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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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CHD7 Disorder

, MD, PhD, , MS, , MD, MRCP, FRCPC, and , MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: September 29, 2022.

Estimated reading time: 36 minutes

Summary

Clinical characteristics.

CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, 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. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. 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. Despite these complications, the life expectancy for many individuals can be normal.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators.

Surveillance: Requires routine follow up of manifestations identified in infancy/childhood, as well as ongoing monitoring of growth, development, educational progress, behavior, and possible endocrine issues.

Agents/circumstances to avoid: Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible.

Genetic counseling.

CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. In rare instances, an individual with CHD7 disorder inherits a pathogenic variant from a heterozygous parent. The risk to the sibs of the proband depends on the genetic status of the proband's parents: (1) If a parent of the proband has a CHD7 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%; (2) If the CHD7 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs of a proband is approximately 1%-2% because of the possibility of parental germline mosaicism. Although many individuals with CHD7 disorder are not able to reproduce, each child of an individual with CHD7 disorder has a 50% chance of inheriting the pathogenic variant. Once the CHD7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

GeneReview Scope

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of heterozygous CHD7 pathogenic variants has broadened to encompass CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The title of this chapter, CHD7 disorder, refers to the entire phenotypic spectrum that can be associated with heterozygous CHD7 pathogenic variants and emphasizes both the need to evaluate an individual found to have a CHD7 pathogenic variant for medically actionable manifestations in the entire phenotypic spectrum (regardless of clinical findings that prompted molecular genetic testing) and the importance of counseling families that the finding of a CHD7 pathogenic variant is not equivalent to a diagnosis of CHARGE syndrome.

Diagnosis

Suggestive Findings

CHD7 disorder should be suspected in individuals with combinations of the following findings and family history.

Clinical and imaging findings

  • Coloboma of the iris, retina, choroid, and/or disc, and/or anophthalmos or microphthalmos
  • Choanal atresia or stenosis: unilateral or bilateral, bony or membranous, confirmed by axial sections of non-enhanced axial CT scan
  • Cleft palate with or without cleft lip (Note: Choanal atresia is rare in the presence of a cleft palate.)
  • Cranial nerve dysfunction or anomaly
    • Cranial nerve I. Hyposmia or anosmia
    • Cranial nerve VII. Facial palsy (unilateral or bilateral)
    • Cranial nerve VIII. Sensorineural hearing loss and/or balance problems, hypoplasia or aplasia on imaging
    • Cranial nerve IX/X. Difficulty with sucking/swallowing and aspiration, gut motility problems
  • Ear malformations (most characteristic of CHD7 disorder)
    • Auricle. Short, wide ear with little or no lobe, "snipped-off" helix, prominent antihelix that is often discontinuous with tragus, triangular concha, decreased cartilage; often protruding and usually asymmetric (See Figure 1.)
    • Middle ear. Ossicular malformations (resulting in a typical wedge-shaped audiogram due to mixed sensorineural and conductive hearing loss)
    • Temporal bone abnormalities (most commonly determined by temporal bone CT scan). Mondini defect of the cochlea (cochlear hypoplasia), absent or hypoplastic semicircular canals
  • Tracheoesophageal fistula or esophageal atresia
  • Cardiovascular malformation, including conotruncal defects (e.g., tetralogy of Fallot), AV canal defects, and aortic arch anomalies [Corsten-Janssen & Scambler 2017]
  • Hypogonadotropic hypogonadism
    • Males at birth. Micropenis and cryptorchidism
    • Females at birth. Hypoplastic labia, abnormal or (rarely) absent uterus
    • Males and females. Delayed or absent puberty, often in combination with anosmia [Bergman et al 2011a]
  • Developmental delay / intellectual disability, delayed motor milestones, often secondary to sensory and balance deficits
  • Growth deficiency. Short stature, usually postnatal with or without growth hormone deficiency
  • Other clinical features
    • Face. Square-shaped with broad forehead, broad nasal bridge, prominent nasal columella, flattened malar area, facial palsy or other asymmetry, cleft lip, and small chin (gets larger and broader with age) (See Figure 2.)
    • Neck. Short and wide with sloping shoulders [O'Grady et al 2016] (See Figure 2.)
    • Hands. Typically, short, wide palm with hockey-stick crease, short fingers, and finger-like thumb (see Figure 3); polydactyly and reduction defects in a small percentage [Van de Laar et al 2007]
  • Brain MRI. Clivus hypoplasia [de Geus et al 2018], hypoplasia of cerebellar vermis [Donovan et al 2017]
Figure 1.

Figure 1.

Ears 1a. Clipped-off helix, prominent antihelix that extends to the outer helical rim, antihelix discontinuous with the antitragus; absent lobe

Figure 2.

Figure 2.

Face 2a. Female age 2.5 years; square face, round eye, straight nose with broad nasal root, unilateral facial palsy

Figure 3.

Figure 3.

Hand Typical CHARGE hand: square hand, short fingers, finger-like thumb, hockey-stick palmar crease

Family history is consistent with autosomal dominant inheritance. While the majority of individuals with CHD7 disorder are simplex cases (i.e., a single occurrence in a family resulting from a de novo CHD7 pathogenic variant), familial occurrences consistent with autosomal dominant inheritance and germline mosaicism have been reported [Bergman et al 2011b, Legendre et al 2017]. Note: Absence of a family history of features consistent with CHD7 disorder does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic (or likely pathogenic) variant in CHD7 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous CHD7 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (CHD7 single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with suggestive findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of CHD7 is performed to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications and/or chromosomal microarray (CMA) to detect whole-gene deletions.

