Genetic Testing, Including Chromosomal Microarray (CMA) Analysis and Next-Generation Sequencing (NGS) Panels, for the Evaluation of Children with Developmental Delay/Intellectual Disability or Autism Spectrum Disorder

Number 12.04.59

Effective Date December 8, 2014

Revision Date(s) 12/08/14; 12/09/13; 02/14/12

Replaces 2.04.59


Chromosomal microarray analysis (CMA) 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) according to accepted Diagnostic and Statistical Manual of Mental Disorders-IV criteria when all of the following conditions are met (see Policy Guidelines for definitions):

  • Any indicated biochemical tests for metabolic disease have been performed, and results are non-diagnostic, and
  • FMR1 gene analysis (for Fragile X), when clinically indicated, 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 training and experience.

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 (see Policy Guidelines) is not medically necessary.

Panel testing using next-generation sequencing (NGS) is considered investigational in all cases of suspected genetic abnormality in children with developmental delay/intellectual disability or autism spectrum disorder

Related Policies


Genetic Testing for FMR1 mutations (including Fragile X Syndrome)


Invasive Prenatal (Fetal) Diagnostic Testing


Chromosomal Microarray Testing for the Evaluation of Early Pregnancy Loss and Intrauterine Fetal Demise


Preimplantation Genetic Testing in Embryos

Policy Guidelines

Definitions, from the American College of Medical Genetics Guideline, Evaluation of the Newborn with Single or Multiple Congenital Anomalies (1):

  • A malformation refers to abnormal structural development.
  • A major malformation is a structural defect that has a significant effect on function or social acceptability. Example: ventricular septal defect or a cleft lip.
  • A minor malformation is a structural abnormality that has minimal effect on function or societal acceptance. Examples: preauricular ear pit or partial syndactyly (fusion) of the second and 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.

In some cases of CMA analysis, the laboratory performing the test confirms all reported CNVs with an alternative technology such as FISH analysis.




Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)


Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities


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) or autism spectrum disorder (ASD). 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. CMA analysis performs a similar, although nonvisual, analysis at a much higher resolution. As a result, CMA has the potential to increase the diagnostic yield in this population and change clinical interpretation in some cases. However, the diagnostic yield remains low in unselected populations without accompanying signs and/or symptoms. In individuals with apparent nonsyndromic DD/ID, or suspected ASD and accompanying malformations, the diagnostic yield is much higher and is higher than the yield of karyotype testing.

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 DD/ID and of 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, 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.

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. AAN 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 (2):

  • 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.

AAP and AAN 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 a 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 found to have clinically relevant genomic abnormalities), leaving most cases without identification of a chromosomal abnormality associated with the child’s condition. CMA analysis 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.

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

CMA analysis detects CNVs by comparing a reference genomic sequence (“normal”) with the corresponding patient sequence. Each sample has a different fluorescent label so that they can be distinguished, and both are co-hybridized to a sample of a specific reference (also normal) DNA fragment of known genomic locus. 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, standard CMA (non-single nucleotide polymorphisms (SNP), see following) 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.

CMA analysis uses thousands of cloned or synthesized DNA fragments of known genomic locus immobilized on a glass slide (microarray) to conduct thousands of comparative reactions at the same time. The prepared sample and control DNA are hybridized to the fragments on the slide, and CNVs are determined by computer analysis of the array patterns and intensities of the hybridization signals. Array resolution is limited only by the average size of the fragment used and by the chromosomal distance between loci represented by the reference DNA fragments on the slide.

There are some differences in CMA technology, most notably in the various types of microarrays. They can differ first by construction; earliest versions were used of DNA fragments cloned from bacterial artificial chromosomes. These have been largely replaced by oligonucleotide (oligos; short, synthesized DNA) arrays, which offer better reproducibility. Finally, arrays that detect hundreds of thousands of SNPs across the genome have some advantages as well. Oligo/SNP hybrid arrays have been constructed to merge the advantages of each. Regardless of the array components used, all microarrays allow the deposition of many thousands of short, DNA probe sequences on a small, solid surface in an orderly fashion. The location of each known probe sequence allows the identification of the test sequence bound to it, and when compared with a control sequence, the identification of missing sequences or sequences with extra copies (i.e., copy number variants).

