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Chromosomal Microarray Analysis 2024-10-20

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Status: Revised Effective Date: 10/20/2024

Doc ID: GEN07-1024.1 Last Review Date: 01/23/2024

Approval and implementation dates for specific health plans may vary. Please consult the applicable health plan for more details.

Clinical Appropriateness Guidelines

Genetic Testing

Appropriate Use Criteria: Chromosomal Microarray Analysis


© 2024 Carelon Medical Benefits Management, Inc. All rights reserved.

Table of Contents

Description and Application of the Guidelines

General Clinical Guideline

Chromosomal Microarray Analysis

General Recommendations

Clinical Indications




Description and Application of the Guidelines

The Carelon Clinical Appropriateness Guidelines (hereinafter “the Carelon Clinical Appropriateness Guidelines” or the “Guidelines”) are designed to assist providers in making the most appropriate treatment decision for a specific clinical condition for an individual. The Guidelines establish objective and evidence-based criteria for medical necessity determinations, where possible, that can be used in support of the following:

  • To establish criteria for when services are medically necessary
  • To assist the practitioner as an educational tool
  • To encourage standardization of medical practice patterns
  • To curtail the performance of inappropriate and/or duplicate services
  • To address patient safety concerns
  • To enhance the quality of health care
  • To promote the most efficient and cost-effective use of services

The Carelon guideline development process complies with applicable accreditation and legal standards, including the requirement that the Guidelines be developed with involvement from appropriate providers with current clinical expertise relevant to the Guidelines under review and be based on the most up-to-date clinical principles and best practices. Resources reviewed include widely used treatment guidelines, randomized controlled trials or prospective cohort studies, and large systematic reviews or meta-analyses. Carelon reviews all of its Guidelines at least annually.

Carelon makes its Guidelines publicly available on its website. Copies of the Guidelines are also available upon oral or written request. Additional details, such as summaries of evidence, a list of the sources of evidence, and an explanation of the rationale that supports the adoption of the Guidelines, are included in each guideline document.

Although the Guidelines are publicly available, Carelon considers the Guidelines to be important, proprietary information of Carelon, which cannot be sold, assigned, leased, licensed, reproduced or distributed without the written consent of Carelon.

Carelon applies objective and evidence-based criteria, and takes individual circumstances and the local delivery system into account when determining the medical appropriateness of health care services. The Carelon Guidelines are just guidelines for the provision of specialty health services. These criteria are designed to guide both providers and reviewers to the most appropriate services based on a patient’s unique circumstances. In all cases, clinical judgment consistent with the standards of good medical practice should be used when applying the Guidelines. Guideline determinations are made based on the information provided at the time of the request. It is expected that medical necessity decisions may change as new information is provided or based on unique aspects of the patient’s condition. The treating clinician has final authority and responsibility for treatment decisions regarding the care of the patient and for justifying and demonstrating the existence of medical necessity for the requested service. The Guidelines are not a substitute for the experience and judgment of a physician or other health care professionals. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment.

The Guidelines do not address coverage, benefit or other plan specific issues. Applicable federal and state coverage mandates take precedence over these clinical guidelines, and in the case of reviews for Medicare Advantage Plans, the Guidelines are only applied where there are not fully established CMS criteria. If requested by a health plan, Carelon will review requests based on health plan medical policy/guidelines in lieu of the Carelon Guidelines. Pharmaceuticals, radiotracers, or medical devices used in any of the diagnostic or therapeutic interventions listed in the Guidelines must be FDA approved or conditionally approved for the intended use. However, use of an FDA approved or conditionally approved product does not constitute medical necessity or guarantee reimbursement by the respective health plan.

The Guidelines may also be used by the health plan or by Carelon for purposes of provider education, or to review the medical necessity of services by any provider who has been notified of the need for medical necessity review, due to billing practices or claims that are not consistent with other providers in terms of frequency or some other manner.

General Clinical Guideline

Clinical Appropriateness Framework

Critical to any finding of clinical appropriateness under the guidelines for a specific diagnostic or therapeutic intervention are the following elements:

  • Prior to any intervention, it is essential that the clinician confirm the diagnosis or establish its pretest likelihood based on a complete evaluation of the patient. This includes a history and physical examination and, where applicable, a review of relevant laboratory studies, diagnostic testing, and response to prior therapeutic intervention.
  • The anticipated benefit of the recommended intervention is likely to outweigh any potential harms, including from delay or decreased access to services that may result (net benefit).
  • Widely used treatment guidelines and/or current clinical literature and/or standards of medical practice should support that the recommended intervention offers the greatest net benefit among competing alternatives.
  • There exists a reasonable likelihood that the intervention will change management and/or lead to an improved outcome for the patient.