A multigene panel (e.g., for developmental delay, coloboma, deafness, heart defects, Kallmann syndrome, normosmic hypogonadotropic hypogonadism) that includes CHD7 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

Because CHD7 disorder typically includes multiple congenital anomalies, it is also reasonable to pursue chromosomal microarray testing first, unless classic features of CHD7 disorder (e.g., the CHARGE syndrome phenotype) are apparent.

Alternatively, if exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with CHD7 disorder [Aref-Eshghi et al 2020, Levy et al 2021]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of CHD7 disorder but in whom no pathogenic variant in CHD7 has been identified via sequence analysis or genomic testing; or (2) suggestive findings of CHD7 disorder and a variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Table 1.

Molecular Genetic Testing Used in CHD7 Disorder

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method 3
CHD7 Sequence analysis 498%
Gene-targeted deletion/duplication analysis 5, 62%
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Percentages based on information from the locus-specific database CHD7​.org [Janssen et al 2012]

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Most deletions detected to date are whole-gene deletions that can be detected with gene-targeted deletion/duplication analysis; however, this method will not provide the size of a larger deletion that may include CHD7 and contiguous genes. Such deletions may also be identifiable by chromosomal microarray analysis [Vuorela et al 2007, Bergman et al 2008, Janssen et al 2012].

Clinical Characteristics

Clinical Description

In the premolecular era, the acronym CHARGE was proposed for the combination of the clinical features coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness) of unknown cause [Pagon et al 1981]. Clinical diagnostic criteria were refined for what became called CHARGE association [Blake et al 1998, Verloes 2005]. Following the discovery that heterozygous CHD7 variants and deletions cause CHARGE syndrome [Vissers et al 2004], molecular genetic testing of family members of probands with CHARGE syndrome expanded the phenotypic spectrum to include phenotypes that do not fulfill the previously proposed CHARGE syndrome clinical diagnostic criteria [Lalani et al 2006, Delahaye et al 2007, Jongmans et al 2009, Bergman et al 2011b, Hale et al 2016]. Thus, CHD7 disorder exhibits a high degree of clinical variability even among individuals in the same family and among individuals from different families with the same pathogenic variant [Jongmans et al 2008].

This section discusses only those reports in which a CHD7 pathogenic variant has been confirmed in affected individuals. To date reports of isolated manifestations of CHD7 disorder have been rare – many of which did not document a clinical workup sufficient to identify other features in the CHD7 disorder phenotypic spectrum. Thus, the percentages in Table 2 (based on persons with molecularly confirmed CHARGE syndrome [van Ravenswaaij-Arts & Martin 2017]) are likely to change over time as individuals with a CHD7 pathogenic variant ascertained through use of a multigene panel or genomic testing undergo a complete clinical evaluation (see Table 5).

Table 2.

Features of CHD7 Disorder in Individuals Ascertained for CHARGE Syndrome

Feature% of Persons w/FeatureComment
Ocular coloboma
(ranging from small retinal coloboma to anophthalmia)		80%Light sensitivity, refractive error, loss of upper visual field/central visual field, blindness, ↑ risk of retinal detachment
Choanal atresia/stenosis 45%
  • Interferes w/breathing & feeding
  • May require several surgeries to remain patent
  • Unilateral stenosis may be easily missed.
Cranial nerve dysfunction/
anomaly 		I: hyposmia or anosmia90%↓ or absent sense of smell predicts hypogonadotropic hypogonadism.
VI: facial palsy40%
  • Asymmetric face or lack of facial expression
  • Facial nerve often has an aberrant course, which correlates w/SNHL & can be damaged during cochlear implant surgery.
VIII: SNHL &/or vestibular dysfunction>95%
  • Hearing loss
  • Cochlear implant may not be successful.
IX/X: suck & swallow, abnormal GI motility60%-80%
  • Lack of coordination of suck & swallow, aspiration, &/or gastroesophageal reflux
  • Oral defensiveness
  • Digestive & constipation issues
Ear malformations Abnormal auricle90%
  • See description in Suggestive Findings, Characteristic ear malformations.
  • SNHL, esp high frequency
Ossicular malformations80%
  • Conductive hearing loss, which may fluctuate w/middle ear disease
  • Complex mixed hearing loss may present as a wedge-shaped audiogram.
Mondini defect90%SNHL, esp high frequency
Semicircular canal defect94%Affects balance & visual processing, → delayed motor development
Cleft lip and/or palate 25%-50%
Endocrine 1 Hypogonadotropic hypogonadism50%-70%
  • Micropenis, cryptorchidism
  • Small labia, uterine abnormality
  • Delayed or absent puberty & infertility
  • Often in combination w/anosmia
Growth deficiency70%May be due to growth hormone deficiency (in ~10%)
Hypothyroidism15%-20%
Developmental delay / Intellectual disability >90% / 60%DD due to sensory deficits (hearing, vision, balance), illness, & hospitalizations
Cardiovascular malformation 74%
  • Conotruncal/outflow defects are particularly common; isolated ASD, VSD, PDA, PFO also occur.
  • Vascular sling/aberrant aortic artery may result in choking.
Tracheoesophageal anomalies 20%Esophageal atresia w/or w/o fistula, laryngotracheomalacia, & gastroesophageal reflux, → feeding & breathing difficulties, aspiration (pneumonia), & sinusitis
Brain Clivus hypoplasia
Hypoplasia/J-shaped sella		95%
Other50%Microcephaly, ventriculomegaly, Dandy-Walker malformation, hypoplastic corpus callosum (30%), hypoplasia of cerebellar vermis (50%), brain stem, &/or frontal lobe
Seizures 30%Onset at any age, mostly general tonic-clonic convulsions as well as absence epilepsy
Renal anomalies 30%
  • Missing, hypoplastic, horseshoe, ectopic, or cystic kidney
  • Vesicoureteral reflux & hydronephrosis

