description: >-
    Hypogonadotropic hypogonadism with genital hypoplasia is a feature of CHARGE
    syndrome, reflecting impaired development/migration of GnRH neurons from the
    olfactory placode and overlapping mechanistically with Kallmann syndrome.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)
    explanation: >-
      Genital hypoplasia (with underlying hypogonadotropic hypogonadism) is part
      of the core CHARGE phenotype described in GeneReviews.
- name: Hearing impairment
  category: Phenotypic
  description: >-
    Hearing loss in CHARGE syndrome may be conductive, sensorineural, or mixed,
    and ear anomalies (including deafness) are a cardinal feature.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ear anomalies (including deafness)
    explanation: >-
      Ear anomalies including deafness are a defining CHARGE feature per
      GeneReviews.
  - reference: PMID:36396635
    reference_title: "CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Results from transcriptome profiling of hair cells reveal disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss.
    explanation: >-
      Identifies disrupted deafness-gene expression in CHD7-deficient hair cells
      as a mechanism for sensorineural hearing loss in CHARGE syndrome.
- name: Growth and developmental delay
  category: Phenotypic
  description: >-
    Postnatal growth deficiency and developmental delay/intellectual disability
    ("retardation of growth and development") are core CHARGE features, with
    variable severity.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)
    explanation: >-
      Retarded growth and development is part of the core CHARGE acronym and
      phenotype.
- name: Seizures
  category: Phenotypic
  description: >-
    Seizures occur as part of the expanded CHARGE phenotype and may contribute to
    morbidity.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies
    explanation: >-
      GeneReviews lists seizures among the expanded CHARGE phenotype.
- name: Hypothyroidism
  category: Phenotypic
  description: >-
    Hypothyroidism is part of the expanded CHARGE phenotype recognized after
    identification of the molecular cause, and is clinically important for
    endocrine surveillance and management.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies
    explanation: >-
      GeneReviews lists hypothyroidism among the expanded CHARGE phenotype.
- name: Brain anomalies
  category: Phenotypic
  description: >-
    Structural brain anomalies are part of the expanded CHARGE phenotype
    recognized after identification of the molecular cause.
  phenotype_term:
    preferred_term: Brain anomalies
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies
    explanation: >-
      GeneReviews lists brain anomalies among the expanded CHARGE phenotype.
- name: Renal anomalies
  category: Phenotypic
  description: >-
    Renal (kidney) anomalies are part of the expanded CHARGE phenotype
    recognized after identification of the molecular cause.
  phenotype_term:
    preferred_term: Renal anomalies
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies
    explanation: >-
      GeneReviews lists renal anomalies among the expanded CHARGE phenotype.
genetic:
- name: CHD7
  gene_term:
    preferred_term: CHD7
    term:
      id: hgnc:20626
      label: CHD7
  association: causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:20301296
      reference_title: "CHD7 Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.
      explanation: >-
        GeneReviews establishes autosomal dominant inheritance of CHD7-related
        CHARGE syndrome.
  notes: >-
    Heterozygous pathogenic variants in CHD7 (chromodomain helicase DNA-binding
    protein 7) on chromosome 8q12.1 cause the majority of CHARGE syndrome. Most
    variants are unique loss-of-function (nonsense/frameshift) changes scattered
    throughout the gene, with no clear genotype-phenotype correlation. A minority
    of cases are caused by contiguous 8q12 microdeletions.
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation.
    explanation: >-
      Establishes CHD7 as the causative gene in most CHARGE cases with broad
      clinical variability and no genotype-phenotype correlation.
  - reference: PMID:15300250
    reference_title: "Mutations in a new member of the chromodomain gene family cause CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome.
    explanation: >-
      Documents 8q12 microdeletion as a less common mechanism of CHARGE
      syndrome involving CHD7.
diagnosis:
- name: Molecular genetic testing for CHD7
  description: >-
    The diagnosis of CHD7 disorder/CHARGE syndrome is established in a proband
    with suggestive clinical and imaging findings and a heterozygous pathogenic
    variant in (or deletion of) CHD7 identified by molecular genetic testing.
    Clinical diagnosis historically relied on the Blake and later Verloes
    major/minor criteria (e.g., coloboma, choanal atresia, characteristic ear
    anomalies, and semicircular canal hypoplasia as major features).
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic variant in or deletion of CHD7 identified by molecular genetic testing.
    explanation: >-
      GeneReviews describes the molecular diagnostic standard for CHARGE
      syndrome.
treatments:
- name: Multidisciplinary supportive management
  description: >-
    Management of CHARGE syndrome is complex and requires a multidisciplinary
    approach involving clinicians, therapists, and educators, with treatment
    directed at the individual's specific manifestations (cardiac surgery,
    choanal atresia repair, feeding/airway support, hearing and vision
    rehabilitation, endocrine management, and developmental/educational support).
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators.
    explanation: >-
      GeneReviews describes multidisciplinary supportive management as the
      mainstay of CHARGE care.
- name: Anesthesia precautions for airway complications
  description: >-
    Because of the increased risk of post-anesthesia airway complications,
    procedures requiring anesthesia should be minimized and combined whenever
    possible. This is a documented "agents/circumstances to avoid" safety
    consideration in CHARGE syndrome.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible.
    explanation: >-
      GeneReviews "Agents/circumstances to avoid" warning on anesthesia-related
      airway complications in CHARGE syndrome.
- name: Cardiac surgery
  description: >-
    Surgical correction of congenital heart defects is required in a large
    proportion of individuals with CHARGE syndrome, reflecting the high
    prevalence and complexity of cardiac malformations in the disorder.
  treatment_term:
    preferred_term: cardiac surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac surgery was performed in more than half of CS patients (150/242, 62%).
    explanation: >-
      Systematic review reporting that cardiac surgery was performed in the
      majority of CHARGE syndrome patients with congenital heart defects.
- name: Genetic counseling
  description: >-
    Genetic counseling is recommended for families given the autosomal dominant
    inheritance and the empiric sibling recurrence risk of approximately 1%-2%
    arising from documented germline mosaicism, with discussion of prenatal and
    preimplantation genetic testing options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.
    explanation: >-
      The autosomal dominant inheritance with de novo and germline-mosaic
      recurrence risk documented in GeneReviews is the basis for genetic
      counseling in CHARGE syndrome.
📚