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.(3)

Targeted CMA analysis 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:

  • CNVs are confirmed by another method (e.g., FISH, multiplex ligation-dependent probe amplification, polymerase chain reaction,).
  • CNVs detected are checked against public databases and, if available, against private databases maintained by the laboratory. Known pathogenic CNVs associated with the same or similar phenotype as the patient are assumed to explain the etiology of the case; known benign CNVs are assumed to be nonpathogenic. (4-6)
  • A pathogenic etiology is additionally supported when a CNV includes a gene known to cause the phenotype when inactivated (microdeletion) or overexpressed (microduplication).5
  • The laboratory may establish a size cutoff; potentially pathogenic CNVs are likely to be larger than benign polymorphic CNVs; cutoffs for CNVs not previously reported typically range from 300 kb to 1 Mb.6-9
  • Parental studies are indicated when CNVs of appropriate size are detected and not found in available databases; CNVs inherited from a clinically normal parent are assumed to be benign polymorphisms whereas those appearing de novo are likely pathogenic; etiology may become more certain as other similar cases accrue. (4,10)

ACMG has also published guidelines for the interpretation and reporting of CNVs in the postnatal setting, to promote consistency among laboratories and CMA results. (11) 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:; 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 the National Center for Biotechnology Information/NIH and curated by a committee of clinical genetics laboratory experts.

A 2012 update from the ISCA summarizes their 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. (12)

Use of the database includes an intralaboratory curation process, whereby laboratories are alerted to any inconsistencies among their own reported CNVs or other mutations, as well as any not consistent 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 will apparently coordinate a volunteer effort to describe the evidence for targeted regions across the genome.

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

CMA testing is commercially available through many laboratories, and includes targeted and whole genome arrays, with or without SNP microarray analysis.

Next-Generation Sequencing

Emory Genetics Laboratory offers a 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 a 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.

Regulatory Status

CMA analysis and NGS are commercially available from several laboratories as laboratory-developed tests. Laboratory-developed tests performed by laboratories licensed for high complexity testing under the Clinical Laboratory Improvement Amendments do not require U.S. Food and Drug Administration (FDA) clearance for marketing.

At a meeting hosted by FDA in July 2010, FDA indicated that the Agency will in the future require microarray manufacturers to seek clearance 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.


Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application



This policy was created in 2010, and has been updated regularly with a search of the MEDLINE literature, with the most recent search through March 2, 2014.

This policy is based on a TEC Special Report on array comparative genomic hybridization (aCGH). (13) Since that Report was written, the technology has rapidly increased in resolution, and chromosomal microarray (CMA) has become the term of general use to accommodate all variations in the technology. Increased resolution arrays have been quickly translated to clinical services with a resulting increase in diagnostic yield, but also an increase in the potential for results of undetermined significance. Surveys conducted 2 to 3 years ago indicated that there is a lack of consensus between laboratories in the interpretation and reporting of copy number variants (CNVs), particularly those that are challenging. (14) The International Standards for Cytogenomic Arrays (ISCA) database now offers increased standardization and classification of CNVs that have been previously reported and should improve consensus in reporting.

Diagnosis of Developmental Delay/Intellectual Disability or Autism Spectrum Disorder

The diagnosis of developmental delay (DD) is reserved for children younger than age five years who have significant delay in two or more of the following developmental domains: gross or fine motor, speech/language, cognitive, social/personal, and activities of daily living. (15) The diagnosis implies DD that may be significant and may predict life-long disability, although not all children diagnosed with DD will later be diagnosed with intellectual disability (ID).

ID is a life-long disability diagnosed at or after age 5 years when intelligence quotient (IQ) testing is considered valid and reliable. The Diagnostic and Statistical Manual of Mental Disorders (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 of areas of adaptive behavior or systems of support.