ASD = atrial septal defect; DD = developmental delay; PDA = patent ductus arteriosus; PFO = patent foramen ovale; SNHL = sensorineural hearing loss; VSD = ventricular septal defect

Based on individuals with molecularly confirmed typical or partial CHARGE syndrome [van Ravenswaaij-Arts & Martin 2017]. Note: percentages in this table are highly ascertainment dependent (i.e., the reason for molecular genetic testing). With the increasing use of multigene panels and genomic testing, it is likely that more individuals with presentations atypical for classic CHARGE syndrome will be diagnosed with CHD7 disorder.

1.

Because the majority of individuals with a pathogenic CHD7 variant have a typical CHARGE syndrome or CHARGE syndrome-like phenotype, the clinical features described below are relevant for most individuals with CHD7 disorder. In contrast, isolated hypogonadotropic hypogonadism with or without anosmia due to a pathogenic CHD7 missense variant appears to be rare [Xu et al 2018].

Development

Motor delay is invariably present due to vestibular anomalies and presents as poor head control, five-point crawl, delayed motor milestones, and reduced fine motor skills.

Language delay is caused by hearing loss, vision loss, vestibular anomalies, hospitalizations and illness, and/or cognitive impairment.

Assessment of cognitive abilities is difficult because of the multiple sensory deficits (vision, hearing, balance, smell), and much of the delay observed in motor and speech/language abilities is secondary to these deficits. Nonetheless, intellectual outcome is within the normal range in 50% of the individuals with clinical features consistent with CHARGE syndrome [Vesseur et al 2016b].

Children with better walking skills and fewer medical problems exhibit better adaptive behavior than children with less mobility and more medical problems [Salem-Hartshorne & Jacob 2005].

Behavioral features often reported are attention-deficit/hyperactivity disorder, repetitive behavior, and obsessive-compulsive behaviors. Self-abuse is occasionally seen. An increased pain threshold may predispose children to behaviors that are incorrectly interpreted by others as aggressive [Hartshorne et al 2005].

Many adults with clinical features consistent with CHARGE syndrome live independently, including many who have college or even advanced degrees. However, the level of independence comprises a broad spectrum [Blake et al 2005, Hartshorne et al 2016], depending, for each individual, on the combination of clinical features, educational program designed to address specific needs, and resources available.

Other Features

Gastrointestinal problems are frequently seen, mainly GI-related motility issues such as gastroesophageal reflux disease, constipation, and abdominal pain. Feeding challenges often result in tube feeding and problems with aspiration.

Late-onset issues can include malrotation of intestines, intussusception, and choking due to mouth overstuffing [Hudson et al 2015, Blake & Hudson 2017].

Immunodeficiency due to absent thymus (rarely) or decreased number or function of T-cells may occur [Wong et al 2015b]. Recurrent upper airway infections are common.

Skeletal involvement can include craniosynostosis, vertebral anomalies, scoliosis (in the majority of affected individuals) [Doyle & Blake 2005], extra or missing ribs, absent long bones (rare), ectrodactyly, polydactyly, finger-like thumb, and (more commonly) brachydactyly [Van de Laar et al 2007].

Hypermobility and contractures can be part of the syndrome.

Neuromuscular problems are common in CHARGE syndrome, mostly hypotonia (often resulting in scoliosis) and abnormal shoulder girdle muscles [O'Grady et al 2016]. Proprioception is diminished and, when in combination with balance problems, often results in a preference for pressure-building postures (upside-down position, legs twisted around one another) [Brown 2005].

Dental problems may include overbite, hypodontia, and poor mineralization of teeth [Chetty et al 2020].

Life expectancy highly depends on the severity of manifestations, since the phenotypic spectrum of CHD7 disorder is substantial. Mortality can be high in the first few years, when severe birth defects (particularly complex heart defects) are present, and are often complicated by airway and feeding issues. Feeding difficulties are usually due to cranial nerve abnormalities and improve gradually.

Multiple complex surgeries, along with the breathing problems or difficulty with anesthesia reported in CHARGE syndrome [Blake et al 2009], increase the risks associated with procedures.

After the first two or three years, mortality (and certainly morbidity and medical fragility) remains increased, with parents reporting frequent illnesses, infections, and hospitalizations [Bergman et al 2010].

In childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration or choking [Corsten-Janssen et al 2016], respiratory issues including obstructive and central apnea, and possibly seizures.

A number of families have reported serious (and in some instances lethal) intestinal issues such as volvulus [Lai & Feng 2006] and intussusception.

Despite these complications, the life span for many individuals can be normal. Individuals with clinical features consistent with CHARGE syndrome in their 60s who are in good health have been observed.

Genotype-Phenotype Correlations

While no clear genotype-phenotype correlations exist for CHD7-related CHARGE syndrome [Legendre et al 2017], in general, but not as a rule, missense variants are associated with a less severe phenotype [Bergman et al 2012].

CHD7-related hypogonadotropic hypogonadism with or without anosmia is more likely to be due to missense variants than nonsense variants.

Prevalence

Because of the more widespread use of genomic testing, it is currently difficult to assess the prevalence of CHD7 disorder.

In the past, when the diagnosis of CHARGE syndrome was based on clinical features or gene-specific molecular testing, its estimated prevalence ranged from one in 15,000 newborns in the Netherlands [Janssen et al 2012] to one in 8,500 in Canada [Issekutz et al 2005].

Differential Diagnosis

Genetic disorders with multiple features overlapping those associated with CHD7 disorder are summarized in Table 3 and Table 4.

Table 3.

Genes to Consider in the Differential Diagnosis of CHD7 Disorder

GeneDisorderMOIClinical Features of the Differential Disorder
Overlapping w/CHD7 DisorderDistinguishing from CHD7 Disorder
≥34 genes Joubert syndrome AR
XL
Digenic		Bilateral chorioretinal coloboma, interstitial fibrosis of kidney → renal insufficiency, hepatic fibrosis, neonatal tachypnea, cerebellar vermis aplasia/hypoplasia, polydactyly"Molar tooth" sign on neuroimaging, characteristic radiologic features, absence of dysmorphic features of CHD7 disorder
EYA1
SIX1
SIX5 		Branchiootorenal spectrum disorder ADDeafness, external ear deformity, lateral semicircular canal hypoplasia, renal malformationBranchial fistulae & cysts, absence of dysmorphic features of CHD7 disorder
KDM6A
KMT2D 		Kabuki syndrome AD
XL		Cleft palate, heart defects, occasional coloboma, hearing loss, growth restrictionTypical facial features: long palpebral fissures w/eversion of lateral 3rd of lower eyelids, sparse eyebrows, large prominent ears (all more prominent w/age), prominent fingertip pads
PAX2 PAX2 disorder
(renal coloboma syndrome)		ADRetinal/optic nerve colobomas; kidney abnormalities; occasional hearing lossAbsence of multiple congenital anomalies
BMP4 Syndromic microphthalmia 6
(OMIM 607932)		ADColobomas, external ear anomalies, hearing loss, congenital heart defect, genital hypoplasia, cleft lip/palate, pituitary problems, renal anomaliesAnophthalmia is more common than in CHD7 disorder.
EFTUD2 Mandibulofacial dysostosis w/microcephaly ADChoanal atresia, external ear anomalies, hearing loss, congenital heart defect, growth deficiency, cleft lip/palate, esophageal atresiaTypical craniofacial features due to malar hypoplasia
FGFR1 FGFR1 Kallmann syndrome 1
(OMIM 147950)		ADColobomas, hearing loss, genital hypoplasia, ↓ or absent sense of smell, cleft lip/palate 1
GLI2 Culler-Jones syndrome
(OMIM 615849)		ADExternal ear anomalies, hearing loss, cleft lip/palate, growth deficiency, pituitary problems, renal anomaliesMidface hypoplasia & postaxial polydactyly
GLI3 Pallister-Hall syndrome ADColobomas, external ear anomalies, congenital heart defect, growth deficiency, genital hypoplasia, cleft lip/palate, pituitary problems, renal anomaliesHypothalamic hamartomas, central polydactyly
JAG1
NOTCH2 		Alagille syndrome ADCongenital heart defect, renal anomaliesCholestasis, butterfly vertebrae, posterior embryotoxon, triangular-shaped face
MYCN Feingold syndrome 1 ADHearing loss, heart defect, esophageal atresia, renal anomaliesBrachymesophalangy
OTX2 Syndromic microphthalmia 5
(OMIM 610125)		ADColobomas, growth deficiency, genital hypoplasia, cleft palate, pituitary problemsAnophthalmia more common than in CHD7 disorder; corpus callosum agenesis; may appear as otocephaly-dysgnathia complex
POLR1C
POLR1D
TCOF1 		Treacher Collins syndrome AD
AR		Choanal atresia, external ear anomalies, hearing loss, cleft palateTypical craniofacial features due to malar hypoplasia; normal intellect
SOX2 SOX2 disorder ADColobomas, hearing loss, congenital heart defect, growth deficiency, genital hypoplasia, esophageal atresia, pituitary problemsAnophthalmia is more common than in CHD7 disorder.
TBX22 Abruzzo-Erickson syndrome
(OMIM 302905)		XLColobomas, hearing loss, growth deficiency, cleft palateRadioulnar synostosis, large & protruding ears
ZEB2 Mowat-Wilson syndrome ADExternal ear anomalies, congenital heart defect, growth deficiency, genital hypoplasia, cleft palate, renal anomaliesDistinctive facial features (incl uplifted ear lobes), Hirschsprung disease, hypospadias in males
1.

