Medical Policy

Policy Num:     11.003.083
Policy Name:    Genetic Testing for CHARGE Syndrome
Policy ID:          [11.003.083]  [Ac / B / M+ / P+]  [2.04.106]

Last Review:      March 12, 2025
Next Review:      March 20, 2026
 

Related Policies: None

Genetic Testing for CHARGE Syndrome

SUMMARY

Description

CHARGE syndrome is a rare genetic condition associated with multiple congenital anomalies. In many individuals, the diagnosis can be made based on clinical findings. However, the phenotype of the disease is highly variable, and some patients do not fulfill the criteria for a definitive diagnosis by clinical findings. Sequence analysis of the CHD7 gene detects variants in most individuals with CHARGE syndrome.

Summary of Evidence

For individuals who have signs and/or symptoms of CHARGE syndrome who receive genetic testing for variants in the CHD7 gene, the evidence includes case series. Relevant outcomes are overall survival, test accuracy and validity, symptoms, morbid events, functional outcomes, quality of life, and resource utilization. Although the clinical sensitivity of CHD7 variant testing cannot be specifically defined, over 90% of patients who fulfill the Blake or Verloes criteria for CHARGE syndrome have a CHD7 variant. A definitive diagnosis may end the need for additional testing in the etiologic workup and direct patient care according to established clinical management guidelines for CHARGE syndrome, including referrals to appropriate specialists, treatment of manifestations, prevention of secondary complications, and surveillance. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether genetic testing improves the net health outcome for individuals with suspected CHARGE syndrome.

POLICY STATEMENTS

Genetic testing for CHARGE syndrome may be considered medically necessary to confirm a diagnosis in a patient with signs/symptoms of CHARGE syndrome when a definitive diagnosis cannot be made with clinical criteria (see Policy Guidelines section).

Genetic testing for CHARGE syndrome is considered investigational in all other situations.

POLICY GUIDELINES

A diagnosis of definitive CHARGE syndrome can be made clinically in individuals with all 4 major characteristics, or 3 major and 3 minor characteristics (Lalani et al [2012]). In individuals without the classical clinical criteria to diagnose CHARGE, in those with a milder phenotype, and/or in those with features that overlap with and cannot be distinguished from other syndromes, genetic testing may provide a definitive diagnosis.

Major characteristics include ocular coloboma, choanal atresia or stenosis, cranial nerve abnormality, and ear anomalies/deafness.

Minor characteristics include genital hypoplasia, hypogonadotropic hypogonadism, developmental delays, cardiac malformations, short stature, cleft lip and/or cleft palate, tracheoesophageal fistula, and distinctive CHARGE facial appearance, consisting of a prominent forehead and a prominent nasal bridge. Other, less frequent manifestations include kidney malformations, immunodeficiency, various limb abnormalities, scoliosis, dental problems, omphalocele, brain malformations, attention-deficit/hyperactivity disorder, and various behavioral problems.

This policy does not address preconception (carrier) testing and prenatal (in utero) testing.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organisation, and the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

CHARGE Syndrome

CHARGE syndrome is a rare genetic condition caused by variants of the CHD7 gene on chromosome 8q12.1.^1, The letters of CHARGE syndrome correspond to clinical features: C = coloboma; H = heart defect; A = atresia choanae; R = retarded growth and development; G = genital hypoplasia; and E = ear anomalies/deafness.^2, A number of other malformations are also common in this condition. In particular, hypoplasia of the semicircular canals has emerged as a frequent and distinctive CHARGE malformation.

Newborns with CHARGE syndrome typically have several major congenital malformations that affect vision, hearing, cardiovascular function, growth, development, neurologic function, and overall well-being. Mortality is relatively high in neonates with bilateral choanal atresia, cyanotic cardiac malformations, central nervous system malformations, and/or tracheoesophageal fistula. In a 1998 series, the death rate was 20% in the first month of life and about 50% by 6 months of age.^3, A formal 2005 epidemiologic study in Canada concluded that those who survived infancy were likely to have long-term survival.^4, Morbidity is chronic and multisystemic. Cognitive outcomes are difficult to assess because both motor skills and language do not necessarily reflect intellect in this group. About 75% have some degree of intellectual disability. Among the 25% with normal intelligence, many are well-educated and live independently as adults.^5, Morbidity can be reduced by early diagnosis and treatment.^2,

Clinical Diagnosis

Investigators have debated the relative importance of certain clinical signs. Consequently, the diagnostic criteria for CHARGE syndrome have been repeatedly revised.

