CAM 204106

Genetic Testing for CHARGE Syndrome

Category:Laboratory   Last Reviewed:January 2021
Department(s):Medical Affairs   Next Review:January 2022
Original Date:April 2014    

CHARGE syndrome is an autosomal dominant genetic disease caused by mutations of the chromodomain helicase DNA binding protein 7 gene (CHD7) gene on chromosome 8q12.1 resulting in a wide range of congenital anomalies, including colobomas, which is a congenital absence of pieces of tissue in eye structures that may cause defects in the iris, retina, or optic nerve; heart defects; choanal atresia, which is an obliteration or blockage of the posterior nasal aperture due to a persistent oronasal membrane that prevents joining of the nose and oropharynx; retarded growth and development; genital hypoplasia; ear anomalies; and deafness.

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.

Genetic testing for known familial variant mutations of CHARGE syndrome in first-degree relatives of an affected individual is considered MEDICALLY NECESSARY.

Mutation testing for CHARGE syndrome is considered investigational and /or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations.

CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities) syndrome is a relatively common cause of congenital anomalies affecting approximately 1 in 8,500 to 10,000 births. First described by Hall (1979) and Hittner, Hirsch, Kreh, and Rudolph (1979), CHARGE syndrome was diagnosed clinically until causative mutations were identified in the CHD7 (Chromodomain-helicase-DNA-binding protein 7/ATP-dependent helicase CHD7) gene. Due to the great variability associated with CHD7 mutations, genetic analysis may be helpful for genotypic diagnostics but will not necessarily assist in phenotypic predictions.

The CHD7 protein is a member of the SWI-SNF superfamily of ATP-dependent chromatin remodelers that bind to DNA and modulate gene expression. The CHD7 gene contains 38 exons that encode for the 300-kDa CHD7 chromatin remodeler protein. It has an important, dosage-dependent role in the development of several different craniofacial tissues and has also been found to assist with orchestrating neural crest and central nervous system development. Further, CHD7 plays a role in additional gene expression programs and cellular interactions during embryogenesis; this likely occurs through the dysregulation of co-transcriptional alternative splicing.

It is worth noting that the CHARGE syndrome acronym does not cover all disorders that may result from this disease; a diagnosis may be responsible for additional sensory deficits and birth defects, including cranial nerve dysfunction, clival pathology, and feeding and gastrointestinal (GI) dysfunction. More than 90% of patients experience feeding and GI dysfunction; this is known to cause a great amount of morbidity and mortality in the CHARGE syndrome patient population. Further, many CHARGE syndrome patients exhibit clival pathology, such as coronal clefts; this is now considered a useful diagnostic malady for patients. Nonetheless, the wide range of gene expression affected by mutations in the CHD7 gene results in a broad phenotype that may involve almost all organ and sensory systems in the body, therefore causing significant variabilities in severity and comorbidity. Hence, no single feature is universally present or sufficient for the clinical diagnosis of CHARGE syndrome.

Clinical Validity
The initial clinical CHARGE syndrome diagnostic criteria was first adapted to include supplemental clinical abnormalities. More recently, the diagnostic criteria were updated to incorporate results of molecular testing. The majority of individuals (90-95%) fulfilling the clinical criteria for a CHARGE syndrome diagnosis have a CHD7 variant that is detectable by Sanger sequencing or next generation sequencing (NGS). However, since the inclusion of CHD7, variants have been described in 14-17% of mildly affected individuals who would not meet the clinical criteria. This has resulted in the addition of CHD7 to NGS gene panels for developmental delay, colobomata, heart defects, and other congenital malformations. The clinical validity of genetic testing that relies on identifying CHD7 gene mutations may create issues in the future; van Ravenswaaij-Arts and Martin (2017) stated that individuals with a missense variant of the CHD7 gene will less often fulfill clinical criteria of CHARGE syndrome, since there may be a decreased prevalence of congenital heart defects and choanal atresia with a missense variant. However, this type of variant is overrepresented in families with parent to child transmission of CHARGE syndrome. 

The cause of CHARGE syndrome remains unclear in approximately 5-10% of cases which may be due to variants, such as whole gene deletions, that are not detectable in currently used assays. Other genes or genetic conditions may also be involved in CHARGE syndrome, such as 22q11.2 deletion (DiGeorge) syndrome, Kallmann syndrome, and Kabuki syndrome; these conditions are known to have an overlapping phenotypic spectrum with CHARGE syndrome. Additionally, it is challenging to distinguish younger patients with Kabuki syndrome from those with CHARGE syndrome since they lack the facial gestalt of Kabuki syndrome but show similar organ malformations to those of CHARGE syndrome patients.

