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Medical Policy: 02.04.26
Original Effective Date: September 2009
Reviewed: January 2012
Revised: January 2012
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
Chromosomal microarray (CMA) testing has been proposed for detection of genetic imbalances in infants or children with characteristics of developmental delay/intellectual disability or autism spectrum disorder. G-banded karyotyping has for many years been the standard first-line test for this purpose. G-banded karyotyping allows visualization and analysis of chromosomes for chromosomal rearrangements including genomic gains and losses. Chromosomal microarray (CMA) analysis performs a similar, although non-visual, analysis at a much higher resolution. As a result, CMA has the potential to increase the diagnostic yield in this population and change the clinical interpretation in some cases.
Children with signs of neurodevelopmental delays or disorders in the first few years of life may eventually be diagnosed with intellectual disability or autism syndromes, serious and lifelong conditions that present significant challenges to families and public health. Cases of developmental delay/intellectual disability (DD/ID) and of autism spectrum disorder (ASD) may be associated with genetic abnormalities. 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 targeted genetic testing of specific genes associated with the diagnosed syndrome. However, for children who do not present with an obvious syndrome, or who have an atypical presentation, genetic testing may be used as a basis for establishing a diagnosis.
Current guidelines for these patients, such as those published by the American Academy of Pediatrics (AAP) and the American Academy of Neurology (AAN), recommend cytogenetic evaluation to look for certain kinds of chromosomal abnormalities that may be causally related to their condition. The AAN guidelines note that only in occasional cases will an etiologic diagnosis lead to specific therapy that improves outcomes, but suggest that more immediate and general clinical benefits of achieving a specific genetic diagnosis from the clinical viewpoint, as follows: limit additional diagnostic testing; anticipate and manage associated medical and behavioral comorbidities; improve understanding of treatment and prognosis; and allow counseling regarding risk of recurrence in future offspring and help with reproductive planning.
Conventional methods of cytogenetic analysis, including karyotyping (e.g., G-banded) and fluorescence in situ hybridization (FISH), have relatively low resolution and a low diagnostic yield, leaving the majority of cases without identification of a chromosomal abnormality associated with the child’s condition. CMA analysis is a newer cytogenetic method that increases chromosomal detection of copy number variants (CNVs), and, as a result, increases the genomic detail beyond that of conventional methods. CMA results are clinically informative in the same way as results derived from conventional methods, and thus CMA represents an extension of standard methods with increased resolution.
Comparative genomic hybridization tests are not subject to approval by the U.S. Food and Drug Administration (FDA) because they are laboratory-developed tests. Laboratories performing these tests are, however, subject to Clinical Laboratory Improvement Amendments (CLIA) licensure. Array platforms, assay protocol, and analysis systems vary from laboratory to laboratory.
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Prior Approval:
Prior approval is recommended for this service. Submit a prior approval now.
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Policy:
Chromosomal microarray analysis may be considered medically necessary for diagnosing a genetic abnormality in children with apparent nonsyndromic cognitive developmental delay/intellectual disability (DD/ID) or autism spectrum disorder (ASD) when all of the following conditions are met:
- Any indicated biochemical test for metabolic disease have been performed, and results are nondiagnostic, AND
- FMR1 gene analysis (for Fragile X syndrome), when clinically appropriate, is negative, AND
- In addition to a diagnosis of nonsyndromic DD/ID or ASD, the child has one or more of the following:
- Two or more major malformations, OR
- A single major malformation or multiple minor malformations, in an infant or child who is also small-for dates, OR
- A single major malformation and multiple minor malformations, AND
- The results for the genetic testing have the potential to impact the clinical management of the patient, AND
- Testing is requested after the parent(s) have been engaged in face-to-face genetic counseling with a healthcare professional who has appropriate genetics treating and experience.
Definitions, from the American College of Medical Genetics Guideline, Evaluation of the Newborn with Single or Multiple Congenital Abnormalities:
- A malformation refers to abnormal structural development
- A major malformation is a structural defect that has a significant effect on function or social acceptability. Examples: ventricular septal defect or a cleft lip.
- A minor malformation is a structural abnormality that has a minimal effect on function or societal acceptance. Examples: preauricular ear pit or partial syndactyly (fusion) of the second or third toes.
- A syndrome is a recognizable pattern of multiple malformations. Syndrome diagnoses are often relatively straightforward and common enough to be clinically recognized without specialized testing. Examples include Down syndrome, neural tube defects and achondroplasia. However, in the very young, or in the case of syndromes with variable presentation, confident identification may be difficult without additional testing.
Healthcare professionals who can provide genetic counseling are certified genetic counselors, medical geneticists, pediatric neurologists or developmental pediatricians.
Chromosomal microarray analysis is considered investigational in all other cases of suspected genetic abnormality in children with developmental delay/intellectual disability or autism spectrum disorder.
Chromosomal microarray analysis to confirm the diagnosis of a disorder or syndrome that is routinely diagnosed based on clinical evaluation alone is considered not medically necessary.
Chromosomal microarray analysis is considered investigational for the screening, diagnosis, and management of hematologic and oncologic malignancies.
Chromosomal microarray analysis is considered investigational as a means to predict or evaluate pregnancy loss.
Chromosomal microarray analysis is considered investigational for screening for prenatal genetic mutations.
Chromosomal microarray analysis is considered investigational for all other indications.
