Genetic Testing for CHARGE Syndrome AHS – M2070

Description of Procedure or Service

CHARGE syndrome is a rare genetic condition caused by mutations of the CHD7 gene on chromosome 8q12.1. The syndrome is an autosomal dominant genetic disorder typically caused by mutation in the chromodomain helicase DNA binding protein 7 gene (CHD7) (Zentner et al., 2010). CHD7 is a member of the SWI-SNF superfamily of ATP-dependent chromatin remodelers that bind to DNA and modulate gene expression (Zainab et al., 2016; Marfella et al., 2007).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for CHARGE syndrome when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for CHARGE Syndrome is covered

Genetic testing for CHARGE syndrome is 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.

When Genetic Testing for CHARGE Syndrome is not covered

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

Policy Guidelines

Background

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.

The acronym "CHARGE" denotes the nonrandom association of coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies, which are frequently present in various combinations and to varying degrees in individuals with CHARGE syndrome. No single feature is universally present or sufficient for the clinical diagnosis of CHARGE syndrome, and numerous guidelines have been published to aid in establishing a likely clinical diagnosis (Verloes et al., 2005).

The typical defining features of CHARGE syndrome include coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies. Other frequently occurring significant features include characteristic face and hand dysmorphology, hypotonia, urinary tract anomalies, anosmia, orofacial clefting, deafness, dysphagia, and tracheoesophageal anomalies. The occasional family member may also have features of this disease.

Coloboma of the eye (70-80%)

This is usually bilateral and affects the posterior segment of the eye (ie, choroid, retina, optic disc). It rarely involves the iris. Microphthalmia and nystagmus are consistently associated with severe coloboma. Coloboma that does not involve the fovea does not affect vision. Retinal detachment is a frequent complication (Nishina te al., 2012).

Heart anomaly (60-70%)

Septal defects (interventricular, interatrial) and conotruncal malformation (aortic valve stenosis, aortic coarctation, and interrupted aortic arch) are the most frequent anomalies. Other anomalies include patent ductus arteriosus and tetralogy of Fallot. All variations of complex heart anomalies are reported.

Choanal atresia/stenosis (30-60%)

Choanal atresia is membranous or bony and bilateral in over 50% of cases, usually presenting in the newborn period with respiratory distress. Choanal atresia is a threat to life because infants cannot establish mouth breathing. A history of polyhydramnios in pregnancy is usually present. Of all features of CHARGE syndrome, choanal atresia (when bilateral) is the most easily ascertained. Its presence indicates poor prognosis for survival and necessitates multiple complex surgeries for correction. When associated with other anomalies (eg, cyanotic heart disease, tracheoesophageal fistula and/or atresia), most children with bilateral atresia do not survive beyond the first year of life. Unilateral atresia may present as persistent nasal discharge in early childhood (Kirk et al., 2015).

Growth retardation (failure to thrive - 80%)

Intrauterine growth retardation and growth failure are observed in approximately 75% of patients. Growth failure is noticeable in the first 6 months of life. It is due to endocrine causes (eg, growth hormone deficiency, gonadotrophin deficiency). Feeding difficulty with poor caloric intake may also contribute to growth failure. No correlation between the severity of the growth defect and the severity of the component anomalies is observed (Kirk et al., 2015).

Intellectual disability (70-75%)

Developmental delay is typically present and is often characterized as mild to moderate. More severe developmental delay is often associated with other significant birth defects and a greater degree of later intellectual disability.
Patients with severe coloboma and inner ear problems are particularly affected.
Poor vision and hearing result in the absence of visual and auditory cues that are essential for early motor development, and abnormalities in the vestibular function affect the adoption of upright posture and, thus, lead to delay in motor development.
The need for multiple and prolonged hospitalizations and lack of active management of the sensory deficit can also contribute to developmental delay. These issues must be adequately addressed in a timely fashion, when present, to maximize developmental outcomes.
Intellectual disability is not universal but is frequent.
One should be careful not to diagnose intellectual disability until the full extent of sensory deficits are known and corrective measures have been implemented (Kirk et al., 2015).

Genital hypoplasia (male 70%, female 30%)

Males have micropenis and are either cryptorchid or have complete absence of testis. Females have labial hypoplasia that is difficult to identify in the neonatal period. Hypogonadotrophic hypogonadism secondary to pituitary or hypothalamic causes is suggested as the cause, as evidenced by poor response to luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (HCG) stimulation tests (Kirk et al., 2015).

Ear malformations (90-100%)

External ear malformation was noted in 90-100% of patients. Ears may be small, simple, low set, and/or cup shaped; protruding helix may be unraveled. External ear malformations are more abnormal on the side of the facial palsy and may be related to denervation early in the developmental process of the ear (Kirk et al., 2015).