References & Deep Research

References

1
PMID:20301296
CHD7 Disorder.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
CHARGE Syndrome — Comprehensive Disease Characteristics Report
Edison Scientific Literature 46 citations 2026-06-03T16:14:24.645092

CHARGE Syndrome — Comprehensive Disease Characteristics Report

Target disease: CHARGE syndrome (Mendelian developmental disorder)
Primary causal gene: CHD7 (autosomal dominant, typically de novo)

1. Disease Information

1.1 Overview (current understanding)

CHARGE syndrome is a clinically defined multiple congenital anomaly disorder originally described as a non-random cluster of malformations. The CHARGE acronym denotes Coloboma, Heart defects, Atresia of choanae, Retarded growth/development, Genital hypoplasia, and Ear anomalies/deafness. (bergman2011chd7mutationsand pages 1-6, mcj2006chargesyndromethe pages 1-2)

A key consistent feature emphasized in early molecular-era cohorts is semicircular canal hypoplasia leading to vestibular areflexia, which helps explain balance and motor delay phenotypes. (mcj2006chargesyndromethe pages 1-2)

1.2 Key identifiers and cross-references

  • OMIM: 214800 (CHARGE syndrome) (mcj2006chargesyndromethe pages 1-2, bergman2011chd7mutationsand pages 1-6)
  • Orphanet/Orpha code: ORPHA:138 (wolanska2025analysisofthe pages 7-10)
  • Synonyms / alternative names: “Hall–Hittner syndrome” (also referred to historically as CHARGE association) (wolanska2025analysisofthe pages 7-10)
  • MONDO / ICD / MeSH: Not found explicitly in the retrieved full-text set; therefore not reported here.

1.3 Evidence type note

Most knowledge summarized here derives from aggregated disease-level resources (systematic reviews, cohort/genotype-phenotype studies, mechanistic studies) rather than EHR-derived real-world datasets. Examples include systematic review evidence for CHD epidemiology and outcomes (polito2024chargesyndromeand pages 1-2, polito2024chargesyndromeand pages 2-3) and mutation-positive cohort summaries (bergman2011chd7mutationsand pages 6-11).

2. Etiology

2.1 Primary causes

Genetic cause (dominant): Pathogenic variants in CHD7 are the major cause of CHARGE syndrome. CHARGE is described as autosomal dominant with variable expressivity; most pathogenic CHD7 variants arise de novo, but parent-to-child transmission occurs. (bergman2011chd7mutationsand pages 1-6, bergman2011chd7mutationsand pages 6-11)

CHD7 was identified as a major gene on chromosome 8q12.1. (mcj2006chargesyndromethe pages 1-2)

2.2 Risk factors

Genetic risk factor: Having a pathogenic CHD7 variant (typically heterozygous loss-of-function) is the dominant risk factor. Clinical genetic counseling must account for de novo predominance plus rare transmission and mosaicism. (mcj2006chargesyndromethe pages 1-2, bergman2011chd7mutationsand pages 24-29)

Non-genetic risk factors: No established environmental/toxic/infectious risk factors were identified in the retrieved sources.

2.3 Protective factors

No validated genetic or environmental protective factors were identified in the retrieved sources.

2.4 Gene–gene / oligogenic interactions (emerging)

A 2024 report proposes digenic inheritance/modifier effects involving CHD7 plus SMCHD1 in a family with variable hypogonadotropic hypogonadism and CHARGE-overlapping features, suggesting oligogenic contributions to penetrance/expressivity in some CHD7-related presentations. (wang2024digenicchd7and pages 1-2, wang2024digenicchd7and pages 2-4)

3. Phenotypes

3.1 Core phenotype spectrum (with frequencies)

Phenotypic variability is high, but several features are highly prevalent in mutation-positive cohorts.

Mutation-positive cohort frequencies (Bergman et al., 2011; CHD7+ cohort, n≈280): * Semicircular canal anomaly: 110/117 (~94%) (bergman2011chd7mutationsand pages 6-11) * Coloboma: 189/234 (~81%) (bergman2011chd7mutationsand pages 6-11) * Choanal atresia: 99/179 (~55%) (bergman2011chd7mutationsand pages 6-11) * Congenital heart defect: 191/252 (~76%) (bergman2011chd7mutationsand pages 6-11) * Feeding difficulties: 90/110, and tube feeding was frequently required (“necessitating tube feeding 82% (32–93%)”) (bergman2011chd7mutationsand pages 6-11) * Cranial nerve dysfunction: 173/174 (~99%) (bergman2011chd7mutationsand pages 6-11)

Broad phenotype frequency summary (Wieland et al., 2020; tabulated summary): * Developmental delay: 100% * Semicircular canal anomaly: 95% * External ear anomaly: 95% * Cranial nerve dysfunction: 95% * Coloboma: 80% * Congenital heart defect: 80% * Feeding difficulties: 80% * Choanal atresia: 50% * Tracheoesophageal anomaly: 25% (among other features) (wieland2020chargesyndrome pages 1-3)

Quality-of-life-related phenotype study (Wolańska, 2024/2025 thesis; 29 genetically confirmed): * Coloboma 100%, heart defects 82.8%, choanal atresia 35%, genital abnormalities 58.6%, hearing loss 86.2%; 76% had height below 3rd percentile. Family QoL measured by PedsQL Family Impact was described as intermediate/average, with higher QoL among parents who accept the child’s illness. (wolanska2025analysisofthe pages 76-79)

3.2 Phenotype characteristics

Age of onset: Predominantly congenital/neonatal with multi-organ malformations; neurodevelopmental features emerge in infancy/childhood. (mcj2006chargesyndromethe pages 1-2, wieland2020chargesyndrome pages 1-3)

Progression: Some domains may be progressive (e.g., mixed hearing loss reported as potentially progressive in clinical management guidance). (wieland2020chargesyndrome pages 10-11)

3.3 Suggested HPO terms (non-exhaustive, for KB mapping)

Below are commonly used HPO concepts aligned to the phenotypes reported in the cited sources: * Coloboma — HP:0000589 * Choanal atresia — HP:0000453 * Congenital heart defect — HP:0001627 * Abnormal semicircular canals / semicircular canal hypoplasia — HP:0008558 (or related vestibular/inner ear structure terms) * Sensorineural hearing impairment — HP:0000407 * Feeding difficulties — HP:0011968 * Facial palsy — HP:0007209 * Cleft lip/palate — HP:0000202 / HP:0000175 * Hypogonadotropic hypogonadism — HP:0000044 * Developmental delay — HP:0001263

(Exact HPO IDs may vary by knowledge base conventions; the above are intended as practical starting points for curation.)

