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Chromosomal microarray (CMA) testing has been proposed for detection of genetic imbalances in infants or children with characteristics of developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), and/or congenital anomalies. CMA testing increases the diagnostic yield over karyotyping in this population and may impact clinical management decisions. Next-generation sequencing (NGS) panel testing allows for simultaneous analysis of a large number of genes and has been proposed as a way to identify single-gene causes of syndromes that have autism as a significant clinical feature, in patients with normal CMA testing.
Chromosomal Microarray (CMA) analysis can identify genomic abnormalities associated with a wide range of developmental disabilities, including cognitive impairment, behavioral abnormalities, and congenital abnormalities. CMA testing can detect copy number variants (CNVs) and the frequency of disease-causing CNVs is highest (20%-25%) in children with moderate-to-severe intellectual disability accompanied by malformations or dysmorphic features. Disease-causing CNVs have been identified in 5% to 10% of cases of autism, being more frequent in severe phenotypes.
Developmental Delay/Intellectual Disability and Autism Spectrum Disorder
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 to public health.
The diagnosis of developmental delay (DD) is reserved for children younger than 5 years of age who have significant delay in 2 or more of the following developmental domains: gross or fine motor, speech/language, cognitive, social/personal, and activities of daily living. Intellectual disability (ID) is a life-long disability diagnosed at or after 5 years of age when intelligence quotient (IQ) testing is considered valid and reliable. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), of the American Psychiatric Association defined patients with ID as having an IQ less than 70, onset during childhood, and dysfunction or impairment in more than two areas of adaptive behavior or systems of support.
According to the DMS-IV, pervasive developmental disorders (PDD) encompass 5 conditions: autistic disorder, Asperger disorder, pervasive developmental disorder‒not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett syndrome. Although not mentioned in the DSM-IV, ASD includes the first 3 on the list. One of the major changes between DSM-IV and DSM-5 is the new diagnostic criteria for ASD, which include removing the term pervasive developmental disorders.
Researchers found that the separate diagnoses included in PDD were not consistently applied across different clinics and treatment centers. Under DSM-5, ASD now encompasses the previous DSM-IV autistic disorder (autism), Asperger disorder, childhood disintegrative disorder, and PDD-NOS. Anyone diagnosed with one of the PDDs from DSM-IV should still meet the criteria for ASD in DSM-5.
In the United States, congenital anomalies, which occur in approximately 3% of all newborns, are the leading cause of neonatal morbidity and mortality. Genetic factors have been identified as an important cause for congenital anomalies. Common chromosomal aneuploidies (eg, monosomy X, trisomies 21, 18, and 13) have traditionally been diagnosed in the neonatal period using conventional karyotyping. Improved methods, such as fluorescence in situ hybridization (FISH) using chromosome or locus-specific probes, enable the diagnosis of some of the common microdeletion syndromes (eg, DiGeorge/velocardiofacial syndrome, Cri-du-chat syndrome, Prader-Willi and Angelman syndromes). However, FISH is applicable only in patients with a strong clinical suspicion of a specific genetic defect, which may be difficult to detect in a neonate with congenital anomalies, because a patient's clinical presentation may be atypical or have nonspecific phenotypic features that may be shared by several different disorders, or a young patient may lack specific syndromic features that appear at a later age. An improved rate of detection of CNVs has been shown with the use of array comparative genomic hybridization (aCGH).
Genetic Associations with DD/ID, ASD, and Congenital Anomalies
Developmental delay/intellectual disability and autism spectrum disorder 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, who are too young for full expression of a suspected syndrome, or who may have an atypical presentation, genetic testing may be used as a basis for establishing a diagnosis.
Complex autism, which comprises approximately 20% to 30% of cases of autism, is defined by the presence of dysmorphic features and/or microcephaly. Essential autism, approximately 70% to 80% of autism cases, is defined as autism in the absence of dysmorphology. Genetic causes of autism include cytogenetically visible chromosomal abnormalities (5%), single-gene disorders (5%), and CNVs (10% to 20%). Single-nucleotide polymorphism (SNP) microarrays to perform high-resolution linkage analysis have revealed suggestive regions on certain chromosomes not been previously associated with autism. The SNP findings in autism, to date, seem consistent with other complex diseases, in which common variation has modest effect size (odds ratio, <2), requiring large samples for robust detection. This makes it unlikely that individual SNPs will have high predictive value.
