print Print

Genetic Testing for CHARGE Syndrome

Policy Number: MP-614

ARCHIVED – Refer to AIM Genetic Testing Guidelines effective 3/1/20

Latest Review Date:   February 2020

Category:  Laboratory 

Policy Grade:  C



Effective for dates of service on or after November 14, 2015:

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 CHARGE syndrome is considered not medically necessary and investigational when a definitive diagnosis CAN be made clinically in individuals with ALL four major characteristics OR three major and three minor characteristics.

  • Major characteristics include:
    • Ocular coloboma
    • Choanal atresia or stenosis
    • Cranial nerve abnormality
    • Ear anomalies/deafness
  • Minor characteristics include:
    • Genital hypoplasia;
    • Hypogonadotropic hypogonadism;
    • Developmental delays;
    • Cardiac malformations;
    • Short stature;
    • Cleft lip and/or cleft palate;
    • Tracheoesophageal fistula;
    • 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 (ADHD), and various behavior problems

Genetic testing for CHARGE syndrome is considered not medically necessary and investigational in all other situations.

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



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 definite diagnosis by clinical findings. Sequence analysis of the CHD7 gene detects variants in most individuals with CHARGE syndrome.

Description of CHARGE Syndrome

CHARGE syndrome is caused by variants of the CHD7 gene on chromosome 8q12.1. The letters of CHARGE syndrome correspond to clinical features: C = ocular coloboma; H = heart defect; A = atresia choanae; R = retarded growth and development; G = genital hypoplasia; and E = ear anomalies/deafness. However, 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 (CNS) malformations, and/or tracheoesophageal fistula. In one series, the death rate was 20% in the first month of life and about 50% by six months of age. A formal 2005 epidemiologic study in Canada concluded that those who survived infancy were likely to have long-term survival. Morbidity is chronic and multisystemic. Cognitive outcome is 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.

Clinical Diagnosis of CHARGE Syndrome

Investigators have conducted an extended debate about the relative importance of certain clinical signs. Consequently, the diagnostic criteria for CHARGE syndrome have been repeatedly revised.

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

A 2012 review proposes that the diagnosis of CHARGE syndrome be considered definite if an individual has four major characteristics or three major and three minor characteristics, criteria initially proposed by Blake (the Blake criteria), and modified by Verloes. Individuals with one or two major characteristics and several minor characteristics would be considered to have probable or possible CHARGE syndrome.

Major Characteristics

  • Ocular coloboma, which may be manifest in the iris and/or the retina, choroid, and optic disc, and sometimes as microphthalmia. (Prevalence 80% to 90% of affected individuals.)
  • Choanal atresia or stenosis, which may be unilateral or bilateral. Complete bilateral choanal atresia is a life-threatening emergency in a newborn, because neonates are obligate nose breathers. Some CHARGE patients have a cleft palate, in which case the cleft fulfills this criterion. (Prevalence 50%-60%)
  • Cranial nerve (CN) abnormality, including hyposmia or anosmia (CN I), facial palsy (CN VII), auditory nerve hypoplasia causing sensorineural hearing loss (CN VIII), and/or swallowing problems (Prevalence 70% to 90%) with or without aspiration (CN IX and CN X).
  • Characteristic auditory manifestation of the external, middle, or inner ear (Prevalence 80%-100%). The external ear is often dysmorphic. A number of ossicular malformations of the middle ear are common. Sensorineural hearing loss is associated with a Mondini malformation of the cochlea, and vestibular dysfunction is caused by aplasia or hypoplasia of the semicircular canals in 95% of individuals with CHARGE. Temporal bone computed tomography (CT) is necessary to diagnose the cochlear and semicircular canal defects.

Minor Characteristics

  • Genital hypoplasia in boys is manifest as micropenis and cryptorchidism, and in girls as hypoplastic labia. Puberty may be delayed because of hypogonadotropic hypogonadism. (Prevalence 50%)
  • Developmental delays; especially gross motor and language delays, which may be intrinsic qualities or caused by impaired balance, deafness, blindness, hypotonia, surgery, or other chronic illness. (Prevalence100%)
  • Congenital cardiac malformations. (Prevalence 80%)
  • Short stature, often with postnatal onset. (Prevalence 75%)
  • Cleft lip and/or cleft palate. (Prevalence 15%)
  • Tracheoesophageal fistula. (Prevalence 15%)
  • Distinctive CHARGE facial appearance, consisting of a prominent forehead and a prominent nasal bridge. (Prevalence 75%)

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.