According to the DSM-IV, pervasive developmental disorders (PDD) encompass five conditions: autistic disorder, Asperger disorder, pervasive developmental disordernot otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett syndrome. While the term autism spectrum disorder (ASD) is not mentioned in the DSM-IV, it is now accepted to include the first three in this list. However, ASD, PDD, and autism are often used interchangeably. (16) These conditions are characterized by varying degrees of restrictions in communication and social interaction, and atypical behaviors.

Some children present with features of both DD/ID and of autism. For example, Yeargin-Allsopp et al. (17) reported that nearly 70% of children with a validated diagnosis of ASD, sampled from five metropolitan Atlanta counties, had cognitive impairment. The evaluation pathway depends on the pediatrician, consulting specialists, and their consensus on the primary neurodevelopmental diagnosis.

Review of Evidence

Chromosomal Microarray

Several studies (see Appendix B13) have conducted CMA analysis on samples with known chromosomal abnormalities by standard karyotyping. In general, currently available CMA clinical services achieve near 100% sensitivity for known chromosomal abnormalities. False-positive rates (i.e., CNVs of undetermined clinical significance) on known normal samples were inconsistently reported and could not be summarized. One study evaluated the analytic validity of an oligo array and reported 99% sensitivity and 99% specificity, with a resolution of 300 to 500 kilobases (Kb) for 10 selected cases with different known chromosomal abnormalities. (18)

Several studies reported the diagnostic yield of CMA analysis in DD/ID or ASD patients with normal standard karyotype and in several cases normal FMR1 gene analysis and/or subtelomere FISH screening (see Appendix C in (13)). Overall, diagnostic yield ranged from 5% to 16.7% in DD/ID patients and from 3.4%to 11.6% in patients with ASD; for this compilation, studies differed considerably in array resolution and in patient selection criteria. This compares well with a synthesis of studies recently published by the ISCA Consortium, reporting an average diagnostic yield of 12.2% across 33 studies. (7) Hochstenback et al. reported a CMA diagnostic yield of 19% for 36,325 DD/ID cytogenetic referrals in the Netherlands (19); and Shen et al. reported a 7% diagnostic yield among 933 ASD referrals. (20) Cooper et al. studied CMA analyses from over 15,000 individuals with DD/ID, ASD, and/or various congenital abnormalities and compared them with CMA analyses from over 8,000 unaffected controls, finding a significant excess of large CNVs among cases compared with controls. (21) Using a common cutoff for CNV size, about 26% of cases had a CNV larger than 400 kb compared with about 12% of controls, suggesting that CNVs of this size account for approximately 14% of cases. CNVs larger than 400 kb were also significantly more common among cases with multiple congenital abnormalities.

Since the introduction of CMA analysis in about 2005, 18 new genomic disorders have been described, more than doubling the number of disorders described in the previous 20 years. (22) Using CMA in place of conventional cytogenetic testing would have missed 0.6% to 0.8% of all cases, i.e., those with balanced translocations. (19, 23)

A portion of the increased diagnostic yield from CMA analysis 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. (24) This contradicts earlier assumptions about inherited, apparently balanced rearrangements and shows that microarray analysis can allow for a less subjective and more accurate interpretation of an abnormal banding pattern. (25)

Neither standard cytogenetic nor CMA analysis have been systematically studied for impact on clinical outcomes other than diagnosis (26, 27); Schaefer and Mendelsohn (28) acknowledge, for example, that a genetic diagnosis “typically will not change interventions for the [autism] patient.” Rather, clinical utility of genetic testing is primarily inferred based on the value of diagnosis to the family, estimation of recurrence risk, and on the importance of early detection and early intervention. (27) Two studies indirectly addressed clinical outcomes other than diagnosis as a result of CMA analysis.

