🏷

Classifications

Harrison's Part

IUIS Category

🔗

Mappings

MONDO

MONDO:0008965 CHARGE syndrome

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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.

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Discussions and Knowledge Gaps

1

How common is a clinically meaningful immune defect in CHARGE syndrome, and which patients warrant immune evaluation?

KNOWLEDGE GAP charge_immunodeficiency_prevalence

Attached to

pathophysiology#Impaired thymic development and T-cell output phenotypes#T-cell lymphopenia phenotypes#Recurrent infections

CHARGE syndrome is listed among the inborn errors of immunity, but the two strongest lines of evidence in this entry do not agree on how much immune disease there is. The pooled phenotype review calls immunological problems a rare feature, reported in too few patients to enter its statistical analysis, while cataloguing thymic aplasia/hypoplasia, IgG2 subclass deficiency, T-cell lymphopenia and, in rare patients, severe combined immunodeficiency. The only prospective study, 21 CHD7-genotyped patients, found an identifiable immune defect in just two of them despite recurrent ear and chest infections in the cohort — yet also recorded persistent lymphopenia in 30% during the first 72 months of life. A dedicated review concludes outright that the prevalence remains unclear. The gap is not merely bookkeeping. It determines whether immune screening should be routine at diagnosis or reserved for patients with an infection phenotype, and the answer is consequential in both directions: SCID in CHARGE syndrome is fatal without immune reconstitution, so missing it is costly, while the recurrent sinopulmonary infections that would trigger screening are readily explained by palatal, airway and aspiration factors that have nothing to do with immunity. Until it is closed, this entry deliberately assigns VERY_RARE bands to the immune phenotypes and types the infection edge as indirect.

Proposed experiments

Adequately powered prospective immune phenotyping of a genotyped CHARGE cohort

charge_prospective_immune_cohort

Measure lymphocyte subsets, naive T cells and recent thymic emigrants, B-cell memory phenotype, immunoglobulins and protein/polysaccharide vaccine responses at fixed ages in a multicentre CHD7-genotyped cohort large enough to estimate the prevalence of each immunophenotype with useful precision, and follow the early-life lymphopenia to determine what fraction resolves.

Attribution of recurrent sinopulmonary infection in CHARGE syndrome

charge_infection_attribution_study

In patients with recurrent sinopulmonary infection, jointly assess immune function and the competing anatomic explanations — palatal competence, eustachian tube function, aspiration on swallow study, and airway patency — to establish what fraction of the infection burden is attributable to immune deficiency rather than to structural causes.

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Pathophysiology

5

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.

CHD7 hgnc:20626 ↓ DECREASED

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.

Growth and developmental delay

Seizures

Hypothyroidism

Brain anomalies

External Ear Anomaly

External Genital Hypoplasia

Growth Retardation

Apnea

Impaired thymic development and T-cell output A minority of individuals with CHD7 haploinsufficiency have thymic aplasia or hypoplasia with reduced T-cell output. The thymus is a pharyngeal-pouch derivative patterned by cranial neural crest, which is the usual rationale offered for the overlap with 22q11.2 deletion syndrome, but no study has established that intermediate chain in CHARGE syndrome itself, so this edge is left indirect.

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

Downstream

Coloboma

Choanal atresia

Congenital heart defect

Feeding difficulties

Facial palsy

Cleft lip and/or palate

Tracheoesophageal fistula

Renal anomalies

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

Downstream

Semicircular canal hypoplasia

Cranial nerve dysfunction

Hypogonadotropic hypogonadism

Hearing impairment

Vestibular Dysfunction

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.

Impaired thymic development and T-cell output

The immune arm of CHD7 disorder, and the reason CHARGE syndrome appears in the IUIS classification of inborn errors of immunity. A minority of patients have thymic aplasia or hypoplasia with consequent reduction in T-cell numbers, ranging from mild T-cell lymphopenia through combined T- and B-cell defects to, in rare patients, a T-B+NK+ severe combined immunodeficiency that is fatal without immune reconstitution. The phenotype overlaps that of 22q11.2 deletion syndrome, with which CHARGE syndrome shares several non-immune features. Two things about this node are deliberately understated. First, it is not a constitutive feature: the source that catalogues it calls immunological problems "a rare feature of CHARGE syndrome", and a prospective cohort of 21 CHD7-genotyped patients found no significant immune defect at the time of testing despite recurrent sinopulmonary infections. Second, the population frequency is genuinely unsettled rather than merely unmeasured here - see the charge_immunodeficiency_prevalence discussion. Nothing in this entry should be read as asserting that T-cell deficiency is expected in an individual with CHARGE syndrome.

Thymus development GO:0048538 ⚠ ABNORMAL

Downstream

T-cell lymphopenia Reduced thymic tissue lowers thymic T-cell output, giving decreased circulating T-cell counts.

Severe combined immunodeficiency At the severe end of the spectrum, absent thymic output produces a T-B+NK+ severe combined immunodeficiency.

Recurrent infections Recurrent sinopulmonary infection is common in CHARGE syndrome, but the cited cohort could not attribute it to a measurable immune defect - airway, palatal and aspiration factors plausibly contribute - so this edge is left indirect rather than typed as immunodeficiency-driven.

Show evidence (3 references)

PMID:20186815 SUPPORT Human Clinical

"Immunological problems are a rare feature of CHARGE syndrome, with a small number of CHARGE patients described as having thymic aplasia or hypoplasia,"

The review that defines this node, and the source of its central qualification: thymic aplasia/hypoplasia occurs in CHARGE syndrome but is a rare rather than a constitutive feature.

PMID:29159871 SUPPORT Human Clinical

"Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution."

A dedicated review setting out the graded severity spectrum this node describes, from reduced T-cell counts through to severe combined immunodeficiency.

PMID:26563674 SUPPORT DIRECT Human Clinical

"Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA)."

A prospective cohort in which the great majority of CHD7-genotyped patients had no identifiable immune defect. It is recorded here as a boundary on the node rather than as a contradiction of it: the recurrent infections were real, but they were not explained by a measurable immune deficiency in this cohort.

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Pathograph

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

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Phenotypes

28

Blood 1

T-cell lymphopenia VERY_RARE Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:20186815 SUPPORT Human Clinical

"IgG2 subclass deficiency, and T-cell lymphopenia"

Lists T-cell lymphopenia among the immunological problems described in CHARGE patients. The band is VERY_RARE because the same sentence opens by calling immunological problems a rare feature of the syndrome.

PMID:26563674 SUPPORT Human Clinical

"A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life."

Quantifies early-life persistent lymphopenia in CHARGE syndrome at 30%, lower than in 22q11.2 deletion syndrome. This is a lymphocyte-count observation in the first 72 months rather than a demonstrated T-cell immunodeficiency, which is why it qualifies the description rather than raising the frequency band.

Cardiovascular 2

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.

Thymic hypoplasia VERY_RARE Hypoplasia of the thymus HP:0000778

Show evidence (1 reference)

PMID:20186815 SUPPORT Human Clinical

"Immunological problems are a rare feature of CHARGE syndrome, with a small number of CHARGE patients described as having thymic aplasia or hypoplasia,"

Documents thymic aplasia/hypoplasia in CHARGE syndrome and, in the same sentence, the rarity that supports the VERY_RARE band. The review states these features were too few to enter its statistical analysis, so the band is the source's qualitative "rare" rather than a counted proportion.

Digestive 2

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 OCCASIONAL HP:0002575

Show evidence (2 references)

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.

PMID:20186815 SUPPORT Human Clinical

"About 19% of CHD7 mutation-positive CHARGE syndrome patients also present with tracheoesophageal (TE) fistula"

Quantifies tracheoesophageal fistula at 19% of CHD7 mutation-positive patients, which falls in the OCCASIONAL band (5-29%).