If hyposmia or anosmia is the presenting feature, Kallmann syndrome must be considered, especially Kallmann syndrome caused by pathogenic variants in FGFR1 (pathogenic variants in 16 genes, including CHD7, are known to be associated with Kallmann syndrome).

Table 4 lists the chromosomal syndromes that overlap significantly with CHD7 disorder. Many other chromosome deletions have at least a few features that overlap with CHD7 disorder.

Table 4.

Chromosomal Syndromes that Significantly Overlap with CHD7 Disorder

Genetic MechanismDisorderClinical Features of Differential Disorder
Overlapping w/CHD7 DisorderDistinguishing from CHD7 Disorder
Deletion 22q11.2 22q11.2 deletion syndrome Congenital heart disease, palatal abnormalities, 1 learning difficulties, immune deficiency, significant feeding problems, renal anomalies, hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, skeletal abnormalitiesAbnormalities of semicircular canals rarely seen; ocular colobomas rare; feeding difficulties typically end sooner than in children w/CHD7 disorder; dysmorphic features (face, ears, hands) are different
Inv dup 22q11Cat-eye syndrome (OMIM 115470)Coloboma of iris, anal atresia w/fistula, preauricular tags &/or pits, frequent occurrence of heart & renal malformationsAbsence of dysmorphic & otologic features of CHD7 disorder

VACTERL association (OMIM 192350). CHD7 disorder and VACTERL association can both include vertebral anomalies, cardiac anomalies, tracheoesophageal fistula (or esophageal atresia), renal anomalies, and limb anomalies. Anal atresia, common in VACTERL, is rare in CHD7 disorder. Typical CHD7 disorder findings of temporal bone anomaly, choanal atresia, characteristic ear findings (outer and inner), and cranial nerve anomalies are rarely reported in VACTERL. The genetic basis of VACTERL association is unknown.

CHARGE syndrome-like features secondary to prenatal teratogen exposure. Exposure to Accutane™ at any time during the first trimester may result in malformations associated with abnormal migration of neural crest cells. These may include microtia/anotia, micrognathia, cleft palate, conotruncal heart defects, and aortic-arch abnormalities, thymic defects, retinal or optic nerve abnormalities, and central nervous system malformations [Lammer et al 1985].

Exposure to antithyroid agents, especially methimazole, has been reported to result in a variety of congenital anomalies including choanal and esophageal atresia, iris and retinal coloboma, hearing loss, and delayed neurodevelopment. The risk of birth defects in fetuses exposed during the first trimester of pregnancy has been estimated at 2%-3% [Andersen et al 2013, Komoike et al 2013, Andersen et al 2017].

Management

The management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators. Published CHARGE syndrome guidelines (including one-page summaries) for clinical management [Trider et al 2017] (see Figure 4) and cranial imaging guidelines [de Geus et al 2017] (full text) are available.

Figure 4.

Figure 4.

CHARGE syndrome checklist Reproduced from Trider et al [2017]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with CHD7 disorder, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in an Individual with a CHD7 Disorder

System/ConcernEvaluationComment
Constitutional Measurement of weight, length/height, & head circumferenceTo assess for growth failure &/or obesity
Eyes Ophthalmology eval
  • Best corrected visual acuity; assess for refractive error, possible amblyopia
  • Assess for iris coloboma, photophobia, & possible corneal exposure due to VIIth nerve palsy.
  • Dilated fundus exam for chorioretinal coloboma, optic nerve coloboma, retinal detachment
  • Functional visual assessment incl visual fields in older individuals
Hearing /
Vestibular
involvement 		Audiology eval 1Assess for conductive & sensorineural hearing impairment.
Clinical assessment for balance issues
MRI/CT temporal boneEvaluate semicircular canals, cochlea, & cranial nerves (see Figure 5 for details).
Nose/Throat Clinical eval for choanal atresia/stenosis
  • Suggestive findings in neonates & infants incl apnea & unilateral nasal discharge
  • Referral to otolaryngologist
Assessment for tracheoesophageal fistulaIf:
  • Aspiration pneumonia
  • Coughing or choking w/feeding
  • Infant has a full, round abdomen
Tonsils & adenoidsIf evidence of obstructive apnea
Mouth Clinical eval for cleft palate, submucous cleft palate, & velopharyngeal insufficiencyConsider referral to craniofacial team.
Baseline eval by dentist, typically from age ~3 yrs (or earlier in those w/cleft palate)
  • Abnormal shape & # of teeth 2
  • Complications due to craniofacial abnormalities &/or bruxism
Cardiovascular EKG & echocardiogram 3Referral to cardiologist as indicated
Respiratory Consider polysomnogram.To assess for sleep apnea
Consider pulmonary function tests.In older individuals w/severe scoliosis who may have restrictive lung disease
Gastrointestinal/
Feeding 		Assess for signs & symptoms of dysphagia & aspiration.Consider VFSS & nutrition/feeding team eval for those w/suggestive features or aspiration & pneumonia.
Assess for history of GERD & GI motility issues. 4Referral to GI specialist as indicated
Genitourinary Males: assess for micropenis &/or cryptorchidism.
  • Cryptorchidism: referral to urologist
  • Micropenis: see Endocrine in this table
Females: consider pelvic ultrasound examination.
  • To assess for uterine & ovarian anomalies
  • Note that ability of US exam &/or MRI to detect uterine anomalies in prepubertal girls is limited.
Musculoskeletal Clinical assessment for scoliosis
  • Consider spine radiographs as a baseline.
  • Consider referral to orthopedist.
Neurologic Clinical assessment for cranial nerve abnormalities
  • To incl assessment for swallowing dysfunction (See Gastrointestinal/Feeding in this table.)
  • If present, consider CT &/or MRI imaging 5
Cranial MRI & EEG if seizures are suspectedConsider referral to neurologist.
Development Developmental assessment
  • A team approach is necessary.
  • Incl motor, speech/language eval, general cognitive abilities, educational needs, &/or vocational opportunities.
  • Incl appropriate testing to assess cognitive function in those w/sensory deficits.
  • Abilities may be underestimated, especially in early yrs.
  • Evaluate for early intervention/special education, referral to deaf-blind programs when appropriate.
Psychiatric/
Behavioral 		Consider neuropsychiatric eval.
  • Adapt testing environment as needed to ↑ patient comfort.
  • Screen for ADHD, anxiety, obsessive-compulsive symptomatology.
Endocrine
  • Males w/micropenis: consider HCG stimulation test, ideally before age 6 mos.
  • Males & females w/delayed or absent puberty: eval for hypogonadotropic hypogonadism 6
Anosmia may be indicative for GnRH dysfunction.
  • Measure calcium & vitamin D levels. 7
  • Thyroid function tests
  • Consider referral to endocrinologist.
Renal Renal US examTo assess for renal anomalies, hydronephrosis, & calcifications
Blood pressure measurementTo assess for hypertension
Immune Consider immunologic eval 8 & referral to immunologist.For those w/recurrent or unexplained infection
Genetic
counseling 		By genetics professionals 9To inform affected persons & their families re nature, MOI, & implications of CHD7 disorder to facilitate medical & personal decision making
Family support
& resources 		Assess need for:

ADHD = attention-deficit/hyperactivity disorder; GERD = gastroesophageal reflux disease; GnRH = gonadotropin-releasing hormone; HCG = human chorionic gonadotropin; MOI = mode of inheritance; US = ultrasound; VFSS = video fluoroscopic swallow study

1.

See Hereditary Hearing Loss and Deafness Overview for details about audiologic evaluations. Also perform audiology evaluation when there was a normal newborn hearing screen.

2.
3.

To assess for arrhythmias and structural heart defects including vascular anomalies [Corsten-Janssen et al 2013]

4.

Other issues may include malrotation, constipation, chronic abdominal pain, bloating, and late dumping syndrome [Morgan et al 2017].

5.
6.

May include measurement of serum concentration of luteinizing hormone, follicle-stimulating hormone, and sex hormones (total testosterone in males, estrogen in females). See also Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.

7.

In adolescents and adults

8.

May include immunoglobulin levels (IgG, IgM, IgA) and T and B cell subsets in case of a history of recurrent infections [Wong et al 2015a]

9.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Management of children with a CHD7 disorder requires coordinated multidisciplinary care (Table 6).

Table 6.

Treatment of Manifestations in Individuals with a CHD7 Disorder

Manifestation/ConcernTreatmentConsiderations/Other
Growth failure See Dysphagia / Inadequate nutrition n this table.
  • Nutrition optimization (team approach)
  • If poor linear growth remains, consider growth hormone stimulation test &/or growth hormone therapy.
Obesity Weight-bearing exercises & dietary interventionAdaptations in school physical education, which may also address sensory needs
Poor visual acuity /
Blindness 		Corrective lenses / standard treatmentCommunity vision services through early intervention or school district; deaf-blind services where available
Corneal exposure Lubricating eye drops
Photophobia Tinted glasses or sun hat
Hearing impairment /
Deafness 		Treatment of SNHL & conductive hearing loss depend on degree of hearing impairment. 1
  • Start hearing habilitation (auditory & speech training, sign language) as soon as possible.
  • Community hearing services through early intervention or school district
Cochlear implantCT of bony landmarks & MRI of vestibular & facial nerves as part of pre-cochlear implant assessment 2, 3
BAHAIf middle ear is disrupted due to abnormalities of middle ear bones but cochlear nerve is intact
FM systemFor those who are school age
Chronic otitis media PET placementMay need to be replaced multiple times until teenage yrs.
Poor balance Adjustments to classroom or therapy setting (incl supine position) to allow for better truncal supportFrequent rest periods may be needed; consult w/OT, PT, & orientation & mobility services as needed
Karate & other programs that promote good balance
Consideration of myofascial releaseMay improve posture & flexibility
Communication Depends on degree of hearing & vision lossRefer to community deaf-blind services & state deaf-blind projects as soon as possible after birth.
Choanal atresia/
stenosis 		Infants: airway bypass by tracheotomy or endotracheal intubationMultiple surgeries/dilatations are often required to maintain patency of nasal airway.
Surgical correction
Esophageal atresia / TEF Standard surgical repair
Cleft palate Surgical correctionIdeally by craniofacial team
Dental decay /
Hypodontia 		May require sedated dental rehabSee Agents/Circumstances to Avoid.
Excessive secretions Standard medication, incl glycopyrrolate or Botox®
Congenital heart defect / Arrhythmia / POTS Treatment per cardiologist
Obstructive sleep apnea Consider tonsillectomy & adenoidectomy.CPAP is sometimes helpful.
Sleep disturbance Sleep hygiene; consider trial of melatonin.Consider referral to sleep disorder specialist.
Dysphagia /
Inadequate nutrition 		Nasogastric or gastrostomy tube may be required.Low threshold for clinical feeding eval &/or radiographic swallowing study when clinical signs or symptoms of dysphagia are present
GERD: standard treatment
Constipation Medication treatment, incl stimulant & osmotic laxatives
  • Simple measures (e.g., ↑ fluid uptake) are often unsuccessful.
  • Referral to gastroenterologist as needed