Saam et al. (29) interviewed 14 physicians (two neurologists, 12 medical geneticists) regarding management changes as a result of positive CMA test results from the University of Utah Cytogenetics Laboratory for 48 patients with DD or ID and normal karyotypes. Only 29% of patients had no management changes reported. For significant proportions of patients, the diagnostic odyssey was ended. However, this study was only a survey and did not attempt to quantitate the diagnostic tests avoided. Saam et al. (29) also reported that 14.6% of patients with genetic diagnoses were referred to medical specialists, and 25% had improved access to insurance and educational services, but the study did not assess the benefits of specialist referrals or screening for comorbidities on patient outcomes, or describe and quantitate the improvement in access to community services.

Coulter et al. identified and reviewed, over the course of 1 year, the medical records of all patients at a tertiary children’s hospital who had CMA results showing an abnormal variant or a variant of possible significance. (30) A board-certified medical geneticist reviewed the clinical notes from the ordering provider and abstracted recommendations for clinical actions (a specialist referral, imaging study, diagnostic test, or medication prescription) made specifically as a result of the CMA result. Of 1,792 patients for whom CMA was ordered during the year reviewed, 131 had an abnormal variant and 104 had a variant of possible significance. Of these, 121 and 73 patients were included in the analysis. Overall, patients with an abnormal variant had a significantly higher rate of recommended clinical action (54%) than patients with a variant of possible significance (34%; p=0.01). Among patients with an abnormal variant and a diagnosis of DD/ID or congenital anomalies, about two-thirds of patients were referred for additional clinical action based on the CMA results, whereas referrals were made for 27% of patients with ASD and an abnormal variant. Referral rates were similar for patients with a CMA result of a variant of possible significance, with the exception of patients with congenital anomalies, who were referred for additional clinical action only 17% of the time. Patients younger than 2 years were significantly more likely to have clinical anomalies and were significantly more likely to have abnormal variants. Cases were described in which ancillary CMA results suggested clinical interventions for the present or future regarding possible co-morbid conditions. In no patients, however, were referrals linked to actual patient outcomes; the authors report that this study is ongoing.

Risk estimates for recurrence of disease in future births can be altered considerably by information from the genetic diagnosis. For example, the average sibling recurrence risk in ASD is 5%. (31) However, if the cause is a dominant single gene disorder with full penetrance and a parent is a carrier, the sibling risk is 50%. If the disorder is recessive but characteristics are otherwise the same, the sibling risk is 25%. If the cause is Fragile X, the recurrence risk in a brother is 50%, while a sister may be only mildly affected but will have a carrier risk of up to 50%. However, in the case of a de novo CNV (i.e., not carried by either parent), the sibling risk remains low, at the population average.

Knowledge of recurrence risk is expected to lead to improved future reproductive decision-making in families with children affected with DD/ID or ASD associated with specific mutations. Turner et al. (32) studied the reproductive decisions of women from 38 families characterized by male members with and a pattern consistent with chromosome X-linked transmission. Most of the women in these families spent many years knowing that they were at some risk of being carriers and of having a boy with mental retardation. Before the availability of pathogenic mutation analysis, the birth rate for these families was below average for the district (United Kingdom-New South Wales), one in 27 versus one in 11 per year, respectively. After pathogenic mutation status was determined, both carriers and non-carriers (previously thought to be at risk) of the mutation had children at the same rate, with 74% of carriers choosing prenatal genetic evaluation. While the results of this study are suggestive, they do not show that knowledge of recurrence risk directly affected reproductive decisions. Saam et al., (29) in the survey described previously, reported that recurrence risk evaluation was possible in about one-third of families after positive aCGH results but did not study the impact of recurrence risk evaluation on reproductive planning.