4. Genetic / Molecular Information

4.1 Causal gene(s)

  • CHD7 (chromodomain helicase DNA-binding protein 7) is the primary causal gene, encoding an ATP-dependent chromatin remodeler. (mcj2006chargesyndromethe pages 1-2, driesen2024chd7disorder—notcharge pages 1-2)

4.2 Pathogenic variant spectrum (human)

In a large clinical genetics review, CHD7 variant classes in clinically diagnosed CHARGE include a predominance of truncating variants (nonsense/frameshift), with additional splice-site and missense variants; haploinsufficiency is emphasized as the key mechanism. (bergman2011chd7mutationsand pages 6-11)

A 2023 case report illustrates challenges in interpreting non-canonical intronic variants and provides a workflow for functional classification. In two unrelated patients, an intronic CHD7 variant c.5607+17A>G was shown to induce aberrant splicing using minigene assays and patient cDNA validation, upgrading a VUS toward pathogenic. (rossi2023casereportfunctional pages 1-2, rossi2023casereportfunctional pages 2-4)

4.3 Inheritance, penetrance, expressivity, mosaicism

CHARGE is autosomal dominant with variable expressivity; most CHD7 mutations occur de novo, but inherited cases occur. (bergman2011chd7mutationsand pages 1-6, bergman2011chd7mutationsand pages 6-11)

Somatic mosaicism has been reported (e.g., in an unaffected mother in a sib pair), supporting germline mosaicism as a recurrence mechanism. (mcj2006chargesyndromethe pages 1-2)

Genetic counseling guidance: recurrence risk from parental mosaicism is estimated at ~2–3%, and transmission risk from an affected individual is 50%; prenatal molecular testing/ultrasound and preimplantation genetic diagnosis are recommended for discussion. (bergman2011chd7mutationsand pages 24-29)

4.4 Modifier genes / oligogenicity

Mouse model work proposes that foliation-related genes (e.g., Engrailed, FGF pathway genes, Zic genes) may modify neurodevelopmental phenotypes in CHARGE. (whittaker2017distinctcerebellarfoliation pages 9-10)

Human family report: co-inheritance of pathogenic CHD7 truncation and a SMCHD1 missense variant is proposed to contribute to intrafamilial variability (not definitive proof of causality but a notable 2024 development). (wang2024digenicchd7and pages 1-2, wang2024digenicchd7and pages 2-4)

4.5 Epigenetics / episignatures (emerging)

CHARGE is considered a “chromatinopathy” (chromatin remodeling disorder) conceptually, and clinical trials are now including DNA methylation episignature characterization for prenatal-onset disorders including CHD7-associated conditions. (NCT06475651 chunk 2)

5. Environmental Information

No consistent environmental, lifestyle, or infectious causal factors were identified in the retrieved evidence set. The condition is primarily genetic/developmental. (bergman2011chd7mutationsand pages 1-6, mcj2006chargesyndromethe pages 1-2)

6. Mechanism / Pathophysiology

6.1 CHD7 function and upstream mechanism

CHD7 encodes an ATP-dependent nucleosome remodeling factor involved in tissue-specific gene regulation during development. (driesen2024chd7disorder—notcharge pages 1-2)

A core mechanistic model is that CHD7 regulates enhancer activity and cell-type-specific transcriptional programs.

6.2 Neural crest dysfunction (neurocristopathy framework)

A human iPSC model supports the long-standing hypothesis that CHARGE is a neurocristopathy: * “CHARGE syndrome modeling using patient-iPSCs reveals defective migration of neural crest cells harboring CHD7 mutations” with altered expression of migration-related genes and impaired delamination/migration/motility. (okuno2017chargesyndromemodeling pages 1-2, okuno2017chargesyndromemodeling pages 5-6)

Enhancer regulation in human neural crest cells: CHD7 binding is enriched at active enhancers, with TFAP2A motifs in hNCC-specific CHD7 peaks and enrichment near neural crest regulators (e.g., SOX9, MSX1/2). (sanosaka2022chromatinremodelerchd7 pages 2-3, sanosaka2022chromatinremodelerchd7 pages 1-2)

Causal chain (conceptual): CHD7 haploinsufficiency → altered enhancer accessibility / target-gene expression in neural crest lineages → impaired NCC migration/adhesion programs → malformations of NCC-derived/populated structures (craniofacial, heart outflow tract, ear, eye). (okuno2017chargesyndromemodeling pages 1-2, sanosaka2022chromatinremodelerchd7 pages 2-3)

6.3 Inner ear / hair cell differentiation mechanisms

Human inner ear organoids show that CHD7 is required for otic lineage specification and sensory epithelium formation: * Loss of CHD7 (or its chromatin remodeling activity) leads to “complete absence of hair cells and supporting cells,” and transcriptome profiling suggests “disruption of deafness gene expression” as a mechanism for CHARGE-associated sensorineural hearing loss. (nie2022chd7regulatesotic pages 1-2)

6.4 p53 pathway contribution (mouse genetics)

A high-impact mouse genetics study provides evidence that inappropriate p53 activation contributes to CHARGE-like phenotypes: * CHD7 binds the p53 promoter and negatively regulates p53; CHD7 loss activates p53 in mouse neural crest cells and patient samples, and p53 reduction partially rescues Chd7-null phenotypes. (nostrand2014inappropriatep53activation pages 1-2)

6.5 Cerebellar developmental defects and modifier pathways

In Chd7 haploinsufficient mice, cerebellar hypoplasia and foliation anomalies show incomplete penetrance (e.g., 67% overall penetrance for specific foliation phenotypes in combined analyses) and may be modified by developmental patterning genes (Engrailed/FGF/Zic pathways). (whittaker2017distinctcerebellarfoliation pages 3-6, whittaker2017distinctcerebellarfoliation pages 9-10)

6.6 Multi-omics (zebrafish; emerging target discovery)

A zebrafish CHARGE model used transcriptomics + proteomics integration to identify dysregulated pathways and candidate downstream mediators; CRISPR knockdown of candidate genes (capgb, nefla, rdh5) phenocopied behavioral defects seen in chd7 mutants, supporting a pipeline for therapeutic target nomination. (hancock2026multiomicanalysesidentify pages 1-3, hancock2026multiomicanalysesidentify pages 11-13)

