Genetic Testing for Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

POLICY NUMBER

A.2.04.59

DESCRIPTION

Chromosomal microarray (CMA) testing has been proposed for the detection of genetic imbalances in infants or children with characteristics of developmental delay/intellectual disability, autism spectrum disorder, and/or congenital anomalies.CMAtesting increases the diagnostic yield over karyotyping in children with the aforementioned characteristics, and CMA testing may impact clinical management decisions. Next-generation sequencing panel testing allows for simultaneous analysis of a large number of genes and, in patients with normal CMA testing, the next-generation testing has been proposed as a way to identify single-gene causes of syndromes that have autism as a significant clinical feature.

Diagnostic Testing

Karyotyping and Fluorescent In Situ HybridizationThe goal of a cytogenetic evaluation is to identify chromosomal imbalances that cause a disorder. The most common imbalances are copy number variants (CNVs) or deletions and duplications of large segments of genomic material. CNVs are common in developmental delay/intellectual disability and autism spectrum disorder (ASD), but more often reflect the normal genetic variation. However, de novo CNVs are observed about four times more frequently in children with ASD than in normal individuals without ASD. Less frequently, other abnormalities such as balanced translocations (ie, exchanges of equally sized DNA loci between chromosomes) may be pathogenic. For many well-described syndromes, the type and location of the associated chromosomal abnormality have been established by studying large patient samples. For others, few patients with similar abnormalities may have been evaluated to establish genotype-phenotype correlation. Finally, in some patients, the cytogenetic analysis will discover chromosomal abnormalities that require study to determine their significance.

Prior to the advent of chromosomal microarray (CMAs), the initial step in the cytogenetic analysis was G-banded karyotyping, which evaluates all chromosomes. High-resolution G-banding can detect changes as small as 3 to 5 megabases in size, although standard G-banding evaluates more than 10 megabases changes. In children with developmental delay/intellectual disability, a review found G-banded karyotyping diagnostic in approximately 3% to 5% of cases. In ASD, high-resolution karyotyping appears to identify abnormalities in up to 5% of cases.

In contrast, molecular cytogenetic techniques can detect small submicroscopic chromosomal alterations. Fluorescent in situ hybridization (FISH), a targeted approach, is used to identify specific chromosomal abnormalities associated with suspected diagnoses such as DiGeorge syndrome. Prior to CMAs, FISH was also used to screen the rearrangement-prone subtelomeric regions. Subtelomeric FISH was found to identify abnormalities in children with developmental delay and intellectual disability, and was diagnostic in approximately 5% to 6% of those with negative karyotypes, but uncommonly in ASD.

Chromosomal MicroarraysTwo types of CMAs are considered here: array comparative genomic hybridization (aCGH) and single nucleotide variants (SNV) arrays. The aCGH approach uses DNA samples from a patient and normal control. Each is labeled with distinct fluorescent dyes (red or green). The labeled samples are then 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 simultaneously. 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 (a deletion) or has the normal sequence plus additional genomic material within that genomic location (eg, a duplication), the sequence imbalance is detected as a difference in fluorescence intensity. For this reason, aCGH cannot detect balanced chromosomal translations (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. A portion of the increased diagnostic yield from CMA over karyotyping comes from the discovery that 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.

Like aCGH, SNV arrays detect CNVs. In an SNV array, the 2 alleles for genes of interest are tagged with different fluorescent dyes. Comparative fluorescence intensity will be increased when there are duplications and diminished with deletions. The resolution provided by aCGH is higher than with SNV arrays. In addition, aCGH has better signal-to-background characteristics than SNV arrays. In contrast to aCGH, SNV arrays will also identify long stretches of DNA homozygosity, which may suggest uniparental disomy or consanguinity. Uniparental disomy occurs when a child inherits 2 copies of a chromosome from one parent and no copies from the other parent. Uniparental disomy can lead to syndromes such as Angelman and Prader-Willi.