Guidelines for patients with ID/DD, ASD, and/or congenital anomalies, such as those published by the American Academy of Pediatrics (AAP) and the American Academy of Neurology (AAN) with the Child Neurology Society (CNS), have recommended cytogenetic evaluation to look for certain kinds of chromosomal abnormalities that may be causally related to their condition. The joint AAN and CNS guidelines have noted that only in occasional cases will an etiologic diagnosis lead to specific therapy that improves outcomes, but suggest the more immediate and general clinical benefits of achieving a specific genetic diagnosis from the clinical viewpoint, as follows:
The AAP and the AAN and CNS joint guidelines have also emphasized the importance of early diagnosis and intervention in an attempt to ameliorate or improve behavioral and cognitive outcomes over time.
At present, a relatively small body of literature has addressed the use of CMA or other genetic testing for predicting disease phenotype or severity. This is not yet a major clinical use of testing and is not a focus in this policy.
Testing to Determine Genetic Etiology
Most commonly, genetic abnormalities associated with neurodevelopmental disorders are deletions and duplications of large segments of genomic material, called "copy number variants" or CNVs. For many well-described syndromes, the type and location of the chromosomal abnormality have been established with the study of a large number of cases and constitute a genetic diagnosis; for others, only a small number of patients with similar abnormalities may exist to support a genotype-phenotype correlation. Finally, for some patients, cytogenetic analysis will discover entirely new chromosomal abnormalities that will require additional study to determine their clinical significance.
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 (i.e., proportion of tested patients found to have clinically relevant genomic abnormalities), leaving the most cases without identification of a chromosomal abnormality associated with the child's condition. CMA testing is a newer cytogenetic analysis method that increases the chromosomal resolution for detection of 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.
Next-generation sequencing (NGS) has been proposed to detect single-gene causes of autism and possibly identify a syndrome that involves autism in patients with normal array-based testing.
The term CMA collectively describes two different array platforms: aCGH and SNP arrays. Both types of arrays can identify loss or gain of DNA (microdeletions or microduplications, respectively), known as CNVs:
Array Comparative Genomic Hybridization and Single-Nucleotide Polymorphism
The aCGH technique uses a DNA sample from the patient and a DNA sample from a normal control. Each is labeled with one color of fluorescent dye (red or green) and the labeled samples are mixed and hybridized to thousands of cloned or synthesized reference (normal) DNA fragments of known genomic locus immobilized on a glass slide (microarray) to conduct thousands of comparative reactions at the same time. CNVs are determined by computer analysis of the array patterns and intensities of the hybridization signals. If the patient sequence is missing part of the normal sequence (deletion) or has the normal sequence plus additional genomic material within that genomic location (e.g., a duplication of the same sequence), the sequence imbalance is detected as a difference in fluorescence intensity. For this reason, aCGH cannot detect balanced CNVs (equal exchange of material between chromosomes) or sequence inversions (same sequence is present in reverse base pair order) because the fluorescence intensity would not change.
SNPs are the most common genetic variation among people and occur normally throughout the DNA. Each SNP represents a difference in a single nucleotide. On average, SNPs occur every 300 nucleotides. SNPs can act as “biological markers,” in that they may identify genes associated with disease. Most SNPs have no deleterious effect, but may predict an individual’s response to certain drugs, susceptibility to environmental factors, and the risk of developing certain diseases. SNPs may also indicate inheritance of disease genes within families.
A portion of the increased diagnostic yield from CMA over karyotyping comes from the discovery that some chromosomal rearrangements that appear balanced (and therefore not pathogenic) by G-banded karyotype analysis are found to have small imbalances with greater resolution. It has been estimated that 40% of apparently balanced de novo or inherited translocations with abnormal phenotype are associated with cryptic deletion if analyzed by CMA testing.
The various types of microarrarys can differ by construction; earliest versions used DNA fragments cloned from bacterial artificial chromosomes. They have been largely replaced by oligonucleotide (oligos; short, synthesized DNA) arrays, which offer better reproducibility. Oligo/SNP hybrid arrays have been constructed to merge the advantages of each.
Microarrays may be prepared by the laboratory utilizing the technology, or, more commonly, by commercial manufacturers, and sold to laboratories that must qualify and validate the product for use in their assay, in conjunction with computerized software for interpretation. The proliferation of in-house developed and commercially available platforms prompted the American College of Medical Genetics (ACMG) to publish guidelines for the design and performance expectations for clinical microarrays and associated software in the postnatal setting.
Copy Number Variants
Targeted CMA provides high-resolution coverage of the genome primarily in areas containing known, clinically significant CNVs. The ACMG guideline for designing microarrays recommends probe enrichment in clinically significant areas of the genome to maximize detection of known abnormalities, but also recommends against the use of targeted arrays in the postnatal setting. Rather, a broad genomic screen is recommended to identify atypical, complex, or completely new rearrangements, and to accurately delineate breakpoints.