6.7 Suggested ontology terms for mechanisms

GO Biological Process (examples): * Chromatin remodeling — GO:0006338 * Regulation of transcription, DNA-templated — GO:0006355 * Neural crest cell migration — GO:0001755 * Inner ear development — GO:0048839 * Sensory perception of sound — GO:0007605

Cell Ontology (CL) (examples): * Neural crest cell — CL:0000135 * Otic progenitor / hair cell / supporting cell (use lineage-appropriate CL terms)

GO Cellular Component (examples): * Nucleus — GO:0005634 * Chromatin — GO:0000785

7. Anatomical Structures Affected

7.1 Organ and system level (primary)

  • Eye (coloboma) (bergman2011chd7mutationsand pages 6-11, wieland2020chargesyndrome pages 1-3)
  • Heart / great vessels (multiple CHDs) (polito2024chargesyndromeand pages 1-2, bergman2011chd7mutationsand pages 6-11)
  • Nasal choanae / upper airway (choanal atresia/stenosis) (bergman2011chd7mutationsand pages 6-11, wieland2020chargesyndrome pages 1-3)
  • Ear (external/middle/inner ear), vestibular apparatus, cochleovestibular nerve (bergman2011chd7mutationsand pages 6-11, wieland2020chargesyndrome pages 10-11)
  • CNS including cerebellum (neurodevelopmental delay; cerebellar anomalies in models) (whittaker2017distinctcerebellarfoliation pages 1-2, wolanska2025analysisofthe pages 76-79)
  • Cranial nerves (feeding/swallowing, facial palsy) (bergman2011chd7mutationsand pages 6-11, webb2021aframeworkfor pages 8-10)
  • Endocrine/reproductive axis (hypogonadotropic hypogonadism; genital hypoplasia) (driesen2024chd7disorder—notcharge pages 8-9, wang2024digenicchd7and pages 2-4)
  • Esophagus/trachea (tracheoesophageal anomalies; feeding/aspiration risk) (wieland2020chargesyndrome pages 1-3, polito2024chargesyndromeand pages 7-8)

7.2 Suggested UBERON terms (examples)

  • Eye — UBERON:0000970
  • Heart — UBERON:0000948
  • Choana — UBERON:0000467
  • Inner ear — UBERON:0001768
  • Semicircular canal — UBERON:0001786
  • Cerebellum — UBERON:0002037
  • Cranial nerve — UBERON:0001021
  • Pituitary gland / hypothalamus — UBERON:0000007 / UBERON:0001898

8. Temporal Development

  • Typical onset: congenital/neonatal (multi-organ malformations) (mcj2006chargesyndromethe pages 1-2, wieland2020chargesyndrome pages 1-3)
  • Course: lifelong, with major early-life morbidity driven by airway/feeding and cardiac anomalies; neurodevelopmental and sensory impairments require long-term supports. (meisner2020congenitalheartdefects pages 5-6, wieland2020chargesyndrome pages 10-11)

9. Inheritance and Population

9.1 Epidemiology

Incidence/prevalence estimates vary by study and ascertainment. * Estimated birth prevalence in early cohort reports: 1/10,000 to 1/15,000; a regional estimate reported 1/8,500 in Atlantic Canada. (mcj2006chargesyndromethe pages 1-2) * A 2024 clinical review estimated CHARGE incidence 1/15,000–1/17,000 live births, and separately estimated CHD7-mutation birth incidence 1/18,400. (driesen2024chd7disorder—notcharge pages 1-2) * A 2024 systematic review states incidence 1–3 per 10,000 births. (polito2024chargesyndromeand pages 1-2)

9.2 Inheritance and counseling-relevant points

  • Autosomal dominant, variable expressivity; mostly de novo variants. (bergman2011chd7mutationsand pages 1-6, bergman2011chd7mutationsand pages 6-11)
  • Mosaicism can occur; recurrence risk and prenatal testing options should be discussed. (mcj2006chargesyndromethe pages 1-2, bergman2011chd7mutationsand pages 24-29)

10. Diagnostics

10.1 Clinical criteria

Two widely used clinical criteria frameworks are Blake (1998) and Verloes (2005). A key Verloes contribution was emphasizing semicircular canal defects as a major criterion. (bergman2011chd7mutationsand pages 1-6, bergman2011chd7mutationsand pages 6-11)

Verloes (2005) criteria (image evidence): Major criteria include coloboma, choanal atresia, and hypoplastic semicircular canals, with typical/partial/atypical categories defined by combinations of major/minor criteria. (driesen2024chd7disorder—notcharge media 9654fd32)

Text-form criteria are also reproduced in primary literature. (mcj2006chargesyndromethe pages 1-2, driesen2024chd7disorder—notcharge pages 8-9)

10.2 Genetic testing strategy

CHD7 testing is recommended broadly (not only those meeting strict criteria), because clinical criteria can miss mutation-positive individuals. (bergman2011chd7mutationsand pages 15-19)

Bergman et al. provide a pragmatic threshold for CHD7 testing (“3 cardinal or 2 cardinal + 1 supportive”) and emphasize semicircular canal imaging and cranial nerve evaluation in the diagnostic workup. (bergman2011chd7mutationsand pages 44-44)

10.3 Imaging and functional tests

  • Temporal bone CT/MRI to detect semicircular canal abnormalities and nerve anatomy. (bergman2011chd7mutationsand pages 44-44, wieland2020chargesyndrome pages 10-11)
  • Cardiac evaluation: standardized transthoracic echocardiography (TTE) first-line; CTA/cardiac MRI for complex extracardiac anatomy. (polito2024chargesyndromeand pages 7-8)

10.4 Differential diagnosis (examples)

Differential diagnoses in overlapping phenotypes include Kabuki syndrome and other craniofacial/multiple anomaly syndromes; genetic testing is emphasized as decisive when phenotypes overlap. (ouassifi2025chargesyndromein pages 1-4)

10.5 Emerging molecular diagnostics

Functional testing for splicing VUS: Minigene assays plus patient RNA/cDNA validation can resolve intronic CHD7 splicing variants that are otherwise difficult to classify by in silico prediction alone. (rossi2023casereportfunctional pages 2-4, rossi2023casereportfunctional pages 5-6)

Episignatures: DNA methylation episignature studies are being operationalized in observational protocols involving CHD7. (NCT06475651 chunk 2)