The complete phenotypic spectrum of CHARGE syndrome was only revealed after identification of the causative gene in 2004, and the phenotypic spectrum of the disease is highly variable.^6,

A 2012 review^5, proposed that the diagnosis of CHARGE syndrome be considered definite if an individual has 4 major characteristics, or 3 major and 3 minor characteristics, criteria initially proposed by Blake (the Blake criteria),^7, and modified by Verloes.^8, Individuals with 1 or 2 major characteristics and several minor characteristics would be considered to have probable or possible CHARGE syndrome (see Table 1).

Table 1. Criteria for the Diagnosis of CHARGE Syndrome

CN: cranial nerve.

Other, less frequent manifestations include kidney malformations (25%), immunodeficiency, various limb abnormalities, scoliosis, dental problems, omphalocele, brain malformations, attention-deficit/hyperactivity disorder, and various behavioral problems. A systematic review and meta-analysis by Thomas et al (2022) investigated the prevalence of phenotypic characteristics and variability in CHARGE syndrome.^9, Prevalence estimates were highest for developmental delay (84%), intellectual disability (64%), aggressive behavior (48%), sleep difficulties (45%), and self-injurious behavior (44%). Meta-regression indicated significant associations between intellectual disability and choanal atresia or inner ear anomalies, and sleep difficulties and growth deficiency or gross motor difficulties.

The diagnosis of CHARGE syndrome is primarily clinical, based on use of the diagnostic criteria above.

External ear anomalies, abnormalities of cranial nerve function, semicircular canal hypoplasia, and gross motor delays seem to be consistent phenotypic manifestations in CHARGE syndrome, but one-third of patients with CHARGE syndrome will lack choanal atresia and/or ocular coloboma, with the most mildly affected showing only abnormal ears and a balance disturbance. Consequently, CHARGE syndrome can closely resemble several other genetic and teratogenic conditions, such as the 22q11.2 deletion syndrome, Kallmann syndrome, VACTERL association, Kabuki syndrome, renal coloboma syndrome, cat-eye syndrome, Joubert syndrome, branchio-oto-renal syndrome, and retinoic embryopathy. In 1 patient with velo-cardio-facial syndrome in whom the chromosome 22q11.2 microdeletion was ruled out, a CHD7 variant was documented.^10, Several patients with Kallmann syndrome were found to have CHD7 disease-associated variants.

In recognition of this expanding CHARGE phenotype, Bergman et al (2011) proposed a revision of cardinal and supporting features and suggested that CHD7 testing be offered to individuals on the milder end of the phenotypic spectrum.^6, Their algorithmic approach to diagnosis also incorporated temporal bone computed tomography scans as an important but not necessary component of the diagnostic workup. Although CHARGE syndrome is most often related to a sporadic disease-associated variant, some investigators (2014) have proposed that family history (any first-degree relative with at least 1 major feature of CHARGE) be incorporated into the clinical diagnosis of CHARGE syndrome as a major diagnostic criterion.^11,

Genetic Etiology

In 2014, certain variants of the CHD7 gene, which encodes chromodomain helicase DNA binding protein, were found to cause CHARGE syndrome. In mouse models, the CHD7 gene has been associated with neural crest migration.^12, Almost all pathogenic variants have proven to be single nucleotide variants, though on rare occasions, there may be a chromosomal translocation with a breakpoint within the CHD7 gene. Microdeletions, as would be detected with chromosome microarray analysis, are rare and probably occur in no more than 2% of individuals.