Ear 4

Semicircular canal hypoplasia VERY_FREQUENT Hypoplasia of the semicircular canal HP:0011382

Show evidence (3 references)

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.

PMID:20186815 SUPPORT Human Clinical

"Inner ear anomalies detected by temporal bone CT or skull x-ray were much more common in mutation-positive (98%) vs. mutation-negative (75%) individuals"

Quantifies inner-ear (temporal bone) anomalies at 98% of CHD7 mutation-positive patients, supporting the VERY_FREQUENT band (80-99%).

PMID:20186815 SUPPORT Human Clinical

"Inner ear malformations are the most highly penetrant clinical feature reported in CHARGE"

Supports the penetrance claim in the description.

Hearing impairment VERY_FREQUENT Sensorineural hearing impairment HP:0000407

Show evidence (4 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.

PMID:20186815 SUPPORT Human Clinical

"Hearing loss was equally common among CHD7 mutation-positive (89%) and mutation-negative (86%) individuals."

Quantifies hearing loss at 89% of CHD7 mutation-positive patients, supporting the VERY_FREQUENT band (80-99%).

+ 1 more reference

External Ear Anomaly VERY_FREQUENT Abnormality of the outer ear HP:0000356

Show evidence (3 references)

PMID:20301296 SUPPORT Human Clinical

"coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)"

GeneReviews lists ear anomalies among the cardinal CHARGE manifestations (the "E" of the mnemonic), which include structural external-ear malformation in addition to deafness.

PMID:20186815 SUPPORT Human Clinical

"External ear malformations were equally common in mutation-positive (91%) and mutation-negative (90%) individuals."

Quantifies external ear malformation at 91% of CHD7 mutation-positive patients, supporting the VERY_FREQUENT band (80-99%).

PMID:20186815 SUPPORT Human Clinical

"These malformations include lowset ears, asymmetric ear shape or size, and small/absent lobes"

Supports the specific external-ear morphology enumerated in the description.

Vestibular Dysfunction Abnormal vestibular function HP:0001751

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 vestibular defects among the expanded CHARGE phenotype identified after the molecular cause was defined.

Endocrine 2

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 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 FREQUENT HP:0000589

Show evidence (3 references)

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.

PMID:20186815 SUPPORT Human Clinical

"Colobomas were more common in mutation-positive (75%) than in mutation-negative (65%) individuals."

Quantifies coloboma at 75% of CHD7 mutation-positive patients, which falls in the FREQUENT band (30-79%).

PMID:20186815 SUPPORT Human Clinical

"Colobomas are commonly bilateral, and can involve chorioretina, and optic nerve"

Supports the anatomic distribution and laterality recorded in the description.

Genitourinary 2

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.

External Genital Hypoplasia FREQUENT HP:0003241

Show evidence (3 references)

PMID:20301296 SUPPORT Human Clinical

"coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)"

GeneReviews lists genital hypoplasia among the cardinal CHARGE manifestations (the "G" of the mnemonic).

PMID:20186815 SUPPORT Human Clinical

"Urogenital abnormalities, including genital hypoplasia, were observed in many (61%) CHARGE patients."

Quantifies genital/urogenital hypoplasia at 61% of patients, in the FREQUENT band (30-79%).

PMID:20186815 SUPPORT Human Clinical

"These defects are less commonly reported in females; thus, the use of urogenital anomalies as a diagnostic feature of CHARGE syndrome is biased towards males."

Supports the ascertainment caveat recorded in the description.

Head and Neck 3

Choanal atresia FREQUENT HP:0000453

Show evidence (3 references)

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.

PMID:20186815 SUPPORT Human Clinical

"CHD7 mutation-positive and mutation-negative patients did not differ in the likelihood of having choanal atresia or stenosis (38% vs. 47%, respectively)."

Quantifies choanal atresia/stenosis at 38% of CHD7 mutation-positive patients, in the FREQUENT band (30-79%), and shows it is not enriched by mutation status.

PMID:20186815 SUPPORT Human Clinical

"the incidence of choanal atresia varies depending upon the incidence of cleft lip/palate, as the choanae are usually normal when clefting is present"

Supports the inverse relationship with clefting recorded in the description.

Facial palsy FREQUENT HP:0010628

Show evidence (2 references)

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.

PMID:20186815 SUPPORT Human Clinical

"We found that mutation-positive individuals were far more likely to have facial palsy (39%) than mutation-negative (19%) CHARGE individuals."

Quantifies facial palsy at 39% of CHD7 mutation-positive patients (FREQUENT band) and supports the roughly two-fold enrichment stated in the description.

Cleft lip and/or palate FREQUENT Cleft palate HP:0000175

Show evidence (2 references)

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.

PMID:20186815 SUPPORT Human Clinical

"We found that cleft lip and/or palate were similarly present in mutation-positive (33%) vs. mutation-negative (29%) individuals"

Quantifies clefting at 33% of CHD7 mutation-positive patients, in the FREQUENT band (30-79%), and supports the lack of enrichment by mutation status.

Immune 2

Severe combined immunodeficiency VERY_RARE HP:0004430

Show evidence (2 references)

PMID:20186815 SUPPORT Human Clinical

"Severe combined immune deficiency (SCID) has also been reported in rare patients"

Documents SCID in CHARGE syndrome, with the rarity supporting the VERY_RARE band stated in the quote itself.

PMID:29159871 SUPPORT Human Clinical

"severe combined immunodeficiency, which is fatal without immune reconstitution"

Supports the clinical consequence recorded in the description, namely that this presentation is fatal unless the immune system is reconstituted.

Recurrent infections FREQUENT HP:0002719

Show evidence (2 references)

PMID:26563674 SUPPORT Human Clinical

"Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted."

Establishes recurrent sinopulmonary infection as a common feature. The FREQUENT band reflects this qualitative "common" rather than a counted proportion, which the source does not give.

PMID:26563674 SUPPORT Human Clinical

"Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing."

The finding behind the caution in the description: recurrent infection in this cohort was not explained by a detectable immune defect.

Musculoskeletal 1

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:20186815 SUPPORT Human Clinical

"Scoliosis is reported in many children with CHARGE, and often includes structural abnormalities of the vertebrae"

Documents scoliosis with vertebral involvement in CHARGE syndrome. The source says "many" without a proportion, so no frequency band is asserted.

Nervous System 6

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 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.

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.

Olfactory bulb hypoplasia Hypoplasia of the olfactory bulb HP:0040326

Show evidence (1 reference)

PMID:20186815 SUPPORT Human Clinical

"Unilateral and bilateral hypoplasia of the olfactory bulb and/or arhinencephaly are most commonly reported in CHARGE, and may contribute to hyposmia or anosmia"

Documents olfactory bulb hypoplasia as the most commonly reported CNS anomaly in CHARGE syndrome and its link to reduced olfaction. No frequency band is asserted because the review states CNS reporting was too incomplete for comparison.

Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:16155193 SUPPORT Human Clinical

"Specific behavioural problems, including autistic-like behaviour, have been described."

Documents autistic-like behavior as a described feature of CHARGE syndrome. The source gives no frequency, so none is asserted.

Respiratory 1

Apnea HP:0002104

Show evidence (1 reference)

PMID:20301296 SUPPORT Human Clinical

"respiratory issues including obstructive and central apnea"

GeneReviews identifies obstructive and central apnea among the respiratory issues contributing to CHARGE morbidity.