11. Outcomes / Prognosis

11.1 Cardiac burden and mortality (recent quantitative evidence)

A 2024 systematic review (68 studies; n=943 reported CHARGE patients) found a 76.6% prevalence of congenital heart defects, with common lesions including PDA (26%), VSD (21%), ASD (18%), TOF (11%), and aortic abnormalities (24%). Cardiac surgery was performed in 62% of reported patients (150/242), and in-hospital mortality in the literature was ~9.5% in case series (and ~12% in case reports). (polito2024chargesyndromeand pages 1-2, polito2024chargesyndromeand pages 2-3)

Aspiration related to feeding problems was a major non-cardiovascular cause of death (“aspiration of secretions due to feeding problems was the most common cause of non-CV death in about 50%”). (polito2024chargesyndromeand pages 7-8)

11.2 Neurodevelopment and QoL

Cognitive outcomes are variable and can be confounded by dual sensory impairment. Prognostic indicators for worse cognitive outcomes include extensive colobomas and brain malformations, but improvement over time is possible with support. (wieland2020chargesyndrome pages 7-8)

Family QoL (29 genetically confirmed children) was described as intermediate/average with parental acceptance associated with higher QoL scores. (wolanska2025analysisofthe pages 76-79)

12. Treatment

There is no disease-modifying therapy for CHARGE; management is multidisciplinary and targeted to organ system complications.

12.1 Multidisciplinary care (real-world implementation)

CHARGE care is repeatedly emphasized as best delivered through specialized multidisciplinary teams, including genetics, ENT/audiology, ophthalmology, cardiology, endocrinology, speech/OT/PT, and others. (wieland2020chargesyndrome pages 6-7, bergman2011chd7mutationsand pages 19-21)

12.2 Cardiac treatment

Corrective cardiac surgery is frequently required; risk is amplified by noncardiac issues (airway/feeding/aspiration), and perioperative management should prioritize aspiration prevention. (meisner2020congenitalheartdefects pages 5-6, polito2024chargesyndromeand pages 7-8)

12.3 Airway and feeding support

Feeding difficulties are common and can require nasogastric feeding and/or gastrostomy; reflux management and dysphagia clinic referral are recommended. (wieland2020chargesyndrome pages 6-7)

Choanal atresia requires acute airway management and surgical repair; endoscopic transnasal approaches and stenting are commonly used, with higher reoperation rates reported in CHARGE. (wieland2020chargesyndrome pages 8-10)

12.4 Hearing interventions

Audiologic evaluation at diagnosis (including ABR and imaging) and ongoing follow-up is recommended. Cochlear implantation can improve outcomes but requires careful assessment due to temporal bone and nerve anomalies; ABI may be considered when cochlear nerve aplasia limits benefit. (wieland2020chargesyndrome pages 10-11)

12.5 Vision and developmental therapies

Early ophthalmology assessment and management (amblyopia screening, low-vision aids, strabismus treatment) plus early developmental therapies (speech/language, OT/PT) are emphasized to maximize function. (wieland2020chargesyndrome pages 7-8, wieland2020chargesyndrome pages 6-7)

12.6 MAXO suggestions (examples for KB annotation)

  • Cardiac surgical repair — MAXO term for congenital heart defect surgery
  • Choanal atresia repair — MAXO term for nasal/airway reconstructive surgery
  • Gastrostomy tube placement — MAXO term for enteral feeding support
  • Fundoplication — MAXO term for anti-reflux surgery
  • Cochlear implantation — MAXO term for cochlear implant procedure
  • Hearing aid fitting — MAXO term for amplification device use
  • Speech therapy / occupational therapy / physical therapy — MAXO therapy terms

13. Prevention

Primary prevention is generally not applicable because CHARGE is primarily genetic and typically de novo. Prevention focuses on: * Genetic counseling (recurrence risk with mosaicism; options for prenatal diagnosis/PGD). (bergman2011chd7mutationsand pages 24-29) * Secondary/tertiary prevention: early detection and management of airway/feeding/cardiac issues to reduce morbidity and early mortality, especially aspiration prevention. (meisner2020congenitalheartdefects pages 5-6, polito2024chargesyndromeand pages 7-8)

14. Other Species / Natural Disease

No naturally occurring veterinary CHARGE syndrome cases were identified in the retrieved sources. The comparative biology evidence base in this report therefore relies on experimental models.

15. Model Organisms and Experimental Models

15.1 Mouse models

  • p53 activation model: p53 hyperactivation induces CHARGE-like developmental defects; CHD7 negatively regulates p53, and p53 reduction partially rescues phenotypes in Chd7-null mice. (nostrand2014inappropriatep53activation pages 1-2)
  • Cerebellar foliation model: Chd7 haploinsufficient mice exhibit mild cerebellar hypoplasia and foliation anomalies with incomplete penetrance (e.g., ~67% for specific patterns) and suggest modifier genes/pathways (Engrailed/FGF/Zic). (whittaker2017distinctcerebellarfoliation pages 3-6, whittaker2017distinctcerebellarfoliation pages 9-10)

15.2 Zebrafish models

Multi-omics datasets from larval zebrafish head tissue in a CHARGE model were integrated to identify candidate downstream effectors; functional CRISPR knockdown of candidate genes phenocopied behavioral defects. (hancock2026multiomicanalysesidentify pages 1-3, hancock2026multiomicanalysesidentify pages 11-13)

15.3 Human iPSC / organoid models

  • Patient iPSC-derived neural crest cells demonstrate defective migration. (okuno2017chargesyndromemodeling pages 1-2)
  • Human inner ear organoids show CHD7 dependence of hair cell/supporting cell differentiation and disruption of deafness gene expression in mutants. (nie2022chd7regulatesotic pages 1-2)

2023–2024 Highlights (recent developments prioritized)

