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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
Chromosomal microarray analysis (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 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.
CMA can identify genomic abnormalities that are associated with a wide range of developmental disabilities, including cognitive impairment, behavioral abnormalities, and congenital abnormalities. CMA 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. Cases of 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.
The diagnosis of 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.
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 defines 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 in 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.
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 cases of autism, 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 which had 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.
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 recognized to be 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 such as DiGeorge/velocardiofacial syndrome, Cri-du-chat syndrome, and 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 in neonates with congenital anomalies, as their clinical presentation may be atypical, they may have nonspecific phenotypic features which may be shared by several different disorders, or they 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).
Current 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), recommend cytogenetic evaluation to look for certain kinds of chromosomal abnormalities that may be causally related to their condition. The AAN/CNS guidelines note 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:
AAP and AAN/CNS guidelines also emphasize the importance of early diagnosis and intervention in an attempt to ameliorate or improve behavioral and cognitive outcomes over time.
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 has been established with the study of large number of cases and constitutes 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 with clinically relevant genomic abnormalities), leaving the majority of cases without identification of a chromosomal abnormality associated with the child's condition. CMA 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.
CMA Analysis to Determine Genetic Etiology
The term CMA collectively describes 2 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:
A portion of the increased diagnostic yield from CMA analysis 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.
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.
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 (Available online at: https://www.iscaconsortium.org/index.php); 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 November 2011, there were over 28,500 total cases 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. A 2012 update from the ISCA summarizes its experience as a model for ongoing efforts to incorporate phenotypic data with genotypic data to improve the quality of research and clinical care in genetics.
Use of the database includes an intralaboratory curation process, whereby laboratories are alerted to any inconsistencies amongst their own reported CNVs or other mutations, as well as any inconsistent with the ISCA “known” pathogenic and “known” benign lists. The intralaboratory conflict rate was initially about 3% overall; following release of the first ISCA curated track, the intralaboratory conflict rate decreased to about 1.5%. A planned interlaboratory curation process, whereby a group of experts curates reported CNVs/mutations across laboratories, is currently in progress.
The Consortium recently proposed “an evidence-based approach to guide the development of content on chromosomal microarrays and to support interpretation of clinically significant copy number variation.” The proposal defines levels of evidence (from the literature and/or the ISCA and other public databases) that describe how well or how poorly detected mutations or CNVs are correlated with phenotype.
The consortium is also developing vendor-neutral recommendations for standards for the design, resolution, and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics, genomics, and bioinformatics.
Commercially Available Tests
Chromosomal Microarray Analysis
CMA testing is commercially available through many laboratories, and include 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 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.
FirstStepDx PLUS is an integrated service that combines proprietary genetic testing, reporting, and genetic counseling.
Ambry Genetics offers a 180 K oligo array and a combined SNP plus aCGH array and states that the tests should be considered for all individuals with syndromic or non-syndromic conditions that may be caused by genomic imbalance.
LabCorp offers the Reveal SNP Microarray-Pediatric for individuals with non-syndromic congenital anomalies, dysmorphic features, DD/ID, mental retardation, and/or ASD.
Emory Genetics Laboratory offers an NGS ASD panel of 61 genes that target genetic syndromes that include autism or autistic features. These genes have been associated with nonsyndromic autism and genes associated with conditions involved in the differential diagnosis of Rett syndrome and/or Angelman syndrome. The panel is offered as tier 2 testing after tier 1 cytogenetics, molecular and biochemical testing, which includes array testing, fragile X CGG repeat analysis, and biochemical testing for some metabolic conditions.
Greenwood Genetics Center offers an NGS panel that includes 62 genes and flanking introns. The panel includes autosomal and X-linked genes that represent the most common single-gene etiologies associated with a syndrome that includes autism as a significant clinical feature. The test is offered as an option for patients with syndromal autism and normal cytogenetic/array-based testing, or as a second tier test for patients with a phenotype that resembles Rett or Angelman syndrome.
Both the Emory and Greenwood Genetics panels use RainDance technology, and the Greenwood Lab panel was developed jointly with Emory.
The Department of Genetics and Genomic Sciences at the Mount Sinai School of Medicine offers a 30-gene sequencing panel.
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 Act (CLIA). Lab tests for CMA 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 the Agency will in the future require microarray manufacturers to seek clearance in order to sell their products for use in clinical cytogenetics.
On January 17, 2014, FDA cleared for marketing the Affymetrix CytoScan® Dx Assay. FDA reviewed the Affymetrix CytoScan Dx Assay through its 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 when 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.
A 2013 guidelines update from American College of Medical Genetics (ACMG) states 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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
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 added.
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.