CHARGE syndrome does not have sex-linked expression and hence affects males and females equally.^2, Most instances of CHARGE syndrome are sporadic events in a family and appear to be caused by de novo CHD7 disease-associated variants. On rare occasions, CHARGE can be inherited as an autosomal dominant condition. Individuals with CHARGE who reproduce have a 50% chance of transmitting the variant to their offspring. Recurrence in siblings because of germline mosaicism has also been reported. The prevalence of CHARGE syndrome is estimated at 1 in 8500 live births.^4,

Genetic testing for variants of CHD7 is available from several commercial laboratories and is generally performed through Sanger sequence analysis. If no disease-associated variant is identified by Sanger sequencing, deletion and duplication analysis can be performed to identify large deletions.

Treatment

Management (medical or surgical) is based on presentation timing, features, and severity.^2, Extensive management guidelines have been developed for CHARGE syndrome.^7,6,13, They include periodic examinations and treatment by ophthalmology, otolaryngology, audiology, occupational therapy, speech therapy, gastroenterology, endocrinology, cardiology, neurology, developmental pediatrics, and genetics. Routine investigations would include choanal computed tomography, nasal endoscopy, brainstem auditory-evoked responses, temporal bone computed tomography, swallowing studies, renal ultrasound, gonadotropin testing, echocardiography, brain magnetic resonance imaging, growth hormone testing, and genetic counseling. Immunologic assessment should be considered, particularly if patients have recurrent lung or ear infections.^14, Based on evaluation of immune dysfunction in children with CHARGE syndrome, Wong et al (2015) recommended immunologic evaluation of patients with CHARGE syndrome who have recurrent infections.^15, Many of these resources might be provided in due course for a child with multiple congenital anomalies in the absence of an exact etiologic diagnosis. However, a number of specific investigations and therapies might not be considered unless CHARGE syndrome has been definitively diagnosed on a clinical basis or, for mildly affected individuals, as the result of genetic testing.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic tests for CHARGE syndrome are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIAs for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

RATIONALE

This evidence review was created in August 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through December 23, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Testing for Suspected CHARGE Syndrome

Clinical Context and Test Purpose

In many cases, the individual clinical manifestations of C = coloboma; H = heart defect; A = atresia choanae; R = retarded growth and development; G = genital hypoplasia; and E = ear anomalies/deafness (CHARGE) syndrome would present on their own and require management without a diagnosis of the larger syndrome. However, given the multisystemic nature of the disease and the well-established recommendations for surveillance for early complications, it is highly likely that outcomes are improved for individuals with CHARGE syndrome if a diagnosis is made.

The purpose of genetic testing for variants in the CHD7 gene in individuals who have suspected CHARGE syndrome is to inform a decision on whether to pursue additional management steps for CHARGE.

The following PICO was used to select literature to inform this review.

Populations

The population of interest includes individuals with signs and/or symptoms of CHARGE syndrome, but who do not meet the clinical definition of CHARGE syndrome.

Interventions

Most disease-causing variants in CHD7 associated with CHARGE syndrome are single nucleotide variants; therefore, Sanger sequencing is an appropriate first step in testing. If that testing is negative, deletion/duplication analysis of the CHD7 gene could be obtained. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

Comparators

The comparator of interest is standard clinical care without genetic testing, where decisions about medical therapy or evaluations are based on symptoms at the time of presentation. Trials of genetic testing or treatment strategies in this population were not found.

Outcomes

The general outcomes of interest are symptoms, morbid events, functional outcomes, quality of life, and resource utilization. Evaluating morbidity and mortality over the course of several years given the disease presentation in early childhood would be reasonable.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for CHARGE syndrome, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).

• Included a suitable reference standard (describe the reference standard).

• Patient/sample clinical characteristics were described.