  1. “CHD7 disorder” spectrum framing (2024): Adoption of the term “CHD7 disorder” to capture presentations that do not meet classic CHARGE criteria, including isolated cochleovestibular dysfunction; emphasizes CHD7 testing in nonsyndromic hearing loss with inner ear malformations. (driesen2024chd7disorder—notcharge pages 1-2, driesen2024chd7disorder—notcharge pages 8-9)
  2. Systematic review of congenital heart disease in CHARGE (2024): Quantifies CHD lesion spectrum, surgery rates, and in-hospital mortality; highlights aspiration from feeding problems as a major cause of death. (polito2024chargesyndromeand pages 1-2, polito2024chargesyndromeand pages 7-8)
  3. Digenic/oligogenic inheritance hypothesis (2024): CHD7+SMCHD1 co-inheritance proposed to underlie intrafamilial variability (hypogonadotropic hypogonadism / CHARGE-overlap). (wang2024digenicchd7and pages 1-2)
  4. Functional resolution of intronic splicing VUS (2023): Minigene + patient cDNA assays demonstrate a CHD7 intronic variant causes aberrant splicing, illustrating a path to improve molecular diagnostic yield. (rossi2023casereportfunctional pages 2-4, rossi2023casereportfunctional pages 1-2)

Key URLs (from retrieved sources)

  • Driesen et al., Genes (Published 2024-05-19): https://doi.org/10.3390/genes15050643 (driesen2024chd7disorder—notcharge pages 1-2)
  • Polito et al., Monaldi Archives for Chest Disease (Published 2024-09): https://doi.org/10.4081/monaldi.2023.2661 (polito2024chargesyndromeand pages 1-2)
  • Wang et al., Heliyon (Published 2024-01): https://doi.org/10.1016/j.heliyon.2023.e23272 (wang2024digenicchd7and pages 1-2)
  • Rossi et al., Frontiers in Genetics (Published 2023-02): https://doi.org/10.3389/fgene.2023.1082100 (rossi2023casereportfunctional pages 1-2)
  • Nie et al., Nature Communications (Published 2022-11): https://doi.org/10.1038/s41467-022-34759-8 (nie2022chd7regulatesotic pages 1-2)
  • Okuno et al., eLife (Published 2017-11): https://doi.org/10.7554/eLife.21114 (okuno2017chargesyndromemodeling pages 1-2)

Limitations of this tool-based synthesis

  • ICD-10/ICD-11, MeSH, and MONDO identifiers were not explicitly present in the retrieved full-text set; therefore they are not asserted here.
  • Some epidemiologic values are ascertainment-sensitive (clinical criteria vs molecular confirmation; regional differences) and thus reported as ranges with source-specific values.

References

  1. (bergman2011chd7mutationsand pages 1-6): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  2. (mcj2006chargesyndromethe pages 1-2): Jongmans Mcj, RJ Admiraal, KP vanderDonk, Vissers Lelm, AF Baas, L. Kapusta, JM vanHagen, D. Donnai, TJ deRavel, J. Veltman, A. GeurtsvanKessel, De Vries, Bba, H. Brunner, L. Hoefsloot, and van Ravenswaaij Cma. Charge syndrome: the phenotypic spectrum of mutations in the chd7 gene. Journal of Medical Genetics, 43:306-314, Sep 2006. URL: https://doi.org/10.1136/jmg.2005.036061, doi:10.1136/jmg.2005.036061. This article has 531 citations and is from a domain leading peer-reviewed journal.

  3. (wolanska2025analysisofthe pages 7-10): E Wolańska. Analysis of the genotype and phenotype of children with charge syndrome and assessment of their families' quality of life. Unknown journal, 2025.

  4. (polito2024chargesyndromeand pages 1-2): Maria Vincenza Polito, Mario Ferraioli, Alessandra Nocilla, Guido Coppola, Federica D'Auria, Antonio Marzano, Luca Barnabei, Marisa Malinconico, Eduardo Bossone, and Francesco Ferrara. Charge syndrome and congenital heart diseases: systematic review of literature. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, Sep 2024. URL: https://doi.org/10.4081/monaldi.2023.2661, doi:10.4081/monaldi.2023.2661. This article has 10 citations.

  5. (polito2024chargesyndromeand pages 2-3): Maria Vincenza Polito, Mario Ferraioli, Alessandra Nocilla, Guido Coppola, Federica D'Auria, Antonio Marzano, Luca Barnabei, Marisa Malinconico, Eduardo Bossone, and Francesco Ferrara. Charge syndrome and congenital heart diseases: systematic review of literature. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, Sep 2024. URL: https://doi.org/10.4081/monaldi.2023.2661, doi:10.4081/monaldi.2023.2661. This article has 10 citations.

  6. (bergman2011chd7mutationsand pages 6-11): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  7. (bergman2011chd7mutationsand pages 24-29): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  8. (wang2024digenicchd7and pages 1-2): Tian Wang, Wu Ren, Fangfang Fu, Hairong Wang, Yan Li, and Jie Duan. Digenic chd7 and smchd1 inheritance unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism. Heliyon, 10:e23272, Jan 2024. URL: https://doi.org/10.1016/j.heliyon.2023.e23272, doi:10.1016/j.heliyon.2023.e23272. This article has 4 citations.

  9. (wang2024digenicchd7and pages 2-4): Tian Wang, Wu Ren, Fangfang Fu, Hairong Wang, Yan Li, and Jie Duan. Digenic chd7 and smchd1 inheritance unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism. Heliyon, 10:e23272, Jan 2024. URL: https://doi.org/10.1016/j.heliyon.2023.e23272, doi:10.1016/j.heliyon.2023.e23272. This article has 4 citations.

  10. (wieland2020chargesyndrome pages 1-3): J Wieland, D Wieland, T Estiphan, and B Weakley. Charge syndrome. Encyclopedia of Autism Spectrum Disorders, Feb 2020. URL: https://doi.org/10.1007/978-1-4614-6430-3_38-2, doi:10.1007/978-1-4614-6430-3_38-2. This article has 140 citations.

  11. (wolanska2025analysisofthe pages 76-79): E Wolańska. Analysis of the genotype and phenotype of children with charge syndrome and assessment of their families' quality of life. Unknown journal, 2025.

  12. (wieland2020chargesyndrome pages 10-11): J Wieland, D Wieland, T Estiphan, and B Weakley. Charge syndrome. Encyclopedia of Autism Spectrum Disorders, Feb 2020. URL: https://doi.org/10.1007/978-1-4614-6430-3_38-2, doi:10.1007/978-1-4614-6430-3_38-2. This article has 140 citations.

  13. (driesen2024chd7disorder—notcharge pages 1-2): Jef Driesen, Helen Van Hoecke, Leen Maes, Sandra Janssens, Frederic Acke, and Els De Leenheer. Chd7 disorder—not charge syndrome—presenting as isolated cochleovestibular dysfunction. Genes, 15:643, May 2024. URL: https://doi.org/10.3390/genes15050643, doi:10.3390/genes15050643. This article has 3 citations.