As noted in the Description, guidelines emphasize the importance of cytogenetic evaluation to look for certain kinds of mutations that may be linked to specific conditions for early diagnosis and intervention. However, the benefits of early intervention for these disorders are uncertain. Few randomized trials have been conducted, and the interventions differ considerably in the available studies, indicating that the field is still early in researching the critical elements of effective early intervention. For well-characterized genetic syndromes, it may be important to incorporate monitoring for comorbidities known to be associated with the condition. For example, 22q11 microdeletion syndrome (includes diGeorge and velo-cardio-facial syndromes) is associated with development of hearing impairment in a significant proportion of patients and subsequent delayed speech. (33) Velo-cardio-facial syndrome is also associated with heart defects. (31) Klinefelter syndrome may first be detected as developmental delay in early childhood; androgen treatment is an important component of therapy. (31) CMA analysis may also predict future conditions for which interventions are possible. In a report of 3 cases, one patient had a chromosomal deletion that included a gene associated with autosomal dominant Peutz-Jeghers syndrome (PJS); tumor screening protocols for males with PJS generally begin with upper and lower endoscopy with small-bowel follow-through radiographs beginning at age 8 years. (34) Two other patients had a de novo deletion of chromosome 17p encompassing the TP53 tumor suppressor gene responsible for Li-Fraumeni syndrome (LFS); tumor screening protocols for LFS also begin in childhood. In another report, a child presenting to a neurology service with unusual behaviors was found to have a deletion that included exons of the DMD gene associated with Becker muscular dystrophy (BMD). Additional testing revealed a markedly elevated creatine kinase, and a thorough physical exam was consistent with BMD. This diagnosis explained some of the child’s behavior and prompted a plan for future surveillance for cardiac and other complications of BMD, as well as carrier testing and surveillance of the child’s mother. (30)

Ellison et al. reported on the clinical utility of CMA in a total of 46,298 postnatal patients. (35) Testing was for a variety of indications, including DD/ID, congenital anomalies, dysmorphic features and neurobehavioral problems. The authors tallied the detection of abnormalities associated with actionable clinical features (i.e., diagnoses which would likely lead to changes in clinical management). A total of 2,088 diagnoses were made of 118 clinically actionable disorders; of these, it was estimated that 94% would likely have been missed by routine karyotyping. Examples of clinically actionable responses to the diagnoses included an electrocardiogram and cardiology referral for those at risk for long QT syndrome, glucose monitoring and endocrine referral for those at increased risk of diabetes, renal ultrasound for those at risk for renal pathology, and platelet count monitoring for those at risk for thrombocytopenia. A subset of cases was monitored for physician response to the microarray finding, and appropriate clinical action was taken more than 90% of the time.

Next-Generation Sequencing

Analytic Validity

Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent.

No peer-reviewed, full-length publications on the analytic validity of the commercially available next-generation sequencing (NGS) ASD panels are identified.

Clinical Validity

Clinical validity is the diagnostic performance of the test (sensitivity, specificity, and positive and negative predictive values) in detecting clinical disease.

No peer-reviewed, full-length publications on the clinical validity of the commercially available NGS ASD panels are identified. According to 1 laboratory’s website, this type of sequencing will pick up more than 97% of DNA mutations at the level of a few base pairs, but that for most genes on the panel, the clinical sensitivity of the assay cannot be estimated individually, because each gene is a rare cause of ASD. (36)

Clinical Utility

Clinical utility is 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.

No peer-reviewed, full-length publications on the clinical utility of the commercially available NGS ASD panels are identified. Importantly, no published data on the rate of variants of unknown significance using NGS panels for autism have been identified.

Clinical Input Received from Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. In response to requests, clinical input was received through 3 physician specialty societies and 2 academic medical centers while this policy was under review in early 2010. Those providing input supported use of targeted CMA analysis in children with DD/ID or ASD in several situations. There was less support for whole-genome array testing. However, targeted array testing is now primarily available for prenatal analysis, whereas whole-genome arrays are recommended as standard.

In 2011, clinical input was obtained with emphasis on the clinical utility of CMA testing. As in 2010, reviewers supported the use of CMA testing for the diagnosis in patients with development disorders and autism spectrum disorder. Reviewers acknowledged the lack of evidence in the literature on clinical utility, such as the lack of literature demonstrating improved outcomes as a result of testing. Reviewers cited multiple anecdotal and theoretical clinical situations in which management changes resulted from results of CMA testing. Reviewers also agreed that this test was widely used in standard care with the support of the genetics community.

