Array comparative genomic hybridization (aCGH) or chromosomal microarray is a rapidly evolving technology in cytogenetic testing used to detect submicroscopic abnormalities such as deletion or duplication of large segments of DNA, known as copy number variants (CNV). The microarray slide is prepared with segments of DNA (i.e. probes) that are either cloned bacterial artificial chromosomes (BAC) or synthesized oligonucleotides. The probes are selected based on the known presence or high suspicion of specific genetic conditions. The DNA for an individual along with DNA from a normal human control compete to attach or hybridize to their corresponding probes. Unequal hybridization, mostly deletions or duplications (CNV) by the individual as compared to the control is significant for DNA alteration.
Targeted CGH arrays provide high resolution coverage in areas with known, clinically significant, CNVs. Whole genome arrays provide high resolution of the entire genome and therefore in addition to the detection of known CNVs can also promote discovery of new CNVs.
Conventional cytogenetic testing, including karyotyping (G Banding) and fluorescence in situ hybridization (FISH), have low resolution and a lower diagnostic yield leaving the majority of cases with an unidentified chromosomal abnormality. Array CGH increases the genomic detail beyond conventional testing and may increase the diagnostic yield.
Array CGH has been proposed for genetic evaluation in individuals with multiple conditions including neurodevelopmental delays, mental retardation and autism spectrum disorder. For children with clear, clinical symptoms and/or physiologic evidence of syndromic neurodevelopmental disorders, diagnoses are based primarily on clinical history and physical examination, and then may be confirmed with genetic testing. However, for children who do not present with an obvious syndrome, who are too young for full expression of a suspected syndrome, or who may have an atypical presentation, genetic testing is used as a basis for establishing a diagnosis.
POLICY
Array Comparative Genomic Hybridization (aCGH) for the genetic evaluation of individuals with cognitive developmental delays/mental retardation is considered investigational.
Array Comparative Genomic Hybridization (aCGH) for prenatal genetic testing is considered investigational.
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ADDITIONAL INFORMATION
A review of literature shows limited studies of aCGH in the diagnosis and treatment of global delays. There are few randomized controlled studies researching the critical elements of impact on clinical outcomes other than diagnostic yield. The clinical benefits of testing are inferred based on the value of a diagnosis to the family with limited evidence based conclusions regarding clinical utility of aCGH.
The American College of Medical Genetics, Use of array-based technology in the practice of medical genetics (2007), discusses the lack of standardization of array testing in individual laboratories. To date abnormality reporting is consistently 8-20% but larger studies in the use of these techniques need to be conducted.
The American Academy of Pediatrics in their 2006 guideline Clinical genetic evaluation of the child with mental retardation and developmental delay, states that there are currently insufficient published reports of the use of this technology in individuals with DD/MR. Clinical utility as suggested by AAP includes ending the diagnostic odyssey, improving management through appropriate specialty referrals and advising on risk of recurrence in future reproduction.
The American College of Obstetrics and Gynecology in their committee opinion, Array comparative genomic hybridization in prenatal diagnosis. (November 2009) recommends that conventional karyotyping should remain the principle mode of cytogenic testing in the prenatal setting.
SOURCES
American Academy of Pediatrics. (2006). Clinical genetic evaluation of the child with mental retardation and developmental delays. Retrieved July 19, 2010 from http://www.pediatrics.org/cgi/content/full/117/6/2304.
American College of Medical Genetics. (2007). ACMG practice guidelines. Use of array-based technology in the practice of medical genetics. Retrieved July 20, 2010 from http://www.acmg.net/AM/Template.cfm?Section=Practice_Guidelines&Template=/CM/ContentDisplay.cfm&ContentID=2745.
American College of Obstetricians and Gynecologists. (2009). ACOG committee opinion. Array comparative genomic hybridization in prenatal diagnosis. Retrieved July 21, 2010 from http://www.acog.org/.
BlueCrossBlueShield Association. Medical Policy Reference Manual. (1:2010). Array Comparative Genomic Hybridization (aCGH) for the Genetic Evaluation of Patients with Developmental Delay/Mental Retardation or Autism Spectrum Disorder (2.04.59) Retrieved July 9, 2010 from BlueWeb. (15 article and/or guidelines reviewed)
Canadian College of Medical Geneticists. (2009) CCMG position statement. Use of array genomic hybridization in constitutional genetic diagnosis in Canada. Retrieved August 6, 2010 from http://www.ccmg-ccgm.org/pdf/policy/aCGH%20for%20pch%20sept%2009.pdf.
Shen, Y., Dies, K., Holm, I., Bridgemohan, C., Sobeih, M., Caronna, E., et al. (2010). Clinical genetic testing for patients with autism spectrum disorder. Pediatrics, 125 (4), e727-e736.
Sagoo, G., Butterworth, A., Sanderson, S., Shaw-Smith, C., Higgins, J., & Burton, H., (2009). Array CGH in patients with learning disability (mental retardation) and congenital anomalies: Updated systematic review and meta-analysis of 19 studies and 13.926 subjects. Genetics in Medicine. 11 (3), 139-146. (Level of evidence 1 Industry sponsored)
ORIGINAL EFFECTIVE DATE: 1/8/2011
MOST RECENT REVIEW DATE: 1/8/2011
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