Cryptorchidism Standard treatment per urologist
Severe scoliosis Standard treatment per orthopedistMay have skeletal &/or neuromuscular causes
Seizure disorder Standard treatment per neurologistStandard ASMs are usually effective.
DD/ID See Developmental Delay / Intellectual Disability Management Issues.Utilize deafblind services where available.
Behavioral issues For OCD, PDD: mindfulness treatment (psychologist & deafblind specialist), then consider medications
  • Behavior therapy combined w/stress reduction may be helpful.
  • Behavior issues may be exacerbated by sensory processing issues.
For ADHD: establish appropriate method of communication & provide adequate stimulation for exploration in safe environment.This may be more helpful than medication.
Hypogonadotropic hypogonadism Standard treatment per endocrinologistTypically, HRT to induce puberty & for general health reasons incl prevention of osteoporosis; see Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.
Hypothyroidism Standard treatment per endocrinologist
Renal malformation Standard therapy per urologist
Hypertension Standard therapy
Recurrent infections Standard therapy per immunologistRevaccination may be required.
Family needs Ensure appropriate social work involvement to connect families w/local resources, respite, & support.Ongoing assessment of need for home nursing
Care coordination to manage multiple subspecialty appointments, equipment, medications, & suppliesConsider involvement in adaptive sports or Special Olympics.

ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; BAHA = bone-anchored hearing aid; CPAP = continuous positive airway pressure; DD = developmental delay; HRT = hormone replacement treatment; ID = intellectual disability; OCD = obsessive-compulsive disorder; OT = occupational therapist; PDD = pervasive developmental disorders; PET = pressure-equalizing tube; POTS = postural orthostatic tachycardia; PT = physical therapist; SNHL = sensorineural hearing loss; TEF = tracheoesophageal fistula

1.

See Hereditary Hearing Loss and Deafness Overview for details about treatment options.

2.

Evaluation of bony landmarks and the structure and pathways of the vestibular and facial nerves (which can be abnormal) is important in surgical planning [Vesseur et al 2016c]. See also Figure 5.

3.

In some individuals, an aberrant course of the facial nerve may be a contraindication for cochlear implant [Vesseur et al 2016a, Vesseur et al 2016c].

Figure 5.

Figure 5.

CT and MR Scanning in CHARGE Syndrome

Reproduced from de Geus et al [2017]

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services may be provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
  • State deaf-blind services:
    • In addition to the educational services in the US discussed above, state-level federally funded programs are mandated to provide services for individuals from birth to age 21 years with combined hearing and vision issues (nationaldb.org/). Of note, the designation "deaf-blind," used to qualify individuals with combined vision and hearing loss for these services, does not imply total hearing loss or total vision loss.
    • State deaf-blind services typically provide information and training to families, technical assistance to schools and early intervention programs, and assistance with IEPs and transitions.

Communication

A growing body of evidence indicates that normal language development can occur if hearing habilitation is started prior to age six months for hearing-impaired children, whether or not they are visually impaired. (See Hereditary Hearing Loss and Deafness Overview, which provides details about management.)

Depending on the degrees of hearing and vision loss, communication may start with touch cues, followed by object cues and proceeding to auditory/oral and/or sign language. Communication training initiated by age three years is critical to the eventual development of symbolic communication [Thelin & Fussner 2005]. Use of all available means of communication (visual, oral, touch, and incorporating gestures, sign and oral languages) is advisable early on. Most affected children are able to migrate to oral communication as they get older, even if they start with sign and/or total communication.

Surveillance

Table 7.