  14. (rossi2023casereportfunctional pages 1-2): Cesare Rossi, Sherin Ramadan, Cecilia Evangelisti, Simona Ferrari, Maria Accadia, Reha M. Toydemir, and Emanuele Panza. Case report: functional characterization of a novel chd7 intronic variant in patients with charge syndrome. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1082100, doi:10.3389/fgene.2023.1082100. This article has 5 citations and is from a peer-reviewed journal.

  15. (rossi2023casereportfunctional pages 2-4): Cesare Rossi, Sherin Ramadan, Cecilia Evangelisti, Simona Ferrari, Maria Accadia, Reha M. Toydemir, and Emanuele Panza. Case report: functional characterization of a novel chd7 intronic variant in patients with charge syndrome. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1082100, doi:10.3389/fgene.2023.1082100. This article has 5 citations and is from a peer-reviewed journal.

  16. (whittaker2017distinctcerebellarfoliation pages 9-10): Danielle E. Whittaker, Sahrunizam Kasah, Alex P. A. Donovan, Jacob Ellegood, Kimberley L. H. Riegman, Holger A. Volk, Imelda McGonnell, Jason P. Lerch, and M. Albert Basson. Distinct cerebellar foliation anomalies in a chd7 haploinsufficient mouse model of charge syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 175:n/a-n/a, Nov 2017. URL: https://doi.org/10.1002/ajmg.c.31595, doi:10.1002/ajmg.c.31595. This article has 34 citations.

  17. (NCT06475651 chunk 2): Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset. Assistance Publique - Hôpitaux de Paris. 2026. ClinicalTrials.gov Identifier: NCT06475651

  18. (okuno2017chargesyndromemodeling pages 1-2): Hironobu Okuno, Francois Renault Mihara, Shigeki Ohta, Kimiko Fukuda, Kenji Kurosawa, Wado Akamatsu, Tsukasa Sanosaka, Jun Kohyama, Kanehiro Hayashi, Kazunori Nakajima, Takao Takahashi, Joanna Wysocka, Kenjiro Kosaki, and Hideyuki Okano. Charge syndrome modeling using patient-ipscs reveals defective migration of neural crest cells harboring chd7 mutations. eLife, Nov 2017. URL: https://doi.org/10.7554/elife.21114, doi:10.7554/elife.21114. This article has 74 citations and is from a domain leading peer-reviewed journal.

  19. (okuno2017chargesyndromemodeling pages 5-6): Hironobu Okuno, Francois Renault Mihara, Shigeki Ohta, Kimiko Fukuda, Kenji Kurosawa, Wado Akamatsu, Tsukasa Sanosaka, Jun Kohyama, Kanehiro Hayashi, Kazunori Nakajima, Takao Takahashi, Joanna Wysocka, Kenjiro Kosaki, and Hideyuki Okano. Charge syndrome modeling using patient-ipscs reveals defective migration of neural crest cells harboring chd7 mutations. eLife, Nov 2017. URL: https://doi.org/10.7554/elife.21114, doi:10.7554/elife.21114. This article has 74 citations and is from a domain leading peer-reviewed journal.

  20. (sanosaka2022chromatinremodelerchd7 pages 2-3): Tsukasa Sanosaka, Hironobu Okuno, Noriko Mizota, Tomoko Andoh-Noda, Miki Sato, Ryo Tomooka, Satoe Banno, Jun Kohyama, and Hideyuki Okano. Chromatin remodeler chd7 targets active enhancer region to regulate cell type-specific gene expression in human neural crest cells. Scientific Reports, Dec 2022. URL: https://doi.org/10.1038/s41598-022-27293-6, doi:10.1038/s41598-022-27293-6. This article has 16 citations and is from a peer-reviewed journal.

  21. (sanosaka2022chromatinremodelerchd7 pages 1-2): Tsukasa Sanosaka, Hironobu Okuno, Noriko Mizota, Tomoko Andoh-Noda, Miki Sato, Ryo Tomooka, Satoe Banno, Jun Kohyama, and Hideyuki Okano. Chromatin remodeler chd7 targets active enhancer region to regulate cell type-specific gene expression in human neural crest cells. Scientific Reports, Dec 2022. URL: https://doi.org/10.1038/s41598-022-27293-6, doi:10.1038/s41598-022-27293-6. This article has 16 citations and is from a peer-reviewed journal.

  22. (nie2022chd7regulatesotic pages 1-2): Jing Nie, Yoshitomo Ueda, Alexander J. Solivais, and Eri Hashino. Chd7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids. Nature Communications, Nov 2022. URL: https://doi.org/10.1038/s41467-022-34759-8, doi:10.1038/s41467-022-34759-8. This article has 43 citations and is from a highest quality peer-reviewed journal.

  23. (nostrand2014inappropriatep53activation pages 1-2): Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung, Daniel R. Fuentes, Margaret M. Kozak, Thomas M. Johnson, Chieh-Yu Lin, Chien-Jung Lin, Donald L. Swiderski, Hannes Vogel, Jonathan A. Bernstein, Tania Attié-Bitach, Ching-Pin Chang, Joanna Wysocka, Donna M. Martin, and Laura D. Attardi. Inappropriate p53 activation during development induces features of charge syndrome. Aug 2014. URL: https://doi.org/10.1038/nature13585, doi:10.1038/nature13585. This article has 171 citations and is from a highest quality peer-reviewed journal.

  24. (whittaker2017distinctcerebellarfoliation pages 3-6): Danielle E. Whittaker, Sahrunizam Kasah, Alex P. A. Donovan, Jacob Ellegood, Kimberley L. H. Riegman, Holger A. Volk, Imelda McGonnell, Jason P. Lerch, and M. Albert Basson. Distinct cerebellar foliation anomalies in a chd7 haploinsufficient mouse model of charge syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 175:n/a-n/a, Nov 2017. URL: https://doi.org/10.1002/ajmg.c.31595, doi:10.1002/ajmg.c.31595. This article has 34 citations.

  25. (hancock2026multiomicanalysesidentify pages 1-3): Melody B. Hancock, Dana R. Ruby, Rachael A. Bieler, D. Chris Cole, and Kurt C. Marsden. Multi-omic analyses identify molecular targets of chd7 that contribute to charge syndrome model phenotypes. Disease Models & Mechanisms, Mar 2026. URL: https://doi.org/10.1242/dmm.052592, doi:10.1242/dmm.052592. This article has 1 citations and is from a domain leading peer-reviewed journal.