A more recent study utilized whole exome sequencing to genetically analyze 28 individuals exhibiting CHARGE syndrome features. Pathogenic variants in CHD7, other genes (RERE, KMT2D, EP300, PUF60), and no pathogenic variants were found in 53.6%, 14.3%, and 28.6% of participants, respectively (Moccia et al., 2018). Based on these results, it was suggested that “the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes”.

In a study by Gonçalves et al. (2019), mutations in the CHD7 gene were observed in patients with isolated congenital hypogonadotropic hypogonadism (CHH), a condition that is characterized by the lack of normal pubertal development resulting from deficient gonadotropin-releasing hormone (GnRH). This demonstrates a limitation to clinical validity in CHD7 genetic testing for CHARGE syndrome. The variable phenotypic expression is related to the type of mutations, as CHARGE syndrome patients seem to have “typically highly deleterious protein-truncating mutations, whereas CHD7 mutations in isolated CHH are typically missense”.

A study conducted by Qin et al. (2020) also found five neonatal patients to have drastically different clinical CHARGE syndrome phenotypes, with postnatal dyspnea as the most prominent symptom in the study cohort. The study found three novel genetic variants (c.2828_2829delAG, c.4667dupC, and c.7873C > T) and two reported variants (c.4667dupC and c.1480C > T) using whole exome sequencing that contributed to CHARGE syndrome clinical presentations. In accordance with this data, researchers concluded that though prenatal diagnosis of CHARGE syndrome may continue to be a challenge, “fetal de novo mutations screening by non-invasive prenatal test (NIPT) with maternal plasma is highly efficient for diagnosis. Detection of mutations in E1 and E38 may also provide clues for predicting severity of CHARGE syndrome by NIPT with maternal plasma”.

Another study was completed with data from 145 participants, all of whom were previously clinically diagnosed with CHARGE syndrome. Researchers surveyed these participants to determine if they had completed genetic testing to confirm a CHARGE syndrome diagnosis. Of the total survey participants, 68% had never received genetic testing; of the 46 patients who did complete genetic testing, 74% tested positive for the CHD7 mutation.

Clinical Utility
Patients with CHARGE syndrome experience a wide spectrum of comorbidities, some more severe than others and the complex management of these comorbidities oftentimes can lead to more issues. The clinical utility of making a definite diagnosis of CHARGE syndrome is high since a confirmed CHARGE diagnosis will lead to changes in clinical management, including well-defined clinical assessment and treatment recommendations. No consensus on the utility of genetic testing in patients who present with a clear clinical diagnosis exists. However, testing may be useful in patients who do not have the classical CHARGE characteristics and may be at risk for the long-term complications of CHARGE syndrome. For instance, many patients with CHARGE syndrome will often have more than one dysfunctional cranial nerve (CN), which can manifest as an absent or reduced sense of smell (CN I), weak chewing/swallowing (CN V), facial palsy (CN VII), sensorineural hearing loss (CN VIII), balance/vestibular problems (CN VIII), and swallowing problems. Hudson, Trider, and Blake (2017) Testing is recommended in all suspected cases of CHARGE syndrome, especially in patients who partially meet the clinical criteria.

Hefner and Fassi (2017) state that a CHARGE syndrome diagnosis “should be considered in patients with any of the major diagnostic features: coloboma, choanal atresia, semicircular canal anomalies, or cranial nerve anomalies.” These features are also common in 22q11.2 deletion (DiGeorge) and Kabuki syndromes, and genetic testing may be used to distinguish between these conditions; further, genetic counseling is an important step in a CHARGE syndrome diagnosis. This will prove to be critical in establishing a multidisciplinary care team for potential developmental concerns of a CHARGE syndrome child, such as combined deafness-blindness. As CHARGE patients grow up, they may have feeding difficulties or orofacial anomalies that may need to be attended to by ENT specialists, cardiovascular malformations that may involve pediatric cardiologists, or concomitant hypogonadotropic hypogonadism HH) that may require the help of pediatric endocrinologists, proving a high clinical utility of CHD7 testing of CHARGE syndrome.

To date, no formal professional society guidelines or recommendations have been found regarding the genetic testing of CHARGE syndrome patients. Therefore, recommendations by subject matter experts in the field are included below.

A comprehensive guideline and clinical checklist was developed by the Atlantic Canadian CHARGE syndrome team. This checklist includes diagnostic criteria such as clinical diagnoses and genetic testing; genetic consultation for CHD7 analysis and array comparative genomic hybridization is recommended. Further, the guideline notes that although “there is no consensus on genetic testing in the presence of a clear clinical diagnosis”, multiple guidelines recommend genetic testing in “all suspected cases of CHARGE syndrome and especially for patients who partially meet the clinical criteria”

According to guidelines published by researchers at The Children’s Mercy Hospitals and Clinics in Kansas City, Missouri, a previously unknown missense mutation in exon 31 of CHD7 can cause a diagnosis of CHARGE syndrome; this mutation may be passed down genetically, showing that family history should be considered as a major diagnostic criterion for CHARGE syndrome. Moreover, orofacial clefting is often seen with a diagnosis of CHARGE syndrome; it is also suggested that patients with this anomaly be tested for CHARGE syndrome.