Recommended Surveillance for Individuals with CHD7 Disorder

System/ConcernEvaluationFrequency
Constitutional Measurement of length/height & weight for evidence of linear growth failure or obesityAt each visit
Eyes Ophthalmologic exam for changes in best corrected visual acuity, cataract, &/or retinal detachment (in those w/chorioretinal coloboma)Every 6 mos or as clinically indicated
Eval by deaf-blind specialist to assess functional visionAs clinically indicated
Ears/Nose/
Throat 		Audiologic eval to determine type & extent of hearing loss & success w/hearing habilitationAnnually or as clinically indicated
Assessment for chronic ear infections &/or effusionsAt each visit through puberty
Mouth Dental evalAt least every 6 mos after age 3 yrs
Cardiovascular EKG & Holter monitor if suspicion of arrhythmia (esp in those w/complex cardiac anomaly)Starting in late childhood/early adolescence, as clinically indicated
Blood pressureAt each visit
Clinical assessment for signs & symptoms of POTSAt each visit in adolescents & adults
Respiratory Clinical assessment for sleep disturbance &/or obstructive sleep apnea 1At each visit
Gastrointestinal/
Feeding 		Assess for signs & symptoms of feeding anomalies incl dysphagia 2, reflux, constipation, & abdominal pain / abdominal migraine.At each visit; note that new feeding issues can arise in adolescents & adults.
Musculoskeletal Clinical &/or radiographic eval for scoliosisAt each visit until growth is complete (can be into early 20s)
Neurologic Assessment for symptoms of seizuresAt each visit
Development Assessment of gross motor skills, fine motor skills, & communication abilities; school assessment for learning challenges
Endocrine Assessment of secondary sexual characteristics for evidence of delayed puberty or pubertal arrest due to hypogonadotropic hypogonadismBetween ages ~7 & 17 yrs
For evidence of hypothyroidismBased on symptoms
DXA scan for bone mineral densityPeriodically starting in adolescence 3
Psychiatric/
Behavioral 		Assessment of overall behavior, incl self-regulation, impulse control, anxiety, obsessions, compulsion, & angerAt each visit after infancy

DXA = dual-energy x-ray absorptiometry; EKG = electrocardiogram; POTS = postural orthostatic tachycardia

1.

Including clinical evaluation of tonsil hypertrophy in those with retained tonsils

2.

With low threshold to perform swallowing study, even in adolescents and adults

3.

Particularly those with hypogonadotropic hypogonadism or those undergoing routine hormone replacement therapy

Agents/Circumstances to Avoid

Anesthesia. Airway problems associated with anesthesia are common in individuals with CHARGE syndrome. They may be attributed to choanal atresia, cleft lip and palate, and other upper-airway structural anomalies and associated cranial nerve abnormalities. Soft cartilage and resultant floppy trachea add to potential anesthesia risk. Neurogenic incoordination of swallow and closure of the epiglottis may complicate the postoperative course, especially with repeated general anesthetics [Blake et al 2009]. Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible [de Geus et al 2017].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband

  • Many individuals with CHD7 disorder are not able to reproduce.
  • Each child of an individual with CHD7 disorder has a 50% chance of inheriting the pathogenic variant.
  • The severity of CHD7 disorder in the proband does not predict the severity of the disorder in heterozygous offspring (a high degree of clinical variability is observed in CHD7 disorder; see Clinical Characteristics).

Other family members. The risk to other family members depends on the genetic status of the proband's parents; if a parent has the CHD7 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

For a review of genetic counseling issues in families in which a child has been diagnosed with CHARGE syndrome, see Hefner & Fassi [2017].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and to young adults who are mildly affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHD7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CHD7 Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CHD7 8q12​.2 Chromodomain-helicase-DNA-binding protein 7 CHD7 database CHD7 CHD7

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CHD7 Disorder (View All in OMIM)

214800CHARGE SYNDROME
608892CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 7; CHD7
612370HYPOGONADOTROPIC HYPOGONADISM 5 WITH OR WITHOUT ANOSMIA; HH5

Molecular Pathogenesis

CHD7 encodes a chromodomain protein that is involved in the ATP-dependent remodeling of chromatin. CHD7 binds to more than 10,000 sites in the mammalian genome and interacts with dozens of other genes. Features of CHD7-related disorders may be due to loss of ribosomal biogenesis or other mechanisms.

CHD7 functions in a multiprotein complex and uses the energy of ATP to remodel nucleosomes. CHD7 is considered an epigenetic regulator because it modifies the degree to which chromatin is "open" or "closed," making it more or less accessible, respectively, to other proteins that activate or repress gene expression. The broad variability in phenotypes observed in individuals with CHD7 disorder is not fully understood, but is likely related to its unique roles in specific cells and tissues at various times during development.

Mechanism of disease causation. Decreased function or loss of function of CHD7 leads to the clinical manifestations of CHD7 disorder.

Chapter Notes

Author History

John W Belmont, MD, PhD; Baylor College of Medicine (2006-2020)
Kim Blake, MD, MRCP, FRCPC (2020-present)
Sandra LH Davenport, MD, CM; Sensory Genetics/Neurodevelopment, Bloomington, Minnesota (2006-2020)
Meg Hefner, MS (2006-present)
Seema R Lalani, MD; Baylor College of Medicine (2006-2020)
Donna M Martin, MD, PhD (2020-present)
Conny M van Ravenswaaij-Arts, MD, PhD (2020-present)

Revision History

  • 29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis, Option 2)
  • 17 September 2020 (bp) Comprehensive update posted live
  • 2 February 2012 (me) Comprehensive update posted live
  • 22 September 2009 (me) Comprehensive update posted live
  • 6 June 2007 (cd) Revision: mutation scanning added
  • 2 October 2006 (me) Review posted live
  • 14 April 2005 (jwb) Original submission

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Suggested Reading

  • Hartshorne T, Hefner M, Davenport SLH, Thelin J. CHARGE Syndrome, 1 ed. Plural Publishing. 2011.
  • Issue devoted entirely to CHARGE syndrome. Am J Med Genet C Semin Med Genet. 2017;175(4)
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