Whole-genome CMA analysis has allowed the characterization of several new genetic syndromes, with other potential candidates currently under study. However, the whole-genome arrays also have the disadvantage of potentially high numbers of apparent false-positive results, because benign CNVs are also found in phenotypically normal populations; both benign and pathogenic CNVs are continuously cataloged, and to some extent, made available in public reference databases to aid in clinical interpretation. Additionally, some new CNVs are neither known to be benign nor causal; these CNVs may require detailed family history and family genetic testing to determine clinical significance and/or may require confirmation by subsequent accumulation of similar cases and so, for a time, may be considered a CNV of undetermined significance (some may eventually be confirmed true positives or causal, others false positives or benign).
To determine clinical relevance (consistent association with a disease) of CNV findings, the following actions are taken:
ACMG has also published guidelines for the interpretation and reporting of CNVs in the postnatal setting, to promote consistency among laboratories and CMA results. Three categories of clinical significance are recommended for reporting: pathogenic, benign, and uncertain clinical significance.
In 2008, the International Standards for Cytogenomic Arrays (ISCA) Consortium was organized; it has established a public database containing de-identified whole-genome microarray data from a subset of the ISCA Consortium member clinical diagnostic laboratories. Array analysis was carried out on subjects with phenotypes including intellectual disability, autism, and developmental delay. As of August 2016, there were over 53,000 subjects with individual-level data in the database. Additional members are planning to contribute data; participating members use an opt-out, rather than an opt-in approach that was approved by the National Institutes of Health (NIH) and participating center institutional review boards. The database is held at National Center for Biotechnology Infromation/NIH and curated by a committee of clinical genetics laboratory experts. In 2011, Kaminsky and colleagues used data from the ISCA consortium, including 15,749 cases and 10,118 published controls available at the time of analysis, to identify the functional significance of 14 rare CNVs in intellectual and developmental disabilities, and to describe a methodology for assessing for pathologic CNVs. In this study, the frequency of pathogenic CNVs was 17.1%.
NGS involves the sequencing of millions of fragments of genetic material in a massively parallel fashion. NGS can be performed on segments of genetic material of a variety of sizes--from the entire genome (whole-genome sequencing) to small subsets of genes (targeted sequencing). NGS allows the detection of SNPs, CNVs, and insertions and deletions. With higher resolution comes higher likelihood of detection of variants of uncertain clinical significance.
Commercially Available Tests
Chromosomal Microarray Analysis
CMA testing is commercially available through many laboratories and includes targeted and whole-genome arrays, with or without SNP microarray analysis.
Affymetrix CytoScan Dx has been cleared by the U.S. Food and Drug Administration (FDA) through the de novo 510(k) process. FDA’s review of the CytoScan Dx Assay included an analytic evaluation of the test’s ability to accurately detect numerous chromosomal variations of different types, sizes, and genome locations compared with several analytically validated test methods. FDA found that the CytoScan Dx Assay could analyze a patient’s entire genome and adequately detect chromosome variations in regions of the genome associated with ID/DD. Reproducibility decreased with the CNV gain or loss size, particularly when less than approximately 400 kilobases (kb; generally recommended as the lower reporting limit).
FirstStepDx PLUS (Lineagen, Salt Lake City, UT) uses Lineagen’s custom-designed microarray platform manufactured by Affymetrix. This microarray consists of 1,953,246 unique nonpolymorphic probes and 743,304 SNP probes that come standard on the Affymetrix CytoScan HD® microarray, with an additional 83,443 custom probes designed by Lineagen.
Ambry Genetics (Aliso Viejo, CA) offers multiple tests (CMA and NGS) that are designed for ASD and neurodevelopmental disorders.
LabCorp offers the Reveal SNP Microarray-Pediatric for individuals with non-syndromic congenital anomalies, dysmorphic features, DD/ID, and/or ASD.
A variety of commercial and academic laboratories offer NGS panels designed for the evaluation of ASD, DD/ID, and congenital anomalies, which vary in terms of the numbers of and specific genes tested.
Courtagen (Woburn, MA) offers 3 NGS panels intended for the assessment of developmental and behavioral phenotypes:
Emory Genetics Laboratory offers an NGS ASD panel of genes targeting genetic syndromes that include autism or autistic features.
Greenwood Genetics Center (Greenwood, SC) offers an NGS panel for syndromic autism that includes 83 genes.
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). Lab tests for CMA testing and NGS are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
In July 2010, the FDA indicated that it would require microarray manufacturers to seek clearance to sell their products for use in clinical cytogenetics.