Summary of Evidence

Chromosomal microarray analysis

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) or autism spectrum disorder (ASD). 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. CMA analysis performs a similar, although nonvisual, analysis at a much higher resolution. As a result, CMA has the potential to increase the diagnostic yield in this population and change clinical interpretation in some cases. However, the diagnostic yield remains low in unselected populations without accompanying signs and/or symptoms. In individuals with apparent nonsyndromic DD/ID, or suspected ASD and accompanying malformations, the diagnostic yield is much higher and is higher than the yield of karyotype testing.

Evidence on the clinical benefit of 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 for defined populations. As a result, CMA may be considered medically necessary in individuals with developmental delay or ASDs who meet the clinical criteria defined the policy statement.

Next-Generation Sequencing Panels

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.

Published data on analytic and clinical validity, clinical utility and variants of unknown significance using NGS panels in this setting are lacking, and therefore, panel testing using NGS is considered investigational in all cases of suspected genetic abnormality in children with DD/ID or ASD.

Practice Guidelines and Position Statements

The American Academy of Neurology and the Practice Committee of the Child Neurology Society updated their guideline regarding the evaluation of unexplained global DD/ID with information on genetic and metabolic (biochemical) testing in order to accommodate advances in the field. (2) The guidelines conclude that CMA testing has the highest diagnostic yield in children with DD/ID, that the often complex results require confirmation and careful interpretation, often with the assistance of a medical geneticist and that CMA should be considered the first-line test. The guidelines acknowledge that “Research is sorely lacking on the medical, social, and financial benefits of having an accurate etiologic diagnosis.”

The American College of Medical Genetics (ACMG) published guidelines on array-based technologies and their clinical utilization for detecting chromosomal abnormalities. (37) Chromosomal microarray testing for copy number variation is recommended as a first-line test in the initial postnatal evaluation of individuals with the following:

  1. Multiple anomalies not specific to a well-delineated genetic syndrome
  2. Apparently non-syndromic developmental delay/ intellectual disability
  3. Autism spectrum disorders

ACMG also recommends against use of CMA in cases of multiple miscarriages.

Additional ACMG guidelines have been published for the design and performance expectations for clinical microarrays and associated software (3) and for the interpretation and reporting of CNVs, (11) both intended for the postnatal setting. A 2013 update includes recommendations for validation of microarray methodologies for both prenatal and postnatal specimens. (38)

The International Standard Cytogenomic Array Consortium published a Consensus Statement in which they recommend offering CMA as the first-tier genetic test, in place of G-banded karyotype, for patients with unexplained DD/ID, ASD, or multiple congenital anomalies (MCA). “Except in special cases, such as those involving family history of multiple miscarriages, a karyotype is not cost effective in a child with DD/ID, ASD, or MCA and a negative array study. CMA testing is not inexpensive, but the cost is less than the cost of a G-banded karyotype plus a customized FISH test such as subtelomeric FISH, and the yield is greater.” (7)

A 2013 guidelines update from the 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 CMA, and second tier to include MECP2 and PTEN testing.39 The guideline states that

“this approach will evolve with continued advancements in diagnostic testing and improved understanding of the ASD phenotype. Multiple additional conditions have been reported in association with an ASD phenotype, but none of these has been evaluated in a large prospective cohort. Therefore, a future third tier of evaluation is a distinct possibility. Further studies would be needed to elevate the evidence to the point of recommended testing. Alternatively, advances in technology may permit bundling of individual tests into an extended, more readily accessible, and less expensive platform”. The accumulating evidence using next-generation sequencing (third tier testing) “will increase the diagnostic yield even more over the next few years.”