The diagnosis of CHARGE syndrome is primarily clinical, based on the 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 fully one third of CHARGE patients 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 one patient with velo-cardio-facial syndrome in whom the chromosome 22q11.2 microdeletion was ruled out, a CHD7 variant was documented. Several patients with Kallmann syndrome were found to have CHD7 disease-associated variants.

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

Genetics of CHARGE Syndrome

In 2014, certain variants of CHD7, which encodes chromodomain helicase DNA-binding protein, were found to cause CHARGE syndrome. In mouse models, the CHD7 gene has been found to be associated with neural crest migration. 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 testing, are rare and probably occur in no more than 2% of individuals.

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 one in 8500 live births.

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

Treatment of CHARGE Syndrome

Extensive management guidelines have been developed for CHARGE syndrome.  These 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 CT, nasal endoscopy, brainstem auditory evoked responses, temporal bone CT, swallowing studies, renal ultrasound, gonadotropin testing, echocardiography, brain magnetic resonance imaging, growth hormone testing, and genetic counseling. Immunological assessment should be considered, particularly if patients have recurrent lung or ear infections. 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 was definitively diagnosed on a clinical basis, or, for mildly affected individuals, as the result of genetic testing.



The most recent literature review was updated through December 9, 2019.

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, test 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 a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

In 2011, Bergman et al proposed guidelines for CHD7 analysis and state that while the diagnosis of CHARGE syndrome remains primarily a clinical diagnosis, molecular testing can confirm the diagnosis in mildly affected patients.

U.S. Preventive Services Task Force Recommendations

Not applicable.



CHARGE, CHARGE syndrome, CHD7, CHD7 gene mutation



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



Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.



CPT Codes:


Molecular pathology procedure, Level 8 (e.g., analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform); includes CHD7 (chromodomain helicase DNA binding protein 7) (e.g., CHARGE syndrome), full gene sequence



  1. 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):334-342.
  2. 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).
  3. 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):159-17
  4. Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: A review. J Paediatr Child Health. Feb 19 201
  5. 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.
  6. Issekutz KA, Graham JM, Jr., 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):309-317.
  7. Jain S, Kim HG, Lacbawan F, et al. Unique phenotype in a patient with CHARGE syndrome. Int J Pediatr Endocrinol. Oct 13 2011; 2011:11.
  8. 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):306-314.
  9. Kim Y, Lee HS, Yu JS, et al. Identification of a novel mutation in the CHD7 gene in a patient with CHARGE syndrome. Korean J Pediatr. Jan 2014; 57(1):46-4
  10. Lalani SR, Hefner MA, Belmont JW, et al. CHARGE Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)1993 (updated Feb 2012).
  11. 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):303-314.
  12. Sanlaville D, Verloes A. CHARGE syndrome: an update. Eur J Hum Genet. Apr 2007; 15(4):389-399.
  13. 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. Apr 13 2014.
  14. 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):402-409.
  15. 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).
  16. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. Mar 15 2005; 133A(3):306-308.
  17. 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):690-694.
  18. 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.



Medical Policy Panel, August 2015

Medical Policy Group, September 2015 (3):  Newly adopted policy.

Medical Policy Administration Committee, October 2015

Available for comment September 29 through November 13, 2015

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points & References.  Mutation Testing” changed to “Genetic Testing” in investigational policy statement but no change in policy statement intent.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (2): 2018 Updates to Key Points and References; no changes to policy statement.

Medical Policy Panel, February 2019

Medical Policy Group, February 2019 (9): 2019 Updates to Description and Key Points; no changes to policy statement.

Medical Policy Panel, February 2020

Medical Policy Group, February 2020 (9): Updates to Key Points. No change to policy statements.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.