Genetic testing for CHARGE syndrome may be considered medically necessary to confirm a diagnosis in a patient with signs and/or symptoms of CHARGE syndrome when a definitive diagnosis cannot be made with clinical criteria. A diagnosis of definite CHARGE syndrome can be made clinically in individuals with:
- All 4 major characteristics, including:
- Choanal atresia or stenosis,
- Cranial nerve abnormality,
- Ear anomalies/deafness; and
- Ocular coloboma, OR
- 3 major and 3 minor characteristics, including:
- Attention deficit hyperactivity disorder (ADHD) or various behavioral problems,
- Brain malformations,
- Cardiac malformations,
- Cleft lip and/or cleft palate,
- Dental problems,
- Developmental delays,
- Distinctive CHARGE facial appearance consisting of a prominent forehead and a prominent nasal bridge,
- Genital hypoplasia,
- Hypogonadotrophic hypogonadism,
- Kidney malformations,
- Short stature,
- Tracheoesophageal fistula,
- Various limb abnormalities,
Mutation testing for CHARGE syndrome is considered experimental, investigational and/or unproven in all other situations.
CPT code 81407 includes full sequence analysis of CHD7 (chromodomain helicase DNA binding protein 7).
This policy is based on a search of the MEDLINE database through June 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of testing for CHARGE syndrome was sought.
Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
Almost all pathogenic mutations are point mutations. On rare occasions, there may be a chromosomal translocation with a break point within the CDH7 gene. Microdeletions or whole-exon deletions occur in less than 5% of patients.
Sequencing of the CHD7 gene has high analytical sensitivity and specificity. Sequence analysis detects greater than 99% of the (point) mutations present in the area that has been investigated. Testing that identifies deletions not readily detected by sequence analysis includes MLPA or chromosomal microarray analysis. MLPA has an estimated sensitivity of greater than 95% for deletions and greater than 90% for individual exons. (7)
The analytical sensitivity (proportion of positive tests if the genotype is present) depends on the method used. If only CHD7 sequencing is performed, deletions are missed less than 5% of the time due to whole-exon or whole-gene deletions. If sequencing is combined with MLPA, it is 100%. (7)
The analytical specificity (proportion of negative tests if the genotype is not present) is almost 100% (some variants may erroneously be interpreted as pathogenic). (7)
Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
Clinical sensitivity and specificity are also high.
The clinical sensitivity (proportion of positive tests if the disease is present) can be dependent on variable factors such as age or family history, and may depend on the clinical criteria used. In over 95% of the patients who fulfill the Blake or Verloes criteria, a mutation is found. (7) In those with suspected CHARGE syndrome, a mutation is found in 60–70% of patients.
CHARGE syndrome sometimes can be excluded if a patient does not fulfill the clinical criteria and does not carry a mutation or deletion of CHD7. Some conditions that mimic CHARGE syndrome are 22q11 deletion syndrome, VACTERL association, chromosomal disorders (e.g., deletions 3p12p21.2) disorders caused by teratogens (e.g., maternal diabetes, Accutane), and Kallmann syndrome. (7)
The clinical specificity (proportion of negative tests if the disease is not present) can be dependent on variable factors such as age or family history. The clinical variability of CHARGE syndrome is considerable. If the diagnosis is based on the Blake criteria, some individuals with CHARGE will be missed. The clinical specificity is greater than 95%, since less than 5% of the patients with a CHD7 mutation do not completely fulfill these criteria. However, it should be taken into account that the mild end of the phenotypic spectrum is not completely known yet. (7)
Therefore, genetic testing for CHARGE syndrome is very good for confirming a diagnosis, but a negative test does not rule out the disease.
The positive clinical predictive value (life-time risk to develop the disease if the test is positive) is 100%, but there is high clinical variability.
The negative clinical predictive value (probability of not developing the disease if the test is negative), assuming an increased risk based on family history, is 100% if the index case in the family has been tested. If the index case in the family has not been tested, it depends on the a priori chance of the index to find a mutation, which is 60-90%.
There are no known genotype-phenotype correlations for specific CHD7 mutations and CHARGE syndrome manifestations, and therefore, the phenotype cannot be predicted from the genotype.
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
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 semi-circular 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. (7)
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 computed tomography (CT), nasal endoscopy, brainstem auditory evoked responses, temporal bone CT, swallowing studies, renal ultrasound, gonadotropin testing, echocardiography, brain magnetic resonance imaging (MRI), growth hormone testing, and genetic counseling.
Almost all patients diagnosed with CHARGE syndrome do not have an affected parent as most are de novo mutations. Only rare instances of transmission from a mildly affected parent have been reported. (8) Therefore, genetic testing in relatives of a patient with CHARGE syndrome has low clinical utility.
Preconception (carrier) testing and prenatal (in utero) testing can also be performed, but are not addressed in this literature review.
CHARGE syndrome is a rare genetic syndrome with multiple associated malformations. Established clinical criteria can provide a diagnosis of definite CHARGE syndrome in some patients; however, due to the variable phenotypes associated with CHARGE syndrome, some patients may be categorized clinically as having possible or probable CHARGE syndrome.
CDH7 is the only gene currently known to be associated with CHARGE syndrome. The analytic sensitivity and specificity for detecting mutations in the CHD7 gene is high. The clinical sensitivity and specificity are also high: among patients with a clinical diagnosis of definite CHARGE syndrome, 90-95% have a mutation of CHD7. For individuals with possible or probable CHARGE syndrome, CHD7 analysis is positive for a mutation in 65-70% of cases.
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..
Practice Guidelines and Position Statements
Bergman et al. have 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. (4)
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