Deafness/hearing loss (60-90%)

Usually bilateral and of mixed type. A unique, wedge-shaped audiogram has been described with a descending bone conduction curve intersecting at low frequencies with a flat curve for air conduction. Inner ear abnormalities include Mondini malformation or partial or complete semicircular canal hypoplasia/aplasia. Vestibular or cochlear defect leads to sensorineural deafness. Middle ear problems cause conductive hearing loss and are commonly due to ossicular malformations, stapedius tendon abnormality, or serous effusion. CT scan of the temporal bone demonstrates partial or complete semicircular canal hypoplasia (Kirk et al., 2015).

Other anomalies

These include the following:
Neurologic anomalies: Cranial nerve palsy (mainly facial nerve but also auditory), glossopharyngeal and vagus nerves, microcephaly, and neonatal brainstem dysfunction, which manifest in the form of feeding difficulty and swallowing difficulty, are observed Cerebellar vermis hypoplasia: A study by Sohn et al found that five out of 17 patients (29.4%) with CHARGE syndrome had cerebellar vermis hypoplasia, suggesting, according to the investigators, that this may also be a sign of the syndrome (Sohn et al. 2016) in another study, Yu et al found cerebellar vermis hypoplasia in seven out of 20 of CHARGE syndrome patients (35%) proven to have a CHD7 mutation (Yu et al., 2013).

Dysmorphic features:

• typically asymmetric square face, malar flattening, unilateral facial nerve paralysis, and micrognathia, 
• Hand dysmorphology: brachydactyly and clinodactyly, 
• Orofacial clefting: Found in approximately 30-50% of patients. 
• Limb anomalies: Seen in approximately one third of patients; contractures, polydactyly, and/or missing digits may also occur (Kirk et al., 2015). 

Occasional anomalies (not consistently present)

• These include the following: 
• Renal - Hydronephrosis, vesicoureteric reflux 
• Larynx - Laryngomalacia, laryngeal clefts 
• Esophageal - Atresia, tracheoesophageal fistula 
• Skeletal - Hemivertebrae, scoliosis, clinodactyly, syndactyly 

Blake et al suggested that a typical clinical diagnosis of CHARGE syndrome requires the presence of at least 4 major features or 3 major features plus at least 3 minor features (Blake et al. 1998). Major features include ocular coloboma or microphthalmia, choanal atresia or stenosis, cranial nerve abnormalities, and characteristic auditory and/or auricular anomalies. Minor features include distinctive facial dysmorphology, facial clefting, tracheoesophageal fistula, congenital heart defects, genitourinary anomalies, developmental delay, and short stature. Other frequently associated abnormal findings include characteristic hand dysmorphology, hypotonia, deafness, and dysphagia (Bergman et al. 2011).

Although most cases of CHARGE syndrome are due to mutation or deletion of the CHD7 gene, some individuals with CHARGE syndrome harbor disparate pathologic cytogenetic anomalies (including 22q11.2 deletions) or mutations in other genes (including SEMA3E) unrelated to CHD7 (Aramaki et al. 2006; Lev et al. 2000; Lalani 2004).

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 1 series, the death rate was 20 percent in the first month of life and about 50 percent by 6 months of age (Tellier et al., 1998). A formal epidemiologic study in Canada concluded that those who survived infancy were likely to have long-term survival (Issekutz et al., 2005). 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 percent have some degree of intellectual disability. Among the 25 percent with normal intelligence, many are well educated and live independently as adults (Lalani et al., 1993; Bergman et al., 2011).

Diagnosis Criteria Later onset features

The CHARGE features opposite are usually congenital, ie, children are born with them, although they may not always be apparent at birth. A number of features are now noted in older patients (Russell-Eggitt et al., 1990; Blake et al., 2005).

These include:

• Curvature of the spine (scoliosis) 
• Migraine (including abdominal migraine) 
• Epilepsy 
• Cataracts 
• Retinal detachment 
• Delayed/arrested puberty 
• Progressive hearing loss.

In addition, a number of behavioral disorders are more commonly described in patients with CHARGE syndrome: obsessive-compulsive disorder (OCD), attention deficit disorder (ADD), Tourette syndrome and autistic spectrum disorder (Sanlaville and Verloes 2007; Kirk et al., 2015).

Differential Diagnosis

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, Branchiootorenal syndrome, and retinoic embryopathy closely resemble CHARGE syndrome. In one patient with velo-cardio-facial syndrome in whom the chromosome 22q11.2 microdeletion was ruled out, a CHD7 mutation was documented. Several patients with Kallmann syndrome were found to have CHD mutations.

Because 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 (Bergman et al., 2011). 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 mutation, 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 (Hughes et al., 2014).

Genetics of CHARGE Syndrome

In 2004, mutations 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 (Schulz et al., 2014). Almost all pathogenic mutations have proven to be point mutations, 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 two percent of individuals.

Most instances of CHARGE syndrome are sporadic events in a family and appear to be caused by de novo CHD7 mutations. On rare occasions CHARGE can be inherited as an autosomal dominant condition. Individuals with CHARGE who reproduce have a 50% chance of transmitting the mutation 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 (Issekutz et al., 2005).

