Genetic Testing for CHARGE Syndrome - CAM 343HB

CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities) syndrome is a multiple congenital anomaly condition affected by mutations in the CHD7 gene (Hsu et al., 2014). Majority of these mutations result in a wide range of congenital anomalies that include colobomas (congenital absence of pieces of tissue in eye structures that may cause defects in the iris, retina, or optic nerve); heart defects; choanal atresia (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 (Guercio & Martyn, 2007; Isaacson, 2022; Jongmans et al., 2006).


Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

  1. To confirm a diagnosis in a patient with signs/symptoms of CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities) syndrome when a definitive diagnosis cannot be made with clinical criteria, genetic testing for CHD7 is considered MEDICALLY NECESSARY.
  2. For asymptomatic individuals who have a first-degree relative (see Note 1) diagnosed with CHARGE syndrome who have a known mutation, genetic testing restricted to the known familial CHD7 mutation is considered MEDICALLY NECESSARY.
  3. For individuals seeking prenatal or pre-implantation screening, genetic testing for CHD7 is considered MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. For all other situations not discussed above, genetic testing for CHARGE syndrome is considered NOT MEDICALLY NECESSARY.


Note 1: First-degree relatives include parents, full siblings, and children of the individual.

Table of Terminology




Adenosine triphosphate


Coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities


Chromodomain helicase deoxyribonucleic acid binding protein 7


Congenital hypogonadotropic hypogonadism

CLIA ’88

Clinical Laboratory Improvement Amendments of 1988


Centers for Medicare and Medicaid Services


Cranial nerve


Cranial nerve absent or reduced sense of smell


Cranial nerve swallowing problem


Cranial nerve weak chewing/swallowing


Cranial nerve facial palsy


Cranial nerve sensorineural hearing loss and balance/ vestibular problems


Deoxyribonucleic acid


Elongation factor Tu GTP binding domain containing 2


Ear, nose, and throat


E1A binding protein p300


Food and Drug Administration




Gonadotropin-releasing hormone


Hypogonadotropic hypogonadism


Lysine methyltransferase 2D


Laboratory-developed tests


Multiplex ligation-dependent probe amplification


Next-generation sequencing


Non-invasive prenatal test


National Organization for Rare Disorders


Poly(U) binding splicing factor 60


Arginine-glutamic acid dipeptide repeats


Single nucleotide polymorphism


Switch/sucrose non-fermentable


T-box transcription factor 1


Zinc finger E-box binding homeobox 2

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 (Longman, 2018). First described by Hall (1979) and Hittner et al. (1979), CHARGE syndrome was diagnosed clinically (Blake et al., 1998; Pagon et al., 1981) until causative mutations were identified in the CHD7 (Chromodomain-helicase-DNA-binding protein 7/ATP-dependent helicase CHD7) gene (Vissers et al., 2004). Due to the variability associated with CHD7 mutations, genetic analysis may be helpful for genotypic diagnostics but will not necessarily assist in phenotypic predictions (Bergman et al., 2011). Most cases of CHARGE syndrome occur through spontaneous mutation of the CHD7 gene; however, the disorder can also be passed from parent to offspring in an autosomal dominant fashion (Usman & Sur, 2022).

The CHD7 gene contains 38 exons that encode for the 300-kDa CHD7 chromatin remodeler protein (Bilan et al., 2012). The CHD7 protein is a member of the SWI-SNF superfamily of ATP-dependent chromatin remodelers that bind to DNA and modulate gene expression (Asad et al., 2016; Marfella & Imbalzano, 2007). CHD7 has an important, dosage-dependent role in the development of several craniofacial tissues (Sperry et al., 2014) and has also been found to assist with orchestrating neural crest and central nervous system development (Bajpai et al., 2010; He et al., 2016; Van Nostrand et al., 2014; Whittaker et al., 2017). 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 (Belanger et al., 2018; Berube-Simard & Pilon, 2018; Schulz et al., 2014). 