Evidence on the clinical benefit for CMA testing is largely anecdotal. Cases have been documented in which the information derived from testing ends a long diagnostic odyssey, aids in planning for surveillance or management of associated comorbidities, and assists in future reproductive decision-making. While systematic studies of the impact of CMA analysis on patient outcomes is lacking, the improvement in diagnostic yield has been well demonstrated, and feedback from physician specialty societies, academic medical centers, and in respected guidelines is consistent in supporting the clinical benefit of CMA testing in the above defined populations.
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Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
- S3870 Comparative genomic hybridization (CGH) microarray testing for developmental delay, autism spectrum disorder and/or mental retardation
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Selected References:
- Edelmann L, Hirschhorn K. Clinical utility of array comparative genomic hybridisation in the diagnosis of learning disability. Ann NY Acad Sci. 2009 Jan; 1151: 157-66.
- Jacquemont ML, Sanlaville D, Redon R et al. Array-based comparative genomic hybridization identifies high frequency of cryptic chromosomal arrangements in patients with syndromic autism spectrum disorders. J Med Genet. 2006 Nov; 43911):843-9.
- Blue Cross Blue Shield Association (BCBSA). Technology Evaluation Center (TEC). Special reports: aCGH for the Genetic Evaluation of Patients with Developmental Delay/Mental Retardation or Autism Spectrum Disorders. TEC Assessment Program. 25(10). Chicago, IL. BCBSA. April 2009. Accessed September 18, 2009. Available at: http://www.bcbs.com/blueresources/tec/vols/23/acgh-genetic-evaluation.html
- ECRI Institute. Array-based Comparative Genomic Hybridization. Plymouth Meeting (PA): ECRI Institute, 2009 August 21. 10 p. [ECRI hotline response]. Accessed September 11, 2009. Available at: http://www.ecri.org
- Shevell MI, Bejjani BA, Srour M et al. Array comparative genomic hybridization in flobal developmental delay. Am J Med Genet B Neuropsychiatr Genet. 2008.
- Baris HN, Tan WH, Kimonis VE et al. Diagnostic utility of array-based comparative genomic hybridization in a clinical setting. Am J Med Genet A. 2007; 143(21):2523-2533.
- Xiang B, Li A, Valentin D et al. Analytical and clinical validity of whole-genome oligonucleotide array comparative genomic hybridization for pediatric patients with mental retardation and developmental delay. Am J Med Genet A. 2008; 146A (15):1942-1954.
- Cheung SW, Shaw CA, Yu W et al. Development and validation of aCGH microarray for clinical cytogenetic diagnosis. Genet Med. 7(6):422-32.
- Fruhman G, Van den Veyver IB. Applications of array comparative genomic hybridization in obstetrics. Obstet Gynecol Clin North Am. 2010 Mar;37(1):71-85
- Sagoo GS, Butterworth AS, Sanderson S et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: an updated systematic review and meta-analysis if 19 studies and 13,926 subjects. Genet Med. 2009 Mar;11(3): 139-46.
- Hilman SC, Pretlove S, Coomarasamy A et al. Additional information from array genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2011 Jan; 37(1):6-14.
- Schaefer GB, Starr L, Pickering D et al. Array comparative genomic hybridization findings in a cohort referred for an autism evaluation. J Child Neurol. 2010 Dec;25(12):1498-503. Epub 2010 Aug 20.
- Korshunov A, Witt H, Hielscher T et al. Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 2010 Jul 1;28(19):2182-90. Epub 2010 Jun1.
- Breckpot J, Thienpont B, Peeters H et al. Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects. J Pediatr 2010 May; 156(5):810-7, 817e1-817e4. Epub 2010 Feb 6.
- Stankiewicz P, Pursley AN, Cheung SW. Challenges in clinical interpretation of microduplications detected by array CGH analysis. Am J Med Genet A. 2010 May;152A(5):1089-100.
- Maciejewski JP, Tiu RV, O'Keefe C. Application of array-based whole genome scanning technologies as a cytogenetic tool in haematological malignancies. Br J Haematol. 2009 Sep;146(5):479-88. Epub 2009 Jun 26.
- Ruano Y, Mollejo M, de Lope AR. Micro-array based genomic hybridization (array-CGH) as a useful tool for identifying genes involved in Glioblastoma (GB). Methods Mol Biol. 2010;653:35-45.
- Michelson DJ, Shevell MI, Sherr EH et al. Evidence Report: Genetic and metabolic testing on children with global developmental delay: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011; 77(17): 1629-35.
- Kearney HM, South ST, Wolff DJ et al. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genet Med 2011; 1397): 676-9.
- Miller DT, Adam MP, Aradhya S et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86(5):749-64.
- Kearney HM, Thorland EC, Brown KK et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011; 13(7): 680-5.
- Shen Y, Dies KA, Holm IA et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010; 125(4): e727-35.
- Cooper GM, Coe BP, Girirajan S et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43(9):838-46.
- South ST, Rector L, Aston E et al. Large clinically consequential imbalances detected at the breakpoints of apparently balanced and inherited chromosome rearrangements. J Mol Diagn 2010; 12(5):725-9.
- Coulter ME, Miller DT, Harris DJ et al. Chromosomal microarray testing influences medial management. Genet Med 2011; 13(9):770-6.
- Freitag CM, Staal W, Klauck SM et al. Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry 2010; 19(3):169-78.
- Hillman SC, Pretlove S, Coomarasamy A et al. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011; 37(1):6-14.
- Manninf M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010; 12(11):742-5.
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Policy History:
Date Reason Action
January 2011 Annual review Policy renewed
January 2012 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.
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