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

The yield of genetic testing in individuals with either diagnosed or suspected CHARGE syndrome can vary depending on factors such as age or family history, and may depend on the clinical criteria used. In 2015, the Clinical Utility Gene Card reported that, in over 90% of the patients who fulfill the Blake or Verloes criteria, a disease-associated variant is found.^16,

In those with suspected CHARGE syndrome, a disease-associated variant is found in 30% to 60% of patients.^16, The proportion varies in individual studies, especially those with small sample sizes. For example, Lalani et al (2006) conducted genetic testing in 110 individuals with a clinical diagnosis of CHARGE syndrome and found disease-associated variants in CHD7 in 64 (58%) of study participants.^17, A study by Vuorela et al (2007) tested 74 patients with suspected CHARGE syndrome and found disease-associated variants in 30 (41%) of them.^18,

CHARGE syndrome sometimes can be excluded if a patient does not fulfill the clinical criteria and does not carry a disease-associated variant or deletion of CHD7. Some conditions that mimic CHARGE syndrome are 22q11 deletion syndrome, VACTERL association, chromosomal disorders (eg, deletions 3p12p21.2), disorders caused by teratogens (eg, maternal diabetes, isotretinoin [Accutane]), and Kallmann syndrome.^13,

The clinical specificity (proportion of patients who do not have the disease who have a negative test) can vary depending on factors such as age or family history. The clinical variability of CHARGE syndrome is considerable. If the diagnosis is based on the Blake criteria, some individuals with CHARGE will be missed. The clinical specificity is greater than 95% because less than 5% of the patients with a CHD7 disease-associated variant do not completely fulfill these criteria. However, it should be taken into account that the mild end of the phenotypic spectrum is not yet completely known.^13,

The penetrance is high, estimated to be 100%, but there is high clinical variability.^16,

The negative predictive value (probability of not developing the disease if the test is negative), assuming an increased risk based on family history, is 100% if the index case in the family has been tested. If the index case in the family has not been tested, it depends on the a priori chance that the index will be found to have a disease-associated variant, which is 60% to 90%.

There are no known genotype-phenotype correlations for specific CHD7 variants and CHARGE syndrome manifestations; therefore, the phenotype cannot be predicted from the genotype. For example, a study by Jongmans et al (2006) of 107 patients tested for CHD7 variants did not identify any obvious genotype-phenotype correlations.^1, Moccia et al (2018) performed whole-exome sequencing in patients who either tested negative for CHD7 mutations or did not have a previous genetic test. ^19, In this cohort, the study found that out of the 28 patients,15 (53%) had a disease-causing CHD7 mutation and 4 (14%) had a pathogenic variant in other genes (RERE, KMT2D, EP300, or PUF60) linked to other developmental disorders. This demonstrates a possible overlap of CHARGE syndrome with other rare syndromes.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

Most cases of CHARGE syndrome can be diagnosed clinically using established major and minor criteria (see Table 1). Scanning of the temporal bones often elicits abnormalities in the semicircular canals, which brings more specificity to the diagnosis. However, not all patients fulfill the clinical criteria for CHARGE syndrome and, based on clinical findings, may be considered to have possible or probable CHARGE syndrome. Mildly affected patients may only have 1 or a few of the features of CHARGE syndrome. Overlapping features with other syndromes may also make a clinical diagnosis challenging. Genetic testing may be useful in patients who do not have the classical CHARGE characteristics and who may be at risk for the long-term complications of CHARGE syndrome.^13,

While extensive management guidelines have been developed for CHARGE syndrome (see Background section),^5, no RCTs were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence can be developed based on clinical validity. In individuals with suspected but not confirmed CHARGE syndrome for whom genetic testing confirms a diagnosis, a definitive diagnosis will likely direct patient care according to established clinical management guidelines for CHARGE syndrome. This can include referrals to the proper specialists, treatment of manifestations, prevention of secondary complications, and surveillance.

Section Summary: Testing for Suspected CHARGE Syndrome

Studies of the testing yield for CHD7 variants have suggested that, in individuals with suspected CHARGE syndrome, approximately 30% to 60% will have an identified CHD7 variant. There is high clinical specificity. Genetic testing for CHARGE syndrome is very good for confirming a diagnosis, but a negative test does not rule out the disease. Most cases of CHARGE syndrome can be diagnosed through established clinical criteria. However, patients who do not meet clinical criteria due to variability in clinical presentation are likely to benefit from genetic testing for CHARGE syndrome. A definitive genetic diagnosis of CHARGE would direct patient care to established clinical management guidelines for CHARGE syndrome.