  26. (hancock2026multiomicanalysesidentify pages 11-13): Melody B. Hancock, Dana R. Ruby, Rachael A. Bieler, D. Chris Cole, and Kurt C. Marsden. Multi-omic analyses identify molecular targets of chd7 that contribute to charge syndrome model phenotypes. Disease Models & Mechanisms, Mar 2026. URL: https://doi.org/10.1242/dmm.052592, doi:10.1242/dmm.052592. This article has 1 citations and is from a domain leading peer-reviewed journal.

  27. (whittaker2017distinctcerebellarfoliation pages 1-2): Danielle E. Whittaker, Sahrunizam Kasah, Alex P. A. Donovan, Jacob Ellegood, Kimberley L. H. Riegman, Holger A. Volk, Imelda McGonnell, Jason P. Lerch, and M. Albert Basson. Distinct cerebellar foliation anomalies in a chd7 haploinsufficient mouse model of charge syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 175:n/a-n/a, Nov 2017. URL: https://doi.org/10.1002/ajmg.c.31595, doi:10.1002/ajmg.c.31595. This article has 34 citations.

  28. (webb2021aframeworkfor pages 8-10): Bryn D. Webb, Irini Manoli, Elizabeth C. Engle, and Ethylin W. Jabs. A framework for the evaluation of patients with congenital facial weakness. Orphanet Journal of Rare Diseases, Apr 2021. URL: https://doi.org/10.1186/s13023-021-01736-1, doi:10.1186/s13023-021-01736-1. This article has 14 citations and is from a peer-reviewed journal.

  29. (driesen2024chd7disorder—notcharge pages 8-9): Jef Driesen, Helen Van Hoecke, Leen Maes, Sandra Janssens, Frederic Acke, and Els De Leenheer. Chd7 disorder—not charge syndrome—presenting as isolated cochleovestibular dysfunction. Genes, 15:643, May 2024. URL: https://doi.org/10.3390/genes15050643, doi:10.3390/genes15050643. This article has 3 citations.

  30. (polito2024chargesyndromeand pages 7-8): Maria Vincenza Polito, Mario Ferraioli, Alessandra Nocilla, Guido Coppola, Federica D'Auria, Antonio Marzano, Luca Barnabei, Marisa Malinconico, Eduardo Bossone, and Francesco Ferrara. Charge syndrome and congenital heart diseases: systematic review of literature. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, Sep 2024. URL: https://doi.org/10.4081/monaldi.2023.2661, doi:10.4081/monaldi.2023.2661. This article has 10 citations.

  31. (meisner2020congenitalheartdefects pages 5-6): Joshua K. Meisner and Donna M. Martin. Congenital heart defects in charge: the molecular role of chd7 and effects on cardiac phenotype and clinical outcomes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 184:81-89, Dec 2020. URL: https://doi.org/10.1002/ajmg.c.31761, doi:10.1002/ajmg.c.31761. This article has 47 citations.

  32. (driesen2024chd7disorder—notcharge media 9654fd32): Jef Driesen, Helen Van Hoecke, Leen Maes, Sandra Janssens, Frederic Acke, and Els De Leenheer. Chd7 disorder—not charge syndrome—presenting as isolated cochleovestibular dysfunction. Genes, 15:643, May 2024. URL: https://doi.org/10.3390/genes15050643, doi:10.3390/genes15050643. This article has 3 citations.

  33. (bergman2011chd7mutationsand pages 15-19): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  34. (bergman2011chd7mutationsand pages 44-44): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  35. (ouassifi2025chargesyndromein pages 1-4): Kawtar El Ouassifi, Anas Douami, Hind Ouair, Ibtihal Benhsaien, Aziz Bousfiha, Jalila El Bakkouri, Siham Salam, and Fatima Ailal. Charge syndrome in a six-month-old male infant: a case report. Cureus, May 2025. URL: https://doi.org/10.7759/cureus.84181, doi:10.7759/cureus.84181. This article has 2 citations.

  36. (rossi2023casereportfunctional pages 5-6): Cesare Rossi, Sherin Ramadan, Cecilia Evangelisti, Simona Ferrari, Maria Accadia, Reha M. Toydemir, and Emanuele Panza. Case report: functional characterization of a novel chd7 intronic variant in patients with charge syndrome. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1082100, doi:10.3389/fgene.2023.1082100. This article has 5 citations and is from a peer-reviewed journal.

  37. (wieland2020chargesyndrome pages 7-8): J Wieland, D Wieland, T Estiphan, and B Weakley. Charge syndrome. Encyclopedia of Autism Spectrum Disorders, Feb 2020. URL: https://doi.org/10.1007/978-1-4614-6430-3_38-2, doi:10.1007/978-1-4614-6430-3_38-2. This article has 140 citations.

  38. (wieland2020chargesyndrome pages 6-7): J Wieland, D Wieland, T Estiphan, and B Weakley. Charge syndrome. Encyclopedia of Autism Spectrum Disorders, Feb 2020. URL: https://doi.org/10.1007/978-1-4614-6430-3_38-2, doi:10.1007/978-1-4614-6430-3_38-2. This article has 140 citations.

  39. (bergman2011chd7mutationsand pages 19-21): J. E. H. Bergman, N. Janssen, L. H. Hoefsloot, M. C. J. Jongmans, R. M. W. Hofstra, and C. M. A. van Ravenswaaij-Arts. Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype. Journal of Medical Genetics, 48:334-342, Mar 2011. URL: https://doi.org/10.1136/jmg.2010.087106, doi:10.1136/jmg.2010.087106. This article has 379 citations and is from a domain leading peer-reviewed journal.

  40. (wieland2020chargesyndrome pages 8-10): J Wieland, D Wieland, T Estiphan, and B Weakley. Charge syndrome. Encyclopedia of Autism Spectrum Disorders, Feb 2020. URL: https://doi.org/10.1007/978-1-4614-6430-3_38-2, doi:10.1007/978-1-4614-6430-3_38-2. This article has 140 citations.

Artifacts

## Context ID: pqac-00000042 Table 1, located on page 8, reproduces the diagnostic criteria for CHARGE syndrome as proposed by Verloes in 2005, including both m