The table below summarizes the cytogenetic tests used to evaluate children with developmental delay/intellectual disability and autism. The table emphasizes the large difference in resolution between karyotyping and CMA.

Resolution and Analysis Comparison of FISH, Karyotyping, and CMA Analysis

Microarrays may be prepared by the laboratory using 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 laboratory-developed and commercially available platforms prompted the American College of Medical Genetics to publish guidelines for the design and performance expectations for clinical microarrays and associated software in the postnatal setting.

Next-Generation SequencingNext-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. Next-generation sequencing involves the sequencing of millions of fragments of genetic material in a massively parallel fashion. Next-generation sequencing can be performed on segments of the genetic material of various sizes—from the entire genome (whole-genome sequencing) to small subsets of genes (targeted sequencing). Next-generation sequencing allows the detection of SNVs, CNVs, insertions, and deletions. With higher resolution comes a higher likelihood of detection of variants of uncertain significance.

Genetic Associations with Developmental Delay/Intellectual Disability and Autism Spectrum Disorder

For common phenotypes and syndromes, the pathogenicity of CNVs may be supported by considerable evidence; for uncommon phenotypes and uncommon CNVs determining pathogenicity requires a systematic evaluation that includes parental studies, examining databases for reported associations, and considering the molecular consequences of the identified variant. Parental studies (eg, “trio” testing of affected child, father, and mother) can identify an inherited CNV from an unaffected parent and therefore considered benign. A variety of databases index the clinical implications of CNVs and their associations with a particular phenotype. CNVs are continuously cataloged and, with growth in CMA testing and improved resolution, databases have become increasingly extensive (eg, DECIPHER, ClinVar). For uncommon CNVs, in addition to reports of CNV-phenotype associations, the location and size of the CNV can offer clues to pathogenicity; larger CNVs are more often pathogenic and the role of affected genes in brain circuitry and effect of CNV on gene expression can implicate pathogenicity. Although uncommon, an observed phenotype can result from unmasking a mutated recessive allele on the unaffected (non-CNV) chromosome. Other considerations when determining pathogenicity include CNV dosage, X linkage, number of reports in the literature of an association between CNV and phenotype, and findings in “normal” individuals.

The American College of Medical Genetics has published guidelines for evaluating, interpreting, and reporting pathogenicity reflecting these principles. The recommended categories of clinical significance for reporting are pathogenic, uncertain clinical significance (likely pathogenic, likely benign, or no subclassification), or benign. The International Standards for Cytogenomic Arrays Consortium more recently proposed “an evidence-based approach to guide the development of content on chromosomal microarrays and to support the interpretation of clinically significant copy number variation.” The proposal defined levels of evidence describe how well or how poorly detected variants or CNVs correlate with phenotype.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Lab tests for CMA testing and next-generation sequencing are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments 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 2010, the FDA indicated that it would require microarray manufacturers to seek clearance to sell their products for use in clinical cytogenetics.

CMA Testing

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

In January 2014, the Affymetrix CytoScan® Dx Assay (Thermo Fisher Scientific) was cleared by the U.S. Food and Drug Administration (FDA) through the de novo 510(k) process. The 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. The FDA found that the CytoScan Dx Assay could detect copy number variations (CNVs) across the genome and adequately detect CNVs in regions of the genome associated with developmental delay/intellectual disability. Reproducibility decreased with the CNV gain or loss size, particularly when less than approximately 400 kilobases (generally recommended as the lower reporting limit). As of September 2024, CytoScan HD Array contains 2.67 million markers for copy number, 750,000 SNVs, and 1.9 million non-polymorphic probes.

Ambry Genetics offers multiple tests (CMA and next-generation sequencing) designed for diagnosing ASD and neurodevelopmental disorders. As of September 2024, the CMA offered by Ambry Genetics includes over 1.9 million probes for copy number and 750,000 SNV probes.