Guidelines published by de Geus et al. (2017) provide a comprehensive overview of all other published recommendations for CHARGE syndrome and introduce guidelines for cranial imaging. A summary of their recommendations regarding genetics of CHARGE is in the table below.



CHARGE is a clinical diagnosis

(Bergman et al., 2011; K. D. Blake et al., 1998; Harris, Robert, & Kallen, 1997; Issekutz, Graham, Prasad, Smith, & Blake, 2005; Verloes, 2005)

CHD7 testing can confirm uncertain diagnosis in mildly affected patients

(Bergman et al., 2011)

CHD7 testing may be performed according to a flow diagram

(Bergman et al., 2011)

A genome‐wide array should be performed in patients with CHARGE syndrome but without a CHD7 mutation

(Corsten-Janssen et al., 2013)

Clinical genetics consultation is indicated, including options for prenatal diagnosis

(Bergman et al., 2011; Lalani, Hefner, Belmont, & Davenport, 2012)

Patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome

(Jongmans et al., 2009)

Olfactory bulb hypoplasia and semicircular canal aplasia should be considered major signs for CHARGE syndrome

(Asakura et al., 2008; Sanlaville et al., 2006)

If a parent has any features of CHARGE syndrome, molecular genetic testing is appropriate if a CHD7 pathogenic variant has been identified in the proband

(Jongmans et al., 2008)

CHD7 analysis should be performed in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency

(Corsten-Janssen et al., 2013)

CHD7 analysis should be performed in patients with Kallmann syndrome who have at least two additional CHARGE features or semicircular canal anomalies

(Bergman et al., 2012; Costa-Barbosa et al., 2013; Jongmans et al., 2009)

CHD7 should be included in massive parallel sequencing gene panels for diagnostics in syndromic heart defects

(Corsten-Janssen et al., 2014)

CHD7 analysis should not be performed routinely in patients with only atrial septal defect or conotruncal heart defects

(Corsten-Janssen et al., 2014)

CHD7 analysis should not be performed in septo‐optic dysplasia patients without features of CHARGE

(Gregory et al., 2013)

MLPA analysis is indicated if no causal CHD7 is mutation is found

(Wincent et al., 2008; Wincent, Schulze, & Schoumans, 2009)

MLPA analysis is not indicated if no CHD7 mutation is found 

(Bergman et al., 2008)

Guidelines for clinical diagnosis have also been published by Hale et al. (2016), which include the identification of a pathogenic CHD7 variant as major criteria for a CHARGE syndrome diagnosis.

Bergman et al. (2011) published recommendations which stated that CHD7 testing can confirm uncertain diagnoses in mildly affected patients; a clinical genetics consultation is also indicated, including options for prenatal diagnosis.

Corsten-Janssen et al. (2014) published recommendations which state that:   

  • CHD7 should be included in massive parallel sequencing gene panels for diagnostics in syndromic heart defects
  • CHD7 analysis should be performed in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency
  • Genome‐wide array should be performed in patients with CHARGE syndrome but without a CHD7 mutation

Jongmans et al. (2008) and Jongmans et al. (2009) recommended that:

  • Patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome
  • If a parent has any features of CHARGE syndrome, molecular genetic testing is appropriate if a CHD7 pathogenic variant has been identified in the proband
  • CHD7 analysis should be performed in patients with Kallmann syndrome who have at least two additional CHARGE features or semicircular canal anomalies

Usman and Sur (2020) compiled guidelines for evaluation that were rooted in temporal bone imaging and clinical findings, and they ultimately concluded that evaluation via prenatal genetic screenings of CHD7 variants was only restricted to familial cases via amniocentesis or chorionic villus screening at 10-12 and 18-20 weeks’ gestation, respectively.


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  55. Wincent, J., Schulze, A., & Schoumans, J. (2009). Detection of CHD7 deletions by MLPA in CHARGE syndrome patients with a less typical phenotype. Eur J Med Genet, 52(4), 271-272. doi:10.1016/j.ejmg.2009.02.005

Coding Section

Codes Number Description
ICD-9-CM Diagnosis 759.89 Other specified congenital anomalies (includes CHARGE syndrome)
ICD-10-CM (effective 10/01/15) Q99.8 Other specified congenital anomalies (includes CHARGE syndrome)
ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     


Annual review, no change to policy intent. Updating description, rationale and references. 


Annual review, no change to policy intent. 


Annual review, adding medical necessity coverage for familial variants related to first-degree relatives. No other changes made. 


Annual review, no change to policy intent. 


Annual review, no change to policy intent. Updating background, description, guidelines, rationale, category, review date and references. 


Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 


Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.


New Policy.

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