It is worth noting that the CHARGE syndrome acronym does not cover all disorders that may result from this disease; a diagnosis may include additional sensory deficits and birth defects, including cranial nerve dysfunction and feeding and gastrointestinal (GI) dysfunction (Blake & Hudson, 2017). It is notable that more than 90% of patients experience feeding and GI dysfunction; this is known to cause significant morbidity and mortality in the CHARGE syndrome patient population (Blake & Hudson, 2017; Hefner & Fassi, 2017). Further, many CHARGE syndrome patients exhibit clival pathology, such as coronal clefts; this is now considered a useful diagnostic criteria for patients (Mahdi & Whitehead, 2018). Nonetheless, the range of 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 (de Geus et al., 2017). 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 (Blake et al., 1998) was first adapted to include supplemental clinical abnormalities (Verloes, 2005). More recently, the diagnostic criteria were updated to incorporate results of molecular testing (Hale et al., 2016a). Most 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) (Bergman et al., 2011; Janssen et al., 2012). However, since the inclusion of CHD7, variants have been described in 14-17% of mildly affected individuals who would not meet the clinical criteria for a CHARGE syndrome diagnosis (Bergman et al., 2011). This has resulted in the addition of CHD7 to NGS gene panels for developmental delay, colobomata, heart defects (Corsten-Janssen et al., 2014), and other congenital malformations (van Ravenswaaij-Arts & Martin, 2017). 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 for a CHARGE syndrome diagnosis, 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 (van Ravenswaaij-Arts & Martin, 2017).  

Despite the availability of molecular diagnostic tools, “the cause of CHARGE syndrome remains unclear in approximately 5-10% of typical CHARGE patients and in 40-60% of suspected cases” (Janssen et al., 2012). Other genetic conditions such as 22q11.2 deletion (DiGeorge) syndrome, Kallmann syndrome, and Kabuki syndrome are known to have an overlapping phenotypic spectrum with CHARGE syndrome (Janssen et al., 2012), which may complicate diagnosis based strictly on clinical criteria. 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 (Pauli et al., 2017).

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” (Moccia et al., 2018). 

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 mutation, as CHARGE syndrome patients seem to have “typically highly deleterious protein-truncating mutations, whereas CHD7 mutations in isolated CHH are typically missense” (Gonçalves et al., 2019).

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” (Qin et al., 2020).

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 a CHD7 mutation (Hartshorne et al., 2011).

Clinical Utility and Validity
Patients with CHARGE syndrome experience a wide spectrum of comorbidities, some more severe than others, and the complex management of these comorbidities can often 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 (de Geus et al., 2017; Trider et al., 2017). 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 (Blake et al., 2011). 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 (CN IX, X) (Hudson et al., 2017). Testing is recommended in all suspected cases of CHARGE syndrome, especially in patients who partially meet the clinical criteria (Bergman et al., 2011; Hale et al., 2016a; Trider et al., 2017). 

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 (Hefner & Fassi, 2017). 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 (Hudson et al., 2017). 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, supporting the high clinical utility of CHD7 testing of CHARGE syndrome (Dijk et al., 2019).

The CHARGE Syndrome Foundation 
The CHARGE Syndrome Foundation states that CHARGE syndrome is marked by key features such as coloboma, cranial nerve abnormalities, choanal atresia, heart defects, characteristic external ears, esophageal defects, small/absent semicircular canals, genitourinary abnormalities, and CHD7 gene mutations, and that its “diagnosis should be made by a Medical Geneticist. Diagnosis is based on key features, ideally with DNA testing for CHD7 mutations”. Though “It does not usually run in families”, the  “Recurrence risk to unaffected parents is 1-2%” and “If a parent has CHARGE Syndrome, the risk to a baby is 50/50” (CHARGE Syndrome Foundation, 2023). 