On January 17, 2014, the Affymetrix CytoScan® Dx Assay was cleared for marketing by FDA through the de novo classification process. For the de novo petition, FDA’s review of the CytoScan® Dx Assay included an analytic evaluation of the test’s ability to accurately detect numerous chromosomal variations of different types, sizes, and genome locations compared with several analytically validated test methods. FDA found that the CytoScan® Dx Assay could analyze a patient’s entire genome and adequately detect chromosome variations in regions of the genome associated with intellectual and developmental disabilities.
Related medical policies -
Chromosomal microarray analysis may be considered medically necessary as first-line testing in the initial postnatal evaluation of individuals with any of the following:
Panel testing using next-generation sequencing is considered investigational in all cases of suspected genetic abnormality in children with developmental delay/intellectual disability, autism spectrum disorder, or congenital anomalies.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
A 2013 guidelines update from American College of Medical Genetics stated that a stepwise or tiered approach to the clinical genetic diagnostic evaluation of autism spectrum disorder is recommended, with the recommendation being for first tier to include fragile X syndrome and chromosomal microarray analysis (CMA).
In some cases of CMA, the laboratory performing the test confirms all reported copy number variants with an alternative technology such as FISH analysis.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY03/25/2010: Approved by Medical Policy Advisory Committee
04/11/2012: Changed "Array Comparative Genomic Hybridization (aCGH)" to "Chromosomal Microarray (CMA) Analysis" in the policy title and throughout the policy. Policy statement revised to state that testing may be considered medically necessary for infants and children with developmental delay, intellectual disability, or autism spectrum disorder under certain conditions. Also changed "mental retardation" to "intellectual disability" throughout the policy and in the title. Added 81228 and 81229 to the Code Reference section and moved S3870 to the Covered Codes table.
04/18/2013: Policy reviewed; no changes.
07/11/2014: Policy title changed from "Chromosomal Microarray (CMA) Analysis for the Genetic Evaluation of Patients with Developmental Delay/Intellectual Disability or Autism Spectrum Disorder" to "Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for Prenatal Evaluation and the Evaluation of Children With Developmental Delay/Intellectual Disability or Autism Spectrum Disorder." Policy statement updated to add the following: 1) Panel testing using next-generation sequencing is considered investigational in all cases of suspected genetic abnormality in children with developmental delay/intellectual disability or autism spectrum disorder. 2) Chromosomal microarray analysis is considered investigational for prenatal genetic testing.
12/31/2014: Policy reviewed; description updated regarding chromosomal microarray and next-generation sequencing testing. Policy statements unchanged. Added the following new 2015 CPT codes to the Code Reference section: 81470 and 81471.
07/30/2015: Policy title changed from "Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for Prenatal Evaluation and the Evaluation of Children With Developmental Delay/Intellectual Disability or Autism Spectrum Disorder" to "Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for the Evaluation of Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and/or Congenital Anomalies." Policy description updated to add information regarding developmental delay/intellectual disability, autism spectrum disorder, congenital anomalies, and CMA analysis to determine genetic etiology. Removed the following policy statement: Chromosomal microarray analysis is considered investigational for prenatal genetic testing. Added link to the Invasive Prenatal (Fetal) Diagnostic Testing medical policy.
08/26/2015: Medical policy revised to add ICD-10 codes.
02/29/2016: Policy description updated regarding CMA testing. Medically necessary statement revised to state that CMA may be considered medically necessary as first-line testing in the initial postnatal evaluation of individuals with any of the following: apparently nonsyndromic developmental delay/intellectual disability, autism spectrum disorder, and multiple congenital anomalies not specific to a well-delineated genetic syndrome. Removed the following statements: 1) CMA is investigational in all other cases suspected of genetic abnormality in children with DD/ID or ASD. 2) CMA to confirm the diagnosis of a disorder or syndrome that is routinely diagnosed based on clinical evaluation alone is not medically necessary. Added congenital anomalies to investigational statement for panel testing using NGS. Removed ACMG definitions in policy guidelines and added current guidelines, genetic counseling information, and medically necessary and investigative definitions. Code descriptions updated in Code Reference section to change "mental retardation" to "intellectual disabilities."
06/06/2016: Policy number A.2.04.59 added.
09/16/2016: Policy title changed from "Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for the Evaluation of Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and/or Congenital Anomalies" to "Genetic Testing for Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies." Policy description updated regarding next-generation sequencing. Policy statements unchanged. Code Reference section updated to make correction: ICD-10 diagnosis code F80.00 should be F80.0.
SOURCESBlue Cross Blue Shield Association Policy # 2.04.59
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.