Growth 1

Growth Retardation Growth delay HP:0001510

Show evidence (1 reference)

PMID:20301296 SUPPORT Human Clinical

"coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness)"

GeneReviews lists retarded growth among the cardinal CHARGE manifestations (the "R" of the mnemonic), and growth is a recommended surveillance parameter.

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Genetic Associations

1

CHD7 (causative)

Gene: CHD7 hgnc:20626 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (7 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:20186815 SUPPORT Human Clinical

"Of the 379 individuals tested, 254 (67%) were CHD7 mutation-positive, whereas 125 (33%) were mutation-negative."

Quantifies the CHD7 diagnostic yield in clinically diagnosed CHARGE syndrome at 67%.

PMID:20186815 SUPPORT Human Clinical

"Of the CHD7 mutations reported thus far, approximately 72% are nonsense or frameshift, 13% are splice site, and 10% are missense"

Source of the variant-class proportions recorded in these notes, and the quantitative basis for describing the mechanism as loss of function.

+ 4 more references

💊

Medical Actions

4

Multidisciplinary supportive management

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

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 Ontology label: Supportive Care NCIT:C15747

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: Cardiac Surgery NCIT:C157806

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 NCIT:C15240

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.

🔬

Diagnosis

2

Molecular genetic testing for CHD7

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).

Show evidence (1 reference)

PMID:20301296 SUPPORT Human Clinical

"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."

GeneReviews describes the molecular diagnostic standard for CHARGE syndrome.

Temporal bone CT

Computed tomography of the temporal bone demonstrates the semicircular canal hypoplasia/aplasia, cochlear hypoplasia and Mondini malformation that are the most highly penetrant findings in CHD7 disorder — present in 98% of mutation-positive patients — which is why the pooled cohort review recommends it as a diagnostic tool and why hypoplastic semicircular canals are a major criterion in the Verloes scheme. Its practical value is greatest in a patient whose external features are equivocal.

Show evidence (3 references)

PMID:20186815 SUPPORT Human Clinical

"These data strongly support the use of temporal bone CT as a diagnostic tool for evaluation of CHARGE patients, and confirm previous reports that inner ear malformations should be considered a diagnostic criterion."

The review's explicit diagnostic recommendation, which is what this record captures.

PMID:20186815 SUPPORT Human Clinical

"These anomalies include semicircular canal hypoplasia/aplasia, cochlear hypoplasia, and Mondini malformation"

Enumerates the specific temporal-bone findings the scan is looking for.

PMID:20186815 SUPPORT Human Clinical

"Revised diagnostic criteria by Verloes include ocular coloboma, choanal atresia/stenosis and hypoplasia of the semicircular canals as major criteria"

Supports the statement that semicircular canal hypoplasia is a major Verloes criterion.

📈

Progression

2

Early life

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. Survival to five years is about 70%, with mortality concentrated in the first year.

Show evidence (3 references)

PMID:37675914 SUPPORT Human Clinical

"CHDs and feeding disorders associated with CS may have a substantial impact on prognosis."

Systematic review concluding that congenital heart defects and feeding disorders substantially affect prognosis in CHARGE syndrome.

PMID:20186815 SUPPORT Human Clinical

"Actuarial analysis of survival in children with CHARGE showed a 70% survival rate to five years of age, with the highest rate of mortality in the first year of life."

Quantifies early-life survival and locates the mortality peak in the first year, which is the claim added to this phase's notes.

PMID:37675914 SUPPORT Human Clinical

"The in-hospital mortality rate was about 9.5% (n=86/900) in case series studies and 12% (n=5/43) in case reports, including cardiovascular (CV) and non-CV causes."

Gives the in-hospital mortality associated with the cardiac burden of the syndrome.

Childhood through adulthood

Beyond infancy, decreased life expectancy reflects residual heart defects, infection, aspiration or choking, obstructive and central apnea, and possibly seizures. This is the phase in which the syndrome's respiratory and infectious morbidity dominates rather than its structural cardiac lesions. Crucially, the outlook is not uniformly poor: many individuals have a normal life expectancy, and the entry should not be read as implying otherwise.

Show evidence (2 references)

PMID:20301296 SUPPORT Human Clinical

"In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures."

GeneReviews enumerates the contributors to reduced life expectancy after infancy, which is what this phase records.

PMID:20301296 SUPPORT Human Clinical

"Despite these complications, the life expectancy for many individuals can be normal."

The counterbalancing statement, quoted so the phase does not read as a uniformly poor prognosis.

📊

Prevalence

1

Worldwide

Birth Prevalence 10.0 per 100,000 1–9 per 10,000 (births)

The cited review words this as an incidence of approximately 1:10,000, which for a congenital multiple-anomaly syndrome is a birth prevalence; 1 in 10,000 is 10 per 100,000. An earlier version of this record asserted a range of 1 in 8,500 to 1 in 17,000 live births, which no cited source stated - the evidence attached to it established only that the disorder is rare. The unsupported range has been replaced by the figure the sources actually give.

Show evidence (2 references)

PMID:20186815 SUPPORT Human Clinical

"CHARGE syndrome (OMIM # 214800) is a rare (incidence ∼1:10,000"

The source of the recorded rate. The review attributes the figure to two independent clinical cohorts.

PMID:37675914 SUPPORT Human Clinical

"CHARGE syndrome (CS) is a rare genetic disease that affects many areas of the body."

Independently confirms rarity. This quote supports the qualitative claim only and is not the source of the numeric rate.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from CHARGE syndrome:

DiGeorge syndrome (22q11.2 deletion syndrome) Not Yet Curated MONDO:0008564

Overlapping Features The most important differential, and the one that matters most to this entry's immune section. The two disorders share genital hypoplasia, cleft palate, congenital heart disease, thymic hypoplasia with T-cell deficiency, and early-life hypocalcemia, and CHD7 variants have been found in patients initially diagnosed as 22q11.2 deletion syndrome. CHARGE syndrome is distinguished by ocular coloboma, choanal atresia and the distinctive inner- and outer-ear anomalies. Immunologically the two separate on degree rather than kind: persistent lymphopenia and hypocalcemia are commoner in 22q11.2 deletion, and T-cell lymphopenia with specific antibody deficiency is characteristic there but not in CHARGE syndrome.

Show evidence (3 references)

PMID:20186815 SUPPORT Human Clinical

"Many of these features, including genital hypoplasia, cleft palate, and heart defects, are shared by other multiple anomaly syndromes such as 22q11.2 deletion"

Documents the shared features that make 22q11.2 deletion syndrome the principal differential.

PMID:20186815 SUPPORT Human Clinical

"however, CHARGE syndrome is considered unique in its combination of these features with distinctive inner and outer ear defects and optic colobomas."

States the features that discriminate CHARGE syndrome from the shared differential.

PMID:26563674 SUPPORT Human Clinical

"In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion."

The head-to-head immunological comparison that supports separating the two disorders by degree of immune involvement.

Kallmann syndrome MONDO:0018800

Overlapping Features Kallmann syndrome shares the olfactory-placode mechanism with CHARGE syndrome — anosmia with hypogonadotropic hypogonadism from failed GnRH-neuron migration — and CHD7 variants have been reported in patients diagnosed with it. A patient presenting as Kallmann syndrome without a typical molecular finding should be examined for the ocular, choanal and inner-ear features of CHARGE syndrome.

Show evidence (2 references)

PMID:20186815 SUPPORT Human Clinical

"CHD7 mutations have also been reported in patients diagnosed with conditions that have significant clinical overlap with CHARGE, including Kallmann"

Documents CHD7 variants in patients carrying a Kallmann syndrome diagnosis, which is what makes it a differential.

PMID:20186815 SUPPORT Human Clinical

"These findings imply that patients presenting with features of these syndromes, but lacking typical molecular findings, should be examined for clinical signs of CHARGE syndrome and tested for CHD7 mutations."