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


  1. American College of Medical Genetics (ACMG). Evaluation of the newborn with single or multiple congenital anomalies: a clinical guideline. American college of Medical Genetics Foundation Clinical Guidelines Project, sponsored by New York State Department of Health. 1999;Available at
  2. 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. Oct 25 2011; 77(17):1629-1635. PMID 21956720
  3. 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. Jul 2011; 13(7):676-679. PMID 21681105
  4. Rodriguez-Revenga L, Mila M, Rosenberg C, et al. Structural variation in the human genome: the impact of copy number variants on clinical diagnosis. Genet Med. 2007 Sep 2007;9(9):600-606.
  5. Vermeesch JR, Fiegler H, de Leeuw N, et al. Guidelines for molecular karyotyping in constitutional genetic diagnosis. Eur J Hum Genet. 2007 Nov 2007;15(11):1105-1114.
  6. Stankiewicz P, Beaudet AL. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. 2007 Jun 2007;17(3):182-192. PMID
  7. 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. May 14 2010; 86(5):749-764. PMID 20466091
  8. Fan YS, Jayakar P, Zhu H, et al. Detection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization. Hum Mutat. 2007 Nov 2007;28(11):1124-1132. PMID
  9. Baldwin EL, Lee JY, Blake DM, et al. Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med. 2008 Jun 2008;10(6):415-429.
  10. Zahir F, Friedman JM. The impact of array genomic hybridization on mental retardation research: a review of current technologies and their clinical utility. Clin Genet. 2007 Oct 2007;72(4):271-287.
  11. 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. Jul 2011; 13(7):680-685. PMID 21681106
  12. Riggs ER, Jackson L, Miller DT, et al. Phenotypic information in genomic variant databases enhances clinical care and research: the International Standards for Cytogenomic Arrays Consortium experience. Hum Mutat. May 2012; 33(5):787-796. PMID 22331816
  13. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). TEC Special Report: Array Comparative Genomic Hybridization (aCGH) for the Genetic Evaluation of Patients with Developmental Delay/Mental Retardation and Autism Spectrum Disorder. TEC Assessments. 2009;24:Tab 10.
  14. Tsuchiya KD, Shaffer LG, Aradhya S, et al. Variability in interpreting and reporting copy number changes detected by array-based technology in clinical laboratories. Genet Med. Dec 2009; 11(12):866-873. PMID 19904209
  15. Moeschler JB. Genetic evaluation of intellectual disabilities. Semin Pediatr Neurol. 2008a Mar 2008; 15(1):2-9. PMID
  16. Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child. 2008 Jun 2008;93(6):518-523.
  17. Yeargin-Allsopp M, Rice C, Karapurkar T, et al. Prevalence of autism in a US metropolitan area. JAMA. 2003 Jan 1 2003;289(1):49-55.
  18. 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. Aug 1 2008; 146A(15):1942-1954. PMID 18627053
  19. Hochstenbach R, van Binsbergen E, Engelen J, et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet. Jul-Aug 2009; 52(4):161-169. PMID 19362174
  20. Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. Apr 2010; 125(4):e727-735. PMID 20231187
  21. Cooper GM, Coe BP, Girirajan S, et al. A copy number variation morbidity map of developmental delay. Nat Genet. Sep 2011; 43(9):838-846. PMID 21841781
  22. Mefford HC. Genotype to phenotype-discovery and characterization of novel genomic disorders in a "genotype-first" era. Genet Med. Dec 2009; 11(12):836-842. PMID 20010361
  23. Rauch A, Hoyer J, Guth S, et al. Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A. 2006 Oct 1 2006;140(19):2063-2074.
  24. Schluth-Bolard C, Delobel B, Sanlaville D, et al. Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases. Eur J Med Genet. Sep-Oct 2009; 52(5):291-296. PMID 19505601
  25. 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. Sep 2010; 12(5):725-729. PMID 20595628
  26. Subramonia-Iyer S, Sanderson S, Sagoo G, et al. Array-based comparative genomic hybridization for investigating chromosomal abnormalities in patients with learning disability: systematic review meta-analysis of diagnostic and false-positive yields. Genet Med. 2007 Feb 2007;9(2):74-79.
  27. Moeschler JB, Shevell M. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics. 2006 Jun 2006;117(6):2304-2316.
  28. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Genet Med. 2008a Apr 2008; 10(4):301-305.
  29. Saam J, Gudgeon J, Aston E, et al. How physicians use array comparative genomic hybridization results to guide patient management in children with developmental delay. Genet Med. 2008 Mar 2008;10(3):181-186.
  30. Coulter ME, Miller DT, Harris DJ, et al. Chromosomal microarray testing influences medical management. Genet Med. 2011; 13(9):770-776.
  31. Freitag CM, Staal W, Klauck SM, et al. Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry. Mar 2010; 19(3):169-178. PMID 19941018
  32. Turner G, Boyle J, Partington MW, et al. Restoring reproductive confidence in families with X-linked mental retardation by finding the causal mutation. Clin Genet. Feb 2008; 73(2):188-190. PMID 18070138
  33. Digilio MC, Pacifico C, Tieri L, et al. Audiological findings in patients with microdeletion 22q11 (di George/velocardiofacial syndrome). Br J Audiol. Oct 1999; 33(5):329-333. PMID 10890147
  34. Adam MP, Justice AN, Schelley S, et al. Clinical utility of array comparative genomic hybridization: uncovering tumor susceptibility in individuals with developmental delay. J Pediatr. Jan 2009; 154(1):143-146. PMID 19187739
  35. Ellison JW, Ravnan JB, Rosenfeld JA, et al. Clinical utility of chromosomal microarray analysis. Pediatrics. Nov 2012; 130(5):e1085-1095. PMID 23071206
  36. Mount Sinai Genetic Testing Laboratory, Molecular Genetics Laboratory. Autism Spectrum Disorder Sequencing Panel: Information Sheet.
  37. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. Nov 2010; 12(11):742-745. PMID 20962661
  38. South ST, Lee C, Lamb AN, et al. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. Nov 2013;15(11):901-909. PMID 24071793
  39. Schaefer GB, Mendelsohn NJ, Professional P, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. May 2013;15(5):399-407. PMID 23519317







Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)



Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities



Comparative genomic hybridization (CGH) microarray testing for developmental delay, autism spectrum disorder and/or mental retardation

Type of Service



Place of Service









Add to Pathology/Laboratory section. - New Policy. Published on 2/1/11 following 90-hold for provider notification.


Replace Policy – Policy updated with literature search; references 1, 2, 6, 10, 19, 20, 24, 29, 30, 33, 35 added. Term “array comparative genomic hybridization (aCGH)” changed to “chromosomal microarray (CMA) analysis” in title, policy statements, and text. Policy statements changed to medically necessary for infants and children with developmental delay, intellectual disability, or autism spectrum disorder under certain conditions; investigational for all other indications. Modified statement about specific types of genetic counselors to a more general description and the term “mental retardation” changed to “intellectual disability” throughout and in the title.


Policy renumbered to 12.04.59 (previously 2.04.59) and reassigned to new Genetic Testing category.


Update Related Policies – Add 12.04.83.


Coding update. CPT codes 83890 – 83913 deleted as of 12/31/12; CPT codes 81200 – 81479 and 81599, effective 1/1/13, are added to the policy.


Update Related Policies. Add 12.04.91.


Update Related Policies. Add 12.04.305.


Replace policy. Policy updated with literature search; references 11, 35, 37, 38 and 40 added. No change in policy statements. CPT codes 81200-81479, 81599, and 88384-88386 removed as they are not specific to this policy; 83890-83913 removed because they are now deleted.


Update Related Policies. Remove 12.04.91.


Annual Review. Policy statement added that NGS panel testing is considered investigational in all cases of suspected genetic abnormality in children with developmental delay/intellectual disability or autism spectrum disorder. Title changed to include NGS. No change to postnatal policy statements. Prenatal testing removed from this policy and added to new policy on Invasive Prenatal (Fetal) Diagnostic Testing. Remove ICD-9 and ICD-10 diagnosis codes; these are not utilized in adjudication of the policy.


Update Related Policies. Add 12.04.116 and 12.04.122.


Update Related Policies. Change title to 12.04.122.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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