In a recent study by Zainab Asad et al. for the first time, reported defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. Zainab et al. also observed defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. CHD7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Thus Zainab et al. concluded that CHD7 is an important player in the specification, migration, fate-choice and differentiation of neural crest (NC) and Sox10 is an important mediator of function of CHD7 in NC. Also, by external regulation of sox10 expression, some aspects of the neural crest derived phenotypes in the CHARGE model can be rescued suggesting possible avenues of intervention in the future (Zainab et al., 2016).

Applicable Federal Regulations

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

Guidelines and Recommendations

Most cases of CHARGE syndrome can be diagnosed clinically using established major and minor criteria. 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 one 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 may be at risk for the long-term complications of CHARGE syndrome (Blake et al., 2011). Sequence analysis of the chromodomain helicase DNA binding protein 7 (CHD7) coding region detects mutations in most individuals with CHARGE syndrome.

The clinical utility of making a definite diagnosis of CHARGE syndrome is high, in that confirming a diagnosis in a patient will lead to changes in clinical management, including clinical assessment and treatment recommendations that are well defined. The clinical utility of genetic testing for CHARGE syndrome is for patients in whom a definite diagnosis cannot be made clinically. Therefore, 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.

Almost all cases of CHARGE syndrome are a result of a de novo mutation, and therefore testing of relatives of a patient with CHARGE syndrome has low clinical utility. Therefore, mutation testing for CHARGE syndrome is considered investigational in all other situations.

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 (Bergman et al., 2011).

Genetic testing for mutations of CHD7 is commercially available from several commercial laboratories and is generally performed through Sanger sequence analysis.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Scientific Background and Reference Sources

Aramaki M, Udaka T, Kosaki R, Makita Y, Okamoto N, Yoshihashi H. Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr. 2006 Mar. 148(3):410-4.

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. PMID 21378379

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

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):159-173. PMID 9545604

Hsu P, Ma A, Wilson M, et al. CHARGE syndrome: A review. J Paediatr Child Health. Feb 19 2014. PMID 24548020

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

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. PMID 15637722

Jones KL. CHARGE association. Smith's Recognizable Patterns of Human Malformation. 5th ed. WB Saunders Co; 1997. 668-70.

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):46-49. PMID 24578717

Kirk, CHARGE syndrome: major and minor medical diagnostic criteria plus later onset features

Lalani SR, Hefner MA, Belmont JW, et al. CHARGE Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle (WA)1993.

Lalani SR, Safiullah AM, Molinari LM, Fernbach SD, Martin DM, Belmont JW. SEMA3E mutation in a patient with CHARGE syndrome. J Med Genet. 2004 Jul. 41(7):e94.

Lev D, Nakar O, Bar-Am I, Zudik A, Watemberg N, Finkelstien S. CHARGE association in a child with de Novo chromosomal aberration 46, X,der(X)t(X;2)(p22.1;q33) detected by spectral karyotyping. J Med Genet. 2000 Dec. 37(12):E47.

Marfella C.G.A., Imbalzano A.N. (1 May 2007) The Chd family of chromatin remodelers. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, V 618, 1-2, Pages 30–40.

Nishina S, Kosaki R, Yagihashi T, Azuma N, Okamoto N, Hatsukawa Y, et al. Ophthalmic features of CHARGE syndrome with CHD7 mutations. Am J Med Genet A. 2012 Mar. 158A(3):514-8.

Pagon RA, Graham JM Jr, Zonana J, Yong SL. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr. 1981 Aug. 99(2):223-7.

Russell-Eggitt, I.M. et al.(1990) The eye in the CHARGE association. British Journal of Ophthalmology. 74(7), pp. 421–6.

Sanlaville D, Verloes A. CHARGE syndrome: an update. Eur J Hum Genet. Apr 2007;15(4):389- 399. PMID 17299439

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. PMID 24728844

Sohn YB, Ko JM, Shin CH, Yang SW, Chae JH, Lee KA. Cerebellar vermis hypoplasia in CHARGE syndrome: clinical and molecular characterization of 18 unrelated Korean patients. J Hum Genet. 2016 Mar. 61 (3):235-9.

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. PMID 9556299

Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A. Mar 15 2005; 133A(3):306-308. PMID 15666308

Yu T, Meiners LC, Danielsen K, et al. Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome. Elife. 2013 Dec 24. 2:e01305.

Zainab Asad, Aditi Pandey, Aswini Babu, Yuhan Sun, Kaivalya Shevade,, Shruti Kapoor,, Ikram Ullah, Shashi Ranjan, Vinod Scaria,, Ruchi Bajpai and Chetana Sachidanandan Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 down regulation, Human Molecular Genetics. doi: 10.1093/hmg/ddw198, July 13, 2016

Zentner G.E., Layman W.S., Martin D.M., Scacheri P.C. (2010) Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am. J.Med. Genet. Part A, 152A, 674–686.

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for genetic testing for CHARGE syndrome when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)