Description
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.¹ The 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.^2-4

Policy
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 the presence of CHD7 variants 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 likely pathogenic or pathogenic variant, genetic testing restricted to the known familial CHD7 variant is considered MEDICALLY NECESSARY.
3. For individuals seeking prenatal or pre-implantation screening, genetic testing for the presence of CHD7 variants is considered MEDICALLY NECESSARY.
4. For individuals with clinical features of CHARGE syndrome who have already tested negative for likely pathogenic or pathogenic variants in CHD7, screening for variants in ZEB2, KMT2D and EFTUD2 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 an individual’s illness.

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

NOTES:

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

Table of Terminology

Rationale
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.⁵ First described by Hall (1979) and Hittner, et al. (1979), CHARGE syndrome was diagnosed clinically^8,9 until causative mutations were identified in the CHD7 (Chromodomain-helicase-DNA-binding protein 7/ATP-dependent helicase CHD7) gene.¹⁰ Due to the variability associated with CHD7 mutations, genetic analysis may be helpful for genotypic diagnostics but will not necessarily assist in phenotypic predictions.¹¹ 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.¹²

The CHD7 gene contains 38 exons that encode for the 300-kDa CHD7 chromatin remodeler protein.¹³ The CHD7 protein is a member of the SWI-SNF superfamily of ATP-dependent chromatin remodelers that bind to DNA and modulate gene expression.^14,15 CHD7 has an important, dosage-dependent role in the development of several craniofacial tissues¹⁶ and has also been found to assist with orchestrating neural crest and central nervous system development.^17-20 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.^21-23

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.²⁴ 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.^24,25 Further, many CHARGE syndrome patients exhibit clival pathology, such as coronal clefts; this is now considered a useful diagnostic criteria for patients.²⁶ 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.²⁷ Hence, no single feature is universally present or sufficient for the clinical diagnosis of CHARGE syndrome.

Clinical Validity
The initial clinical CHARGE syndrome diagnostic criteria8 was first adapted to include supplemental clinical abnormalities.²⁸ More recently, the diagnostic criteria were updated to incorporate results of molecular testing.²⁹ 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).^11,30 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.¹¹ This has resulted in the addition of CHD7 to NGS gene panels for developmental delay, colobomata, heart defects,³¹ and other congenital malformations.³² 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.³²

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.”³⁰ 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,³⁰ 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.³³

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.³⁴ Based on these results, it was suggested that “the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes.”³⁴

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.”³⁵

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.”³⁶

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.³⁷

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.27,38 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.39 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).40 Testing is recommended in all suspected cases of CHARGE syndrome, especially in patients who partially meet the clinical criteria.^11,29,38

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.²⁵ 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.⁴⁰ 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.⁴¹

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.”⁴²

The National Organization for Rare Disorders (NORD)
The NORD states that “diagnosis can be confirmed by molecular genetic testing identifying the variants in the CHD7 gene associated with the condition. If no disease-causing variants are found, a SNP chromosomal microarray should be done, because in a few patients, there has been a submicroscopic change in the chromosome 8q12.2 region. 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 new variants in the ZEB2, KMT2D and EFTUD2 genes have been found in children previously diagnosed as having CHARGE syndrome.”⁴³

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.”³⁸

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.⁴⁴ 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.⁴⁴

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.²⁷

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. In a response to comments received on their publication by,³⁹ 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.¹¹ 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.”⁵⁸

Bergman, et al. (2011) asserted that CHD7 testing can confirm uncertain diagnoses in mildly affected patients. Moreover, 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 (2025) compiled guidelines for the diagnosis of CHARGE syndrome that state that the “only gene associated with CHARGE syndrome is CHD7, encrypting the chromodomain helicase DNA binding protein. This sequencing 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 the 4C’s: 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).”¹²

References 

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30. Janssen N, Bergman JE, Swertz MA, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. Aug 2012;33(8):1149-60. doi:10.1002/humu.22086
31. Corsten-Janssen N, du Marchie Sarvaas GJ, Kerstjens-Frederikse WS, et al. CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects. Am J Med Genet A. Dec 2014;164A(12):3003-9. doi:10.1002/ajmg.a.36747
32. van Ravenswaaij-Arts C, Martin DM. New insights and advances in CHARGE syndrome: Diagnosis, etiologies, treatments, and research discoveries. Am J Med Genet C Semin Med Genet. Dec 2017;175(4):397-406. doi:10.1002/ajmg.c.31592
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47. Corsten-Janssen N, Saitta SC, Hoefsloot LH, et al. More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated. Molecular syndromology. Jun 2013;4(5):235-45. doi:10.1159/000351127
48. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, et al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. Jan 2009;75(1):65-71. doi:10.1111/j.1399-0004.2008.01107.x
49. Asakura Y, Toyota Y, Muroya K, et al. Endocrine and radiological studies in patients with molecularly confirmed CHARGE syndrome. The Journal of clinical endocrinology and metabolism. Mar 2008;93(3):920-4. doi:10.1210/jc.2007-1419
50. Sanlaville D, Etchevers HC, Gonzales M, et al. Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet. Mar 2006;43(3):211-217. doi:10.1136/jmg.2005.036160
51. Jongmans MC, Hoefsloot LH, van der Donk KP, et al. Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability. Am J Med Genet A. Jan 1 2008;146A(1):43-50. doi:10.1002/ajmg.a.31921
52. Bergman JE, de Ronde W, Jongmans MC, et al. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. The Journal of clinical endocrinology and metabolism. May 2012;97(5):E858-62. doi:10.1210/jc.2011-2652
53. Costa-Barbosa FA, Balasubramanian R, Keefe KW, et al. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. The Journal of clinical endocrinology and metabolism. May 2013;98(5):E943-53. doi:10.1210/jc.2012-4116
54. Gregory LC, Gevers EF, Baker J, et al. Structural pituitary abnormalities associated with CHARGE syndrome. The Journal of clinical endocrinology and metabolism. Apr 2013;98(4):E737-43. doi:10.1210/jc.2012-3467
55. Wincent J, Holmberg E, Stromland K, et al. CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome. Clin Genet. Jul 2008;74(1):31-8. doi:10.1111/j.1399-0004.2008.01014.x
56. Wincent J, Schulze A, Schoumans J. Detection of CHD7 deletions by MLPA in CHARGE syndrome patients with a less typical phenotype. European journal of medical genetics. Jul-Aug 2009;52(4):271-2. doi:10.1016/j.ejmg.2009.02.005
57. Bergman JE, de Wijs I, Jongmans MC, Admiraal RJ, Hoefsloot LH, van Ravenswaaij-Arts CM. Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome. European journal of medical genetics. Sep-Oct 2008;51(5):417-25. doi:10.1016/j.ejmg.2008.03.003
58. Hale CL, Niederriter AN, Green GE, Martin DM. Response to correspondence to Hale et al. atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. Am J Med Genet A. Dec 2016;170(12):3367-3368. doi:10.1002/ajmg.a.37629

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