LabCorp offers the Reveal® SNP Microarray-Pediatric for individuals with non-syndromic congenital anomalies, dysmorphic features, developmental delay/intellectual disability, and/or ASD. The Reveal microarray has over 2 million probes.

Next-Generation Sequencing

A variety of commercial and academic laboratories offer next-generation sequencing panels designed for the evaluation of ASD, developmental delay/intellectual disability, and congenital anomalies, which vary in terms of the numbers of and specific genes tested.

Emory Genetics Laboratory offers a next-generation sequencing ASD panel of genes targeting genetic syndromes that include autism or autistic features. Fulgent Genetics offers a next-generation sequencing ASD panel that includes hundreds of genes. Ambry Genetics also offers numerous next-generation sequencing panels for neurodevelopmental disorders.

Related medical policies -

• Invasive Prenatal (Fetal) Diagnostic Testing

POLICY

Chromosomal microarray analysis may be considered medically necessaryas first-line testing in the initial evaluation (see Policy Guidelines) of individuals with any of the following:

• Apparent nonsyndromic developmental delay/intellectual disability,

• Autism spectrum disorder, or

• Multiple congenital anomalies not specific to a well-delineated genetic syndrome.

Chromosomal microarray is considered investigational for the evaluation of all other conditions of delayed development, including, but not limited to, idiopathic growth or language delay.

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.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Use of chromosomal microarray (CMA) testing as outlined in this policy is not intended for use in the prenatal period.

A guideline update from the 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) testing.

Recommendations from the American College of Medical Genetics on array-based technologies and their clinical utilization for detecting chromosomal abnormalities include the following: "Appropriate follow-up is recommended in cases of chromosome imbalance identified by CMA, to include cytogenetic/FISH [fluorescent in situ hybridization] studies of the patient, parental evaluation, and clinical genetic evaluation and counseling."

In some cases of CMA, the laboratory performing the test confirms all reported copy number variants with an alternative technology, such as fluorescent in situ hybridization analysis.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

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 Mental Health Disorders, 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 medical necessity, “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 HISTORY

03/25/2010: 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 investigationalfor 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.

09/21/2017: Policy description updated regarding next-generation sequencing and CMA testing. Added policy statement that CMA is considered investigational for the evaluation of all other conditions of delayed development, including but not limited to idiopathic growth or language delay. Policy Guidelines updated regarding standard terminology for variant classification.

10/25/2018: Policy description updated regarding developmental delay/intellectual disability, autism spectrum disorder, and diagnostic testing. Policy statements unchanged. Policy Guidelines updated regarding the use of CMA testing. Genetic counseling information updated.

01/03/2020: Policy reviewed. Medically necessary statement updated to change "initial postnatal evaluation" to "initial evaluation." Policy Guidelines updated.

09/22/2020: Code Reference section updated to add CPT code 0209U, effective 10/01/2020.

11/19/2020: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature update.

12/15/2021: Code Reference section updated to revise code description for CPT codes 81228 and 81229, effective 01/01/2022.

01/13/2022: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

03/28/2022: Code Reference section updated to add new 04/01/2022 CPT code 0318U.

12/07/2022: Policy description updated. Policy statements unchanged.

09/29/2023: Code Reference section updated to add new ICD-10 diagnosis codes G11.5, Q87.83, Q87.84, Q87.85, and Q93.52, effective 10/01/2023.

11/13/2023: Policy description updated regarding next-generation sequencing. Policy statements unchanged.

01/07/2025: Policy description updated regarding CMA testing and next-generation sequencing. Policy statements unchanged.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes QA0.0109, QA0.011, QA0.012, QA0.0131, QA0.0139, QA0.0141, QA0.0142, QA0.0149, QA0.0151, QA0.0159, and QA0.8.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 2.04.59

CODE REFERENCE

This 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.   

Covered Codes      

Non-Covered Codes

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