The National Organization for Rare Disorders (NORD)
NORD states that “molecular genetic testing is available for mutations in the CHD7 gene associated with the condition, and if this is negative, a SNP chromosomal microarray should be done, because in a few cases, there has been a submicroscopic genomic alteration of chromosome 8q12.2. If both these tests are negative, whole genome exome sequencing should be done, since other genetic disorders share some clinical features with CHARGE syndrome, and de novo mutations in ZEB2, KMT2D and EFTUD2 have been detected in children previously diagnosed as having CHARGE syndrome” (National Organization for Rare Disorders, 2021).

Other Recommendations
Guidelines by professional societies and organizations about genetic testing for CHARGE syndrome are limited; however, recommendations by subject matter experts in the field are included below. 

A comprehensive guideline and clinical checklist were 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 also 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” (Trider et al., 2017).

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 can be inherited, showing that family history should be considered as a major diagnostic criterion for CHARGE syndrome (Hughes et al., 2014). Moreover, because orofacial clefting is often observed with a diagnosis of CHARGE syndrome, it is also suggested that patients with this anomaly be tested for CHARGE syndrome (Hughes et al., 2014).

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 is included in the table below (de Geus et al., 2017).



CHARGE is a clinical diagnosis

(Bergman et al., 2011; Blake et al., 1998; Harris et al., 1997; Issekutz et al., 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 et al., 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 et al., 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. (2016a), which include the identification of a pathogenic CHD7 variant as major criteria for a CHARGE syndrome diagnosis. In a response to comments received on their publication by (Blake et al., 2011), Hale and colleagues reaffirmed the appropriateness of CHD7 testing under the right circumstances. They state “there are specific (and extremely useful) guidelines for when to test for CHD7 sequence variants in individuals with CHARGE features (Bergman et al., 2011). Accurate and meaningful genetic information can lead to improved understanding of etiology, provide accurate recurrence risks, and help pave the way toward better clinical care. We advocate incorporating CHD7 sequence variant information into the diagnostic algorithm, when it is available, since this information can improve understanding of disease causation, pathogenesis, and treatment options. In cases when CHD7 variant testing is not available, the diagnosis can still be made based on appropriate clinical assessments” (Hale et al., 2016b).

Bergman et al. (2011) asserted that CHD7 testing can confirm uncertain diagnoses in mildly affected patients. Moreover, 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 (2022) compiled guidelines for the diagnosis of CHARGE syndrome that state “the sequencing of CHD7 encrypting the chromodomain helicase DNA binding protein detects pathogenic variants in maximum individuals with typical CHARGE syndrome with the following criteria of having the three primary characteristics or four major and three minor characteristics.” The major criteria are coloboma, cranial nerve abnormalities, choanal atresia, and typical CHARGE ear. The minor criteria are heart defects, cleft lip or palate, genital abnormalities, hypotonia, kidney abnormalities, esophageal atresia, poor growth, typical CHARGE face, and typical CHARGE hand. The authors summarize the outline of diagnosis as: 

  • “Clinical diagnosis: It is a combination of major and minor diagnostic characteristics, having the three primary features or four major and three minor characteristics.”
  • “Laboratory analysis: It includes having the blood workup done, such as complete blood count (CBC), serum electrolytes, renal function test, luteinizing hormone-releasing hormone, Human chorionic gonadotropin (hCG), blood urea nitrogen (BUN), creatinine, growth hormone levels, and immunologic studies.”
  • “Genetic analysis: Prenatal screening for CHD7 variants is restricted to familial cases, via amniocentesis chorionic or villus sampling at 10–12 and 18–20 weeks’ gestation.”
  • “Imaging studies: Involves a skeletal survey, abdominal ultrasound, barium swallow, echocardiography, chest x-ray, cranial ultrasound in neonates, and head computed tomography (CT) scan and magnetic resonance imaging (MRI)” (Usman & Sur, 2022).


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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 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" 

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