The review's explicit recommendation, which is the practical content of this differential record.

{ }

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
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Monogenic multiple-congenital-anomaly syndrome, most often caused by de
      novo heterozygous CHD7 variants.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      IUIS 2022 classification of inborn errors of immunity (Tangye et al.,
      PMID:35748970), Table 2 "Combined immunodeficiencies with associated or
      syndromic features", section 3 "Thymic Defects with Additional
      Congenital Anomalies", row "CHARGE syndrome" (genes CHD7 AD, SEMA3E AD,
      or unknown; OMIM 608892 and 608166). The cached PDF extraction runs the
      row's gene columns into the disease name ("608166CHARGE syndrome"), so
      the evidence quotes the row's associated-features column instead.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like"
      explanation: >-
        Associated-features column of the CHARGE syndrome row in Table 2
        section 3 (thymic defects with additional congenital anomalies),
        including the SCID-like immunophenotype of some patients; the quote
        joins the row's wrapped lines in the cached PDF extraction.
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: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10.0
  notes: >-
    The cited review words this as an incidence of approximately 1:10,000, which
    for a congenital multiple-anomaly syndrome is a birth prevalence; 1 in 10,000
    is 10 per 100,000. An earlier version of this record asserted a range of 1 in
    8,500 to 1 in 17,000 live births, which no cited source stated - the evidence
    attached to it established only that the disorder is rare. The unsupported
    range has been replaced by the figure the sources actually give.
  evidence:
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHARGE syndrome (OMIM  # 214800) is a rare (incidence ∼1:10,000
    explanation: >-
      The source of the recorded rate. The review attributes the figure to two
      independent clinical cohorts.
  - 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: >-
      Independently confirms rarity. This quote supports the qualitative claim
      only and is not the source of the numeric rate.
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. Survival to five
    years is about 70%, with mortality concentrated in the first year.
  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.
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Actuarial analysis of survival in children with CHARGE showed a 70% survival rate to five years of age, with the highest rate of mortality in the first year of life.
    explanation: >-
      Quantifies early-life survival and locates the mortality peak in the first
      year, which is the claim added to this phase's notes.
  - reference: PMID:37675914
    reference_title: "CHARGE syndrome and congenital heart diseases: systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The in-hospital mortality rate was about 9.5% (n=86/900) in case series studies and 12% (n=5/43) in case reports, including cardiovascular (CV) and non-CV causes.
    explanation: >-
      Gives the in-hospital mortality associated with the cardiac burden of the
      syndrome.
- phase: Childhood through adulthood
  notes: >-
    Beyond infancy, decreased life expectancy reflects residual heart defects,
    infection, aspiration or choking, obstructive and central apnea, and possibly
    seizures. This is the phase in which the syndrome's respiratory and
    infectious morbidity dominates rather than its structural cardiac lesions.
    Crucially, the outlook is not uniformly poor: many individuals have a normal
    life expectancy, and the entry should not be read as implying otherwise.
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures.
    explanation: >-
      GeneReviews enumerates the contributors to reduced life expectancy after
      infancy, which is what this phase records.
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite these complications, the life expectancy for many individuals can be normal.
    explanation: >-
      The counterbalancing statement, quoted so the phase does not read as a
      uniformly poor prognosis.
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.
  gene:
    preferred_term: CHD7
    modifier: DECREASED
    term:
      id: hgnc:20626
      label: CHD7
  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.
    evidence:
    - reference: PMID:33127760
      reference_title: "CHD7 regulates cardiovascular development through ATP-dependent and -independent activities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development.
      explanation: >-
        Chd7 deletion alters the developmental gene-expression program of neural
        crest cells, directly linking loss of CHD7 activity to this mechanism.
  - target: Inappropriate p53 activation
    description: >-
      CHD7 normally binds the p53 promoter to repress p53; haploinsufficiency
      releases this repression and causes inappropriate p53 activation.
    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: >-
        The study directly places p53 activation downstream of CHD7 loss.
  - 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: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 directly link loss of CHD7 remodeling activity
        to defective otic progenitor development.
  - target: Growth and developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews identifies growth and developmental delay as a defining
        manifestation of heterozygous CHD7-related disease; the intermediates
        between CHD7 insufficiency and this outcome remain unresolved.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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 places seizures in the CHD7-disorder spectrum while the
        intervening causal mechanism is not established.
  - target: Hypothyroidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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 places hypothyroidism in the CHD7-disorder spectrum while
        the intervening causal mechanism is not established.
  - target: Brain anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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 places brain anomalies in the CHD7-disorder spectrum while
        the intervening causal mechanism is not established.
  - target: External Ear Anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews supports ear anomalies as a cardinal CHARGE manifestation;
        the cited passage does not isolate external-ear malformation or its
        developmental intermediates.
  - target: External Genital Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews identifies genital hypoplasia as a defining CHD7-disorder
        manifestation; this conservative edge leaves the intermediates open.
  - target: Growth Retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews identifies growth retardation as a defining CHD7-disorder
        manifestation; its precise downstream mechanism remains unresolved.
  - target: Apnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301296
      reference_title: "CHD7 Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        respiratory issues including obstructive and central apnea
      explanation: >-
        GeneReviews documents obstructive and central apnea in CHD7 disorder;
        this edge does not overstate an unresolved intervening mechanism.
  - target: Impaired thymic development and T-cell output
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A minority of individuals with CHD7 haploinsufficiency have thymic aplasia
      or hypoplasia with reduced T-cell output. The thymus is a pharyngeal-pouch
      derivative patterned by cranial neural crest, which is the usual rationale
      offered for the overlap with 22q11.2 deletion syndrome, but no study has
      established that intermediate chain in CHARGE syndrome itself, so this edge
      is left indirect.
    evidence:
    - reference: PMID:20186815
      reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a small number of CHARGE patients described as having thymic aplasia or hypoplasia
      explanation: >-
        Places thymic aplasia/hypoplasia in the CHD7-disorder spectrum while
        making explicit that it affects only a small number of patients.
  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.
  downstream:
  - target: Coloboma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Coloboma is enriched in CHD7 mutation-positive CHARGE, but the terminal
        intermediates downstream of disrupted neural crest development are not
        fully resolved.
  - target: Choanal atresia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews supports choanal atresia as a cardinal CHARGE manifestation
        but does not establish the intermediate developmental mechanism.
  - target: Congenital heart defect
    causal_link_type: DIRECT
    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: >-
        Neural-crest-specific Chd7 deletion directly produces severe
        conotruncal heart defects.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Feeding disorders are clinically associated with CHARGE syndrome, while
        their multiple neural and structural intermediates remain unresolved.
  - target: Facial palsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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,
        with unresolved intermediates downstream of the developmental defect.
  - target: Cleft lip and/or palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Cleft lip/palate is a documented congenital CHARGE anomaly; its terminal
        intermediates downstream of the neural crest defect are not specified.
  - target: Tracheoesophageal fistula
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Tracheo-oesophageal fistula is a documented congenital CHARGE anomaly;
        its terminal developmental intermediates remain unresolved.
  - target: Renal anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Renal anomalies are part of the CHD7-disorder spectrum, but the
        intervening developmental mechanism remains unresolved.
- 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 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 reduction of p53 partially rescues Chd7-null phenotypes,
        supporting p53 activation as a contributor to the developmental defect.
  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.
  downstream:
  - target: Semicircular canal hypoplasia
    causal_link_type: DIRECT
    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: >-
        The clinical cohort identifies semicircular-canal hypoplasia as a
        consistent CHARGE feature.
  - target: Cranial nerve dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Cranial nerve anomalies are part of the CHD7-disorder spectrum, while
        the terminal steps from placodal dysfunction remain unresolved.
  - target: Hypogonadotropic hypogonadism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        GeneReviews supports genital hypoplasia as a cardinal endpoint, which is
        compatible with hypogonadotropic hypogonadism, but does not establish
        the placode-to-GnRH-neuron mechanism.
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - 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: >-
        CHD7-deficient human inner-ear organoids identify a molecular mechanism
        for CHARGE-associated sensorineural hearing loss.
  - target: Vestibular Dysfunction
    causal_link_type: DIRECT
    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: >-
        The human study directly connects semicircular-canal hypoplasia to
        vestibular areflexia.
- name: Impaired thymic development and T-cell output
  description: >-
    The immune arm of CHD7 disorder, and the reason CHARGE syndrome appears in
    the IUIS classification of inborn errors of immunity. A minority of patients
    have thymic aplasia or hypoplasia with consequent reduction in T-cell
    numbers, ranging from mild T-cell lymphopenia through combined T- and B-cell
    defects to, in rare patients, a T-B+NK+ severe combined immunodeficiency that
    is fatal without immune reconstitution. The phenotype overlaps that of
    22q11.2 deletion syndrome, with which CHARGE syndrome shares several
    non-immune features.