For individuals who have signs and/or symptoms of CHARGE syndrome who receive genetic testing for variants in the CHD7 gene, the evidence includes case series. Relevant outcomes are overall survival, test accuracy and validity, symptoms, morbid events, functional outcomes, quality of life, and resource utilization. Although the clinical sensitivity of testing CHD7 variant testing cannot be specifically defined, over 90% of patients who fulfill the Blake or Verloes criteria for CHARGE syndrome have a CHD7 variant. A definitive diagnosis may end the need for additional testing in the etiologic workup and direct patient care according to established clinical management guidelines for CHARGE syndrome, including referrals to appropriate specialists, treatment of manifestations, prevention of secondary complications, and surveillance. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Bergman et al (2011) proposed guidelines for CHD7 analysis and stated that, while the diagnosis of CHARGE syndrome remains primarily a clinical diagnosis (Table 1), molecular testing can confirm the diagnosis in mildly affected patients.^6,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in December 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

REFERENCES

1. Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. Apr 2006; 43(4): 306-14. PMID 16155193
2. Usman N, Sur M. CHARGE Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 6, 2023. PMID 32644625
3. Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: report of 47 cases and review. Am J Med Genet. Apr 13 1998; 76(5): 402-9. PMID 9556299
4. Issekutz KA, Graham JM, Prasad C, et al. An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study. Am J Med Genet A. Mar 15 2005; 133A(3): 309-17. PMID 15637722
5. Lalani SR, Hefner MA, Belmont JW, et al. CHARGE Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2012.
6. Bergman JE, Janssen N, Hoefsloot LH, et al. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet. May 2011; 48(5): 334-42. PMID 21378379
7. Blake KD, Davenport SL, Hall BD, et al. CHARGE association: an update and review for the primary pediatrician. Clin Pediatr (Phila). Mar 1998; 37(3): 159-73. PMID 9545604
8. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. Mar 15 2005; 133A(3): 306-8. PMID 15666308
9. Thomas AT, Waite J, Williams CA, et al. Phenotypic characteristics and variability in CHARGE syndrome: a PRISMA compliant systematic review and meta-analysis. J Neurodev Disord. Aug 31 2022; 14(1): 49. PMID 36045324
10. Jain S, Kim HG, Lacbawan F, et al. Unique phenotype in a patient with CHARGE syndrome. Int J Pediatr Endocrinol. Oct 13 2011; 2011(1): 11. PMID 21995344
11. Hughes SS, Welsh HI, Safina NP, et al. Family history and clefting as major criteria for CHARGE syndrome. Am J Med Genet A. Jan 2014; 164A(1): 48-53. PMID 24214489
12. Schulz Y, Wehner P, Opitz L, et al. CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance. Hum Genet. Aug 2014; 133(8): 997-1009. PMID 24728844
13. Blake K, van Ravenswaaij-Arts CM, Hoefsloot L, et al. Clinical utility gene card for: CHARGE syndrome. Eur J Hum Genet. Sep 2011; 19(9). PMID 21407266
14. Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: a review. J Paediatr Child Health. Jul 2014; 50(7): 504-11. PMID 24548020
15. Wong MT, Lambeck AJ, van der Burg M, et al. Immune Dysfunction in Children with CHARGE Syndrome: A Cross-Sectional Study. PLoS One. 2015; 10(11): e0142350. PMID 26544072
16. van Ravenswaaij-Arts CM, Blake K, Hoefsloot L, et al. Clinical utility gene card for: CHARGE syndrome - update 2015. Eur J Hum Genet. Nov 2015; 23(11). PMID 25689928
17. Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet. Feb 2006; 78(2): 303-14. PMID 16400610
18. Vuorela P, Ala-Mello S, Saloranta C, et al. Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions. Genet Med. Oct 2007; 9(10): 690-4. PMID 18073582
19. Moccia A, Srivastava A, Skidmore JM, et al. Genetic analysis of CHARGE syndrome identifies overlapping molecular biology. Genet Med. Sep 2018; 20(9): 1022-1029. PMID 29300383

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