    Two things about this node are deliberately understated. First, it is not a
    constitutive feature: the source that catalogues it calls immunological
    problems "a rare feature of CHARGE syndrome", and a prospective cohort of 21
    CHD7-genotyped patients found no significant immune defect at the time of
    testing despite recurrent sinopulmonary infections. Second, the population
    frequency is genuinely unsettled rather than merely unmeasured here - see the
    charge_immunodeficiency_prevalence discussion. Nothing in this entry should
    be read as asserting that T-cell deficiency is expected in an individual with
    CHARGE syndrome.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: Thymus development
    term:
      id: GO:0048538
      label: thymus development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological problems are a rare feature of CHARGE syndrome, with a small number of CHARGE patients described as having thymic aplasia or hypoplasia,
    explanation: >-
      The review that defines this node, and the source of its central
      qualification: thymic aplasia/hypoplasia occurs in CHARGE syndrome but is a
      rare rather than a constitutive feature.
  - reference: PMID:29159871
    reference_title: Immunodeficiency in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes including reduction in T-cell counts, combined T-B cell defects rarely requiring antibiotic prophylaxis or immunoglobulin replacement, and severe combined immunodeficiency, which is fatal without immune reconstitution.
    explanation: >-
      A dedicated review setting out the graded severity spectrum this node
      describes, from reduced T-cell counts through to severe combined
      immunodeficiency.
  - reference: PMID:26563674
    reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA).
    explanation: >-
      A prospective cohort in which the great majority of CHD7-genotyped patients
      had no identifiable immune defect. It is recorded here as a boundary on the
      node rather than as a contradiction of it: the recurrent infections were
      real, but they were not explained by a measurable immune deficiency in this
      cohort.
  downstream:
  - target: T-cell lymphopenia
    causal_link_type: DIRECT
    description: >-
      Reduced thymic tissue lowers thymic T-cell output, giving decreased
      circulating T-cell counts.
    evidence:
    - reference: PMID:20186815
      reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        IgG2 subclass deficiency, and T-cell lymphopenia
      explanation: >-
        Names T-cell lymphopenia among the immunological problems reported in
        CHARGE patients, in the same sentence that reports the thymic hypoplasia
        upstream of it.
  - target: Severe combined immunodeficiency
    causal_link_type: DIRECT
    description: >-
      At the severe end of the spectrum, absent thymic output produces a
      T-B+NK+ severe combined immunodeficiency.
    evidence:
    - reference: PMID:20186815
      reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Severe combined immune deficiency (SCID) has also been reported in rare patients
      explanation: >-
        Documents SCID as a rare severe outcome in CHARGE syndrome, with the
        rarity stated in the quote itself.
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recurrent sinopulmonary infection is common in CHARGE syndrome, but the
      cited cohort could not attribute it to a measurable immune defect - airway,
      palatal and aspiration factors plausibly contribute - so this edge is left
      indirect rather than typed as immunodeficiency-driven.
    evidence:
    - reference: PMID:26563674
      reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted.
      explanation: >-
        Establishes that recurrent sinopulmonary infection is common while
        stating the evidential gap that keeps this edge indirect.
phenotypes:
- name: Coloboma
  category: Phenotypic
  frequency: FREQUENT
  description: >-
    Ocular coloboma is a cardinal feature of CHARGE syndrome and is more frequent
    in CHD7 mutation-positive individuals. It typically involves the choroid,
    retina and optic nerve and is commonly bilateral; iris, eyelid and optic-disc
    colobomas are described less often.
  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.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Colobomas were more common in mutation-positive (75%) than in mutation-negative (65%) individuals.
    explanation: >-
      Quantifies coloboma at 75% of CHD7 mutation-positive patients, which falls
      in the FREQUENT band (30-79%).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Colobomas are commonly bilateral, and can involve chorioretina, and optic nerve
    explanation: >-
      Supports the anatomic distribution and laterality recorded in the
      description.
- name: Choanal atresia
  category: Phenotypic
  frequency: FREQUENT
  description: >-
    Atresia (or stenosis) of the choanae, the bony or membranous narrowing of the
    posterior nasal passages, is one of the defining CHARGE anomalies. Its
    incidence is inversely related to that of clefting, the choanae usually being
    normal when a cleft is present.
  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.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 mutation-positive and mutation-negative patients did not differ in the likelihood of having choanal atresia or stenosis (38% vs. 47%, respectively).
    explanation: >-
      Quantifies choanal atresia/stenosis at 38% of CHD7 mutation-positive
      patients, in the FREQUENT band (30-79%), and shows it is not enriched by
      mutation status.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the incidence of choanal atresia varies depending upon the incidence of cleft lip/palate, as the choanae are usually normal when clefting is present
    explanation: >-
      Supports the inverse relationship with clefting recorded in the
      description.
- 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
  frequency: VERY_FREQUENT
  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 and, at 98% of CHD7 mutation-positive patients, the most highly
    penetrant feature of the syndrome — the finding that makes temporal bone CT
    the single most informative diagnostic image.
  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.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inner ear anomalies detected by temporal bone CT or skull x-ray were much more common in mutation-positive (98%) vs. mutation-negative (75%) individuals
    explanation: >-
      Quantifies inner-ear (temporal bone) anomalies at 98% of CHD7
      mutation-positive patients, supporting the VERY_FREQUENT band (80-99%).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inner ear malformations are the most highly penetrant clinical feature reported in CHARGE
    explanation: >-
      Supports the penetrance claim in the description.
- name: Facial palsy
  category: Phenotypic
  frequency: FREQUENT
  description: >-
    Facial nerve (cranial nerve VII) palsy is a frequent cranial nerve anomaly in
    CHARGE syndrome and is roughly twice as common in CHD7 mutation-positive as
    in mutation-negative 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.
  - 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 mutation-positive individuals were far more likely to have facial palsy (39%) than mutation-negative (19%) CHARGE individuals.
    explanation: >-
      Quantifies facial palsy at 39% of CHD7 mutation-positive patients
      (FREQUENT band) and supports the roughly two-fold enrichment stated in the
      description.
- 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
  frequency: FREQUENT
  description: >-
    Cleft lip and/or cleft palate are commonly associated orofacial anomalies in
    CHARGE syndrome, present in about a third of patients and at similar rates
    regardless of CHD7 mutation status.
  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.
  - 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 cleft lip and/or palate were similarly present in mutation-positive (33%) vs. mutation-negative (29%) individuals
    explanation: >-
      Quantifies clefting at 33% of CHD7 mutation-positive patients, in the
      FREQUENT band (30-79%), and supports the lack of enrichment by mutation
      status.
- name: Tracheoesophageal fistula
  category: Phenotypic
  frequency: OCCASIONAL
  description: >-
    Tracheoesophageal and esophageal anomalies, including tracheo-oesophageal
    fistula, occur in a subset of individuals with CHARGE syndrome, cause feeding
    difficulty and aspiration in infancy, and are typically corrected surgically.
  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.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About 19% of CHD7 mutation-positive CHARGE syndrome patients also present with tracheoesophageal (TE) fistula
    explanation: >-
      Quantifies tracheoesophageal fistula at 19% of CHD7 mutation-positive
      patients, which falls in the OCCASIONAL band (5-29%).
- 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
  frequency: VERY_FREQUENT
  description: >-
    Hearing loss in CHARGE syndrome may be conductive (from inner-ear structural
    anomalies), sensorineural (from cranial nerve VIII deficiency), or mixed, and
    ear anomalies including deafness are a cardinal feature. It affects close to
    90% of patients regardless of CHD7 mutation status.
  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.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss was equally common among CHD7 mutation-positive (89%) and mutation-negative (86%) individuals.
    explanation: >-
      Quantifies hearing loss at 89% of CHD7 mutation-positive patients,
      supporting the VERY_FREQUENT band (80-99%).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss can be conductive in nature owing to structural anomalies of the inner ear, sensorineural due to deficiencies in cranial nerve VIII function, or mixed conductive/sensorineural
    explanation: >-
      Supports the three hearing-loss types and their distinct anatomic origins
      recorded in the description.
- 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.
- name: External Ear Anomaly
  category: Phenotypic
  frequency: VERY_FREQUENT
  description: >-
    Structural anomalies of the external (outer) ear — classically low-set,
    cup-shaped, or asymmetric ears with small or absent lobes — are the "E" (ear
    anomalies) of the CHARGE mnemonic and a cardinal external feature, distinct
    from the sensorineural hearing loss and inner-ear (semicircular canal)
    findings already captured in this entry. They are present in about 90% of
    patients.
  phenotype_term:
    preferred_term: External ear anomaly
    term:
      id: HP:0000356
      label: Abnormality of the outer ear
  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: >-
      GeneReviews lists ear anomalies among the cardinal CHARGE manifestations
      (the "E" of the mnemonic), which include structural external-ear
      malformation in addition to deafness.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      External ear malformations were equally common in mutation-positive (91%) and mutation-negative (90%) individuals.
    explanation: >-
      Quantifies external ear malformation at 91% of CHD7 mutation-positive
      patients, supporting the VERY_FREQUENT band (80-99%).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These malformations include lowset ears, asymmetric ear shape or size, and small/absent lobes
    explanation: >-
      Supports the specific external-ear morphology enumerated in the
      description.
- name: External Genital Hypoplasia
  category: Phenotypic
  frequency: FREQUENT
  description: >-
    Genital hypoplasia — the "G" of the CHARGE mnemonic — reflects underlying
    hypogonadotropic hypogonadism and presents most often as micropenis with
    cryptorchidism in males and hypoplasia of the uterus and labia in females.
    Because the female findings are less readily detected, use of this feature as
    a diagnostic criterion is biased toward males.
  phenotype_term:
    preferred_term: External genital hypoplasia
    term:
      id: HP:0003241
      label: External genital hypoplasia
  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: >-
      GeneReviews lists genital hypoplasia among the cardinal CHARGE
      manifestations (the "G" of the mnemonic).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urogenital abnormalities, including genital hypoplasia, were observed in many (61%) CHARGE patients.
    explanation: >-
      Quantifies genital/urogenital hypoplasia at 61% of patients, in the
      FREQUENT band (30-79%).
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These defects are less commonly reported in females; thus, the use of urogenital anomalies as a diagnostic feature of CHARGE syndrome is biased towards males.
    explanation: >-
      Supports the ascertainment caveat recorded in the description.
- name: Growth Retardation
  category: Phenotypic
  description: >-
    Postnatal growth retardation is the "R" (retarded growth and development) of
    the CHARGE mnemonic and a recognized manifestation warranting ongoing
    monitoring of growth; it is distinct from the developmental/cognitive delay
    already captured in this entry.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth 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: >-
      GeneReviews lists retarded growth among the cardinal CHARGE manifestations
      (the "R" of the mnemonic), and growth is a recommended surveillance
      parameter.
- name: Vestibular Dysfunction
  category: Phenotypic
  description: >-
    Vestibular (balance) dysfunction, related to the semicircular canal
    anomalies characteristic of CHARGE, is part of the expanded CHD7-disorder
    phenotype and contributes to delayed motor milestones and gait imbalance.
  phenotype_term:
    preferred_term: Vestibular dysfunction
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  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 vestibular defects among the expanded CHARGE phenotype
      identified after the molecular cause was defined.
- name: Apnea
  category: Phenotypic
  description: >-
    Both obstructive and central apnea occur in CHARGE syndrome, contributing —
    with airway and feeding issues — to respiratory morbidity and decreased life
    expectancy, and requiring airway surveillance.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:20301296
    reference_title: "CHD7 Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      respiratory issues including obstructive and central apnea
    explanation: >-
      GeneReviews identifies obstructive and central apnea among the respiratory
      issues contributing to CHARGE morbidity.
- name: Olfactory bulb hypoplasia
  category: Phenotypic
  description: >-
    Unilateral or bilateral hypoplasia of the olfactory bulb, or arhinencephaly,
    is the most commonly reported CNS anomaly in CHARGE syndrome and contributes
    to hyposmia or anosmia. It is the anatomic correlate of the olfactory-placode
    defect that also underlies the GnRH-neuron migration failure behind
    hypogonadotropic hypogonadism, which is why the same lesion links the CNS and
    endocrine arms of the syndrome.
  phenotype_term:
    preferred_term: Olfactory bulb hypoplasia
    term:
      id: HP:0040326
      label: Hypoplasia of the olfactory bulb
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unilateral and bilateral hypoplasia of the olfactory bulb and/or arhinencephaly are most commonly reported in CHARGE, and may contribute to hyposmia or anosmia
    explanation: >-
      Documents olfactory bulb hypoplasia as the most commonly reported CNS
      anomaly in CHARGE syndrome and its link to reduced olfaction. No frequency
      band is asserted because the review states CNS reporting was too
      incomplete for comparison.
- name: Autistic behavior
  category: Phenotypic
  description: >-
    Specific behavioral problems, including autistic-like behavior, are described
    in CHARGE syndrome. Behavior in this disorder must be interpreted against the
    combined sensory deficit — the majority of patients have both hearing loss
    and visual impairment from coloboma — so an autism-like presentation is not
    straightforwardly a primary social-communication phenotype.
  phenotype_term:
    preferred_term: Autistic-like behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:16155193
    reference_title: "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific behavioural problems, including autistic-like behaviour, have been described.
    explanation: >-
      Documents autistic-like behavior as a described feature of CHARGE
      syndrome. The source gives no frequency, so none is asserted.
- name: Scoliosis
  category: Phenotypic
  description: >-
    Scoliosis is reported in many children with CHARGE syndrome and often
    involves structural vertebral anomalies; spina bifida occulta and kyphosis
    also occur. It is a surveillance item rather than a diagnostic criterion.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scoliosis is reported in many children with CHARGE, and often includes structural abnormalities of the vertebrae
    explanation: >-
      Documents scoliosis with vertebral involvement in CHARGE syndrome. The
      source says "many" without a proportion, so no frequency band is asserted.
- name: Thymic hypoplasia
  category: Immunological
  frequency: VERY_RARE
  description: >-
    Aplasia or hypoplasia of the thymus, sometimes described as a DiGeorge
    sequence, occurs in a small minority of individuals with CHARGE syndrome and
    is the anatomic basis of the T-cell deficiency that places the disorder in
    the IUIS classification of inborn errors of immunity. It is not a general
    feature of the syndrome.
  phenotype_term:
    preferred_term: Thymic aplasia or hypoplasia
    term:
      id: HP:0000778
      label: Hypoplasia of the thymus
  evidence:
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunological problems are a rare feature of CHARGE syndrome, with a small number of CHARGE patients described as having thymic aplasia or hypoplasia,
    explanation: >-
      Documents thymic aplasia/hypoplasia in CHARGE syndrome and, in the same
      sentence, the rarity that supports the VERY_RARE band. The review states
      these features were too few to enter its statistical analysis, so the band
      is the source's qualitative "rare" rather than a counted proportion.
- name: T-cell lymphopenia
  category: Immunological
  frequency: VERY_RARE
  description: >-
    Decreased circulating T-cell counts follow reduced thymic output. Severity
    ranges from isolated mild T-cell lymphopenia to profound T-cell deficiency.
    Transient lymphopenia in the first years of life is separately reported and
    is more common than a persistent identifiable T-cell defect.
  phenotype_term:
    preferred_term: T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IgG2 subclass deficiency, and T-cell lymphopenia
    explanation: >-
      Lists T-cell lymphopenia among the immunological problems described in
      CHARGE patients. The band is VERY_RARE because the same sentence opens by
      calling immunological problems a rare feature of the syndrome.
  - reference: PMID:26563674
    reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life.
    explanation: >-
      Quantifies early-life persistent lymphopenia in CHARGE syndrome at 30%,
      lower than in 22q11.2 deletion syndrome. This is a lymphocyte-count
      observation in the first 72 months rather than a demonstrated T-cell
      immunodeficiency, which is why it qualifies the description rather than
      raising the frequency band.
- name: Severe combined immunodeficiency
  category: Immunological
  frequency: VERY_RARE
  description: >-
    A T-B+NK+ severe combined immunodeficiency has been reported in rare
    individuals with CHD7 pathogenic variants. It is the one immunological
    presentation of CHARGE syndrome that is fatal without immune reconstitution,
    which is why it matters clinically out of proportion to its frequency.
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  evidence:
  - reference: PMID:20186815
    reference_title: Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Severe combined immune deficiency (SCID) has also been reported in rare patients
    explanation: >-
      Documents SCID in CHARGE syndrome, with the rarity supporting the
      VERY_RARE band stated in the quote itself.
  - reference: PMID:29159871
    reference_title: Immunodeficiency in CHARGE syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe combined immunodeficiency, which is fatal without immune reconstitution
    explanation: >-
      Supports the clinical consequence recorded in the description, namely that
      this presentation is fatal unless the immune system is reconstituted.
- name: Recurrent infections
  category: Immunological
  frequency: FREQUENT
  description: >-
    Recurrent ear and sinopulmonary infections are common in children with
    CHARGE syndrome. Importantly, they are usually not attributable to a
    measurable immune defect: palatal, airway, eustachian-tube and aspiration
    factors contribute, and the prospective cohort cited here found an
    identifiable immune abnormality in only 2 of 21 patients. Recurrent infection
    in CHARGE syndrome should therefore prompt immune testing rather than be
    assumed to establish immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:26563674
    reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted.
    explanation: >-
      Establishes recurrent sinopulmonary infection as a common feature. The
      FREQUENT band reflects this qualitative "common" rather than a counted
      proportion, which the source does not give.
  - reference: PMID:26563674
    reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing.
    explanation: >-
      The finding behind the caution in the description: recurrent infection in
      this cohort was not explained by a detectable immune defect.
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 — about
    two thirds of clinically diagnosed patients in a pooled review of 379 tested
    individuals. Roughly 72% of reported variants are nonsense or frameshift, 13%
    splice site and 10% missense; they are scattered throughout the coding
    sequence without meaningful clustering, recurrent variants are rare, and
    there is no clear genotype-phenotype correlation even between relatives
    sharing a variant. A minority of cases are caused by contiguous 8q12
    microdeletions or by whole- or partial-gene deletions not detected by
    sequencing alone, so deletion/duplication analysis matters in a
    sequencing-negative patient.
  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:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 379 individuals tested, 254 (67%) were CHD7 mutation-positive, whereas 125 (33%) were mutation-negative.
    explanation: >-
      Quantifies the CHD7 diagnostic yield in clinically diagnosed CHARGE
      syndrome at 67%.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the CHD7 mutations reported thus far, approximately 72% are nonsense or frameshift, 13% are splice site, and 10% are missense
    explanation: >-
      Source of the variant-class proportions recorded in these notes, and the
      quantitative basis for describing the mechanism as loss of function.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 mutations are reported throughout the entire coding sequence of the gene and do not appear to cluster in any meaningful way.
    explanation: >-
      Supports the absence of variant clustering stated in the notes.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent work indicates that CHARGE patients without detectable single-base mutations may have heterozygous deletions of CHD7
    explanation: >-
      Supports the recommendation that deletion analysis be pursued in a
      sequencing-negative patient.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of CHD7 mutations are predicted to be loss of function, likely leading to an aberrant mRNA targeted for degradation via nonsense-mediated decay. Therefore, haploinsufficiency for CHD7 is the most likely pathogenic mechanism underlying CHARGE syndrome.
    explanation: >-
      States the inference from the variant spectrum to haploinsufficiency, the
      mechanism this entry's initiating pathophysiology node asserts.
  - 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.
- name: Temporal bone CT
  description: >-
    Computed tomography of the temporal bone demonstrates the semicircular canal
    hypoplasia/aplasia, cochlear hypoplasia and Mondini malformation that are the
    most highly penetrant findings in CHD7 disorder — present in 98% of
    mutation-positive patients — which is why the pooled cohort review recommends
    it as a diagnostic tool and why hypoplastic semicircular canals are a major
    criterion in the Verloes scheme. Its practical value is greatest in a patient
    whose external features are equivocal.
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data strongly support the use of temporal bone CT as a diagnostic tool for evaluation of CHARGE patients, and confirm previous reports that inner ear malformations should be considered a diagnostic criterion.
    explanation: >-
      The review's explicit diagnostic recommendation, which is what this record
      captures.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These anomalies include semicircular canal hypoplasia/aplasia, cochlear hypoplasia, and Mondini malformation
    explanation: >-
      Enumerates the specific temporal-bone findings the scan is looking for.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Revised diagnostic criteria by Verloes include ocular coloboma, choanal atresia/stenosis and hypoplasia of the semicircular canals as major criteria
    explanation: >-
      Supports the statement that semicircular canal hypoplasia is a major
      Verloes criterion.
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: NCIT:C15747
      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: NCIT:C15747
      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: NCIT:C157806
      label: Cardiac Surgery
  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: NCIT:C15240
      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.
differential_diagnoses:
- name: DiGeorge syndrome (22q11.2 deletion syndrome)
  disease_term:
    preferred_term: 22q11.2 deletion syndrome
    term:
      id: MONDO:0008564
      label: DiGeorge syndrome
  description: >-
    The most important differential, and the one that matters most to this
    entry's immune section. The two disorders share genital hypoplasia, cleft
    palate, congenital heart disease, thymic hypoplasia with T-cell deficiency,
    and early-life hypocalcemia, and CHD7 variants have been found in patients
    initially diagnosed as 22q11.2 deletion syndrome. CHARGE syndrome is
    distinguished by ocular coloboma, choanal atresia and the distinctive inner-
    and outer-ear anomalies. Immunologically the two separate on degree rather
    than kind: persistent lymphopenia and hypocalcemia are commoner in 22q11.2
    deletion, and T-cell lymphopenia with specific antibody deficiency is
    characteristic there but not in CHARGE syndrome.
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many of these features, including genital hypoplasia, cleft palate, and heart defects, are shared by other multiple anomaly syndromes such as 22q11.2 deletion
    explanation: >-
      Documents the shared features that make 22q11.2 deletion syndrome the
      principal differential.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      however, CHARGE syndrome is considered unique in its combination of these features with distinctive inner and outer ear defects and optic colobomas.
    explanation: >-
      States the features that discriminate CHARGE syndrome from the shared
      differential.
  - reference: PMID:26563674
    reference_title: The Immune Phenotype of Patients with CHARGE Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion.
    explanation: >-
      The head-to-head immunological comparison that supports separating the two
      disorders by degree of immune involvement.
- name: Kallmann syndrome
  disease_term:
    preferred_term: Kallmann syndrome
    term:
      id: MONDO:0018800
      label: Kallmann syndrome
  description: >-
    Kallmann syndrome shares the olfactory-placode mechanism with CHARGE
    syndrome — anosmia with hypogonadotropic hypogonadism from failed GnRH-neuron
    migration — and CHD7 variants have been reported in patients diagnosed with
    it. A patient presenting as Kallmann syndrome without a typical molecular
    finding should be examined for the ocular, choanal and inner-ear features of
    CHARGE syndrome.
  evidence:
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHD7 mutations have also been reported in patients diagnosed with conditions that have significant clinical overlap with CHARGE, including Kallmann
    explanation: >-
      Documents CHD7 variants in patients carrying a Kallmann syndrome
      diagnosis, which is what makes it a differential.
  - reference: PMID:20186815
    reference_title: "Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings imply that patients presenting with features of these syndromes, but lacking typical molecular findings, should be examined for clinical signs of CHARGE syndrome and tested for CHD7 mutations.
    explanation: >-
      The review's explicit recommendation, which is the practical content of
      this differential record.
discussions:
- discussion_id: charge_immunodeficiency_prevalence
  kind: KNOWLEDGE_GAP
  prompt: >-
    How common is a clinically meaningful immune defect in CHARGE syndrome, and
    which patients warrant immune evaluation?
  rationale: >-
    CHARGE syndrome is listed among the inborn errors of immunity, but the two
    strongest lines of evidence in this entry do not agree on how much immune
    disease there is. The pooled phenotype review calls immunological problems a
    rare feature, reported in too few patients to enter its statistical analysis,
    while cataloguing thymic aplasia/hypoplasia, IgG2 subclass deficiency,
    T-cell lymphopenia and, in rare patients, severe combined immunodeficiency.
    The only prospective study, 21 CHD7-genotyped patients, found an identifiable
    immune defect in just two of them despite recurrent ear and chest infections
    in the cohort — yet also recorded persistent lymphopenia in 30% during the
    first 72 months of life. A dedicated review concludes outright that the
    prevalence remains unclear.

    The gap is not merely bookkeeping. It determines whether immune screening
    should be routine at diagnosis or reserved for patients with an infection
    phenotype, and the answer is consequential in both directions: SCID in
    CHARGE syndrome is fatal without immune reconstitution, so missing it is
    costly, while the recurrent sinopulmonary infections that would trigger
    screening are readily explained by palatal, airway and aspiration factors
    that have nothing to do with immunity. Until it is closed, this entry
    deliberately assigns VERY_RARE bands to the immune phenotypes and types the
    infection edge as indirect.
  attaches_to:
  - pathophysiology#Impaired thymic development and T-cell output
  - phenotypes#T-cell lymphopenia
  - phenotypes#Recurrent infections
  proposed_experiments:
  - experiment_id: charge_prospective_immune_cohort
    name: Adequately powered prospective immune phenotyping of a genotyped CHARGE cohort
    description: >-
      Measure lymphocyte subsets, naive T cells and recent thymic emigrants,
      B-cell memory phenotype, immunoglobulins and protein/polysaccharide vaccine
      responses at fixed ages in a multicentre CHD7-genotyped cohort large enough
      to estimate the prevalence of each immunophenotype with useful precision,
      and follow the early-life lymphopenia to determine what fraction resolves.
  - experiment_id: charge_infection_attribution_study
    name: Attribution of recurrent sinopulmonary infection in CHARGE syndrome
    description: >-
      In patients with recurrent sinopulmonary infection, jointly assess immune
      function and the competing anatomic explanations — palatal competence,
      eustachian tube function, aspiration on swallow study, and airway patency —
      to establish what fraction of the infection burden is attributable to
      immune deficiency rather than to structural causes.

📚

References & Deep Research

References

1

PMID:20301296

CHD7 Disorder.

No top-level findings curated for this source.

Deep Research

1

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

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)

“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)
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)
Digenic/oligogenic inheritance hypothesis (2024): CHD7+SMCHD1 co-inheritance proposed to underlie intrafamilial variability (hypogonadotropic hypogonadism / CHARGE-overlap). (wang2024digenicchd7and pages 1-2)
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

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(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.
(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.
(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.
(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.
(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.
(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.
(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

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Classifications

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

CHARGE Syndrome — Comprehensive Disease Characteristics Report

1. Disease Information

1.1 Overview (current understanding)

1.2 Key identifiers and cross-references

1.3 Evidence type note

2. Etiology

2.1 Primary causes

2.2 Risk factors

2.3 Protective factors

2.4 Gene–gene / oligogenic interactions (emerging)

3. Phenotypes

3.1 Core phenotype spectrum (with frequencies)

3.2 Phenotype characteristics

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

4. Genetic / Molecular Information

4.1 Causal gene(s)

4.2 Pathogenic variant spectrum (human)

4.3 Inheritance, penetrance, expressivity, mosaicism

4.4 Modifier genes / oligogenicity

4.5 Epigenetics / episignatures (emerging)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 CHD7 function and upstream mechanism

6.2 Neural crest dysfunction (neurocristopathy framework)

6.3 Inner ear / hair cell differentiation mechanisms

6.4 p53 pathway contribution (mouse genetics)

6.5 Cerebellar developmental defects and modifier pathways

6.6 Multi-omics (zebrafish; emerging target discovery)

6.7 Suggested ontology terms for mechanisms

7. Anatomical Structures Affected

7.1 Organ and system level (primary)

7.2 Suggested UBERON terms (examples)

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance and counseling-relevant points

10. Diagnostics

10.1 Clinical criteria

10.2 Genetic testing strategy

10.3 Imaging and functional tests

10.4 Differential diagnosis (examples)

10.5 Emerging molecular diagnostics

11. Outcomes / Prognosis

11.1 Cardiac burden and mortality (recent quantitative evidence)

11.2 Neurodevelopment and QoL

12. Treatment

12.1 Multidisciplinary care (real-world implementation)

12.2 Cardiac treatment

12.3 Airway and feeding support

12.4 Hearing interventions

12.5 Vision and developmental therapies

12.6 MAXO suggestions (examples for KB annotation)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms and Experimental Models

15.1 Mouse models

15.2 Zebrafish models

15.3 Human iPSC / organoid models

2023–2024 Highlights (recent developments prioritized)

Key URLs (from retrieved sources)

Limitations of this tool-based synthesis