Providers may be required to submit clinical documentation in support of a request for services. Such documentation must a) accurately reflect the clinical situation at the time of the requested service, and b) sufficiently document the ordering provider’s clinical intent.

If these elements are not established with respect to a given request, the determination of appropriateness will most likely require a peer-to-peer conversation to understand the individual and unique facts that would justify a finding of clinical appropriateness. During the peer-to-peer conversation, factors such as patient acuity and setting of service may also be taken into account to the extent permitted by law.

Simultaneous Ordering of Multiple Diagnostic or Therapeutic Interventions

Requests for multiple diagnostic or therapeutic interventions at the same time will often require a peer-to-peer conversation to understand the individual circumstances that support the medical necessity of performing all interventions simultaneously. This is based on the fact that appropriateness of additional intervention is often dependent on the outcome of the initial intervention.

Additionally, either of the following may apply:

  • Current literature and/or standards of medical practice support that one of the requested diagnostic or therapeutic interventions is more appropriate in the clinical situation presented; or
  • One of the diagnostic or therapeutic interventions requested is more likely to improve patient outcomes based on current literature and/or standards of medical practice.

Repeat Diagnostic Intervention

In general, repeated testing of the same anatomic location for the same indication should be limited to evaluation following an intervention, or when there is a change in clinical status such that additional testing is required to determine next steps in management. At times, it may be necessary to repeat a test using different techniques or protocols to clarify a finding or result of the original study.

Repeated testing for the same indication using the same or similar technology may be subject to additional review or require peer-to-peer conversation in the following scenarios:

  • Repeated diagnostic testing at the same facility due to technical issues
  • Repeated diagnostic testing requested at a different facility due to provider preference or quality concerns
  • Repeated diagnostic testing of the same anatomic area based on persistent symptoms with no clinical change, treatment, or intervention since the previous study
  • Repeated diagnostic testing of the same anatomic area by different providers for the same member over a short period of time

Repeat Therapeutic Intervention

In general, repeated therapeutic intervention in the same anatomic area is considered appropriate when the prior intervention proved effective or beneficial and the expected duration of relief has lapsed. A repeat intervention requested prior to the expected duration of relief is not appropriate unless it can be confirmed that the prior intervention was never administered. Requests for on-going services may depend on completion of previously authorized services in situations where a patient’s response to authorized services is relevant to a determination of clinical appropriateness.

Chromosomal Microarray Analysis

General Recommendations

Genetic Counseling

Counseling is encouraged prior to chromosomal microarray analysis (CMA) and should include ALL of the following components:

  • Interpretation of personal and family medical histories to provide a risk assessment for disease occurrence or recurrence
  • Education about inheritance patterns, genetic testing, disease management, prevention, risk reduction, and resources
  • Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition
  • Counseling for the psychological aspects of genetic testing
  • Counseling should include the following details:
    • Limitations of the testing used
    • A negative result does not indicate heritable risk is zero or low
    • Identification of incidental and inconclusive results called variants of uncertain significance is possible
    • Modifications to genetic variants’ pathogenicity interpretations can occur, and patients may be recontacted with reclassified results in the future

Note: Post-test counseling should be performed for any genetic test result.


Genetic testing is a procedure that involves risk that accompanies its potential benefits. The clinical team and the patient should consider the balance of risks and potential benefits before testing is pursued through informed consent. As with any procedure, the clinical utility of the genetic test must be considered along with its psychological and sociologic implications.1 Counseling, either by a genetic counselor and/or team clinician, provides a patient-centered approach to the care of individuals who are undergoing a diagnostic genetic test.2

It is also recognized that the accessibility to genetic counselors is limited by available resources as well as other social determinants of health. Therefore, as it relates to screening, the importance should be placed on counseling in a general sense, such as informed consent, as noted above.3

Genomic technologies generate large amounts of data, and this increases the potential for uncertainty in managing and adapting to this information.4 Clinicians are tasked with accurately interpreting and communicating information about test validity and the reliability of test results, as well as the probability for individual patient benefit.4, 5 Uncovering incidental findings and being overwhelmed with information are important barriers to genetic testing, particularly among vulnerable patient subgroups.4 Genetic counseling is an invaluable resource for patients undergoing genetic testing, but there are practical limitations because of the scarcity of genetic counselors relative to the current need, as noted above.

Clinical Indications

General Requirements

Diagnostic testing using chromosomal microarray analysis (CMA) should occur only once per fetus per pregnancy.

Condition-Specific Requirements

Postnatal evaluation

Chromosomal microarray analysis (CMA) is considered medically necessary as a first-line test in the initial postnatal evaluation of individuals with ANY of the following:

  • Multiple congenital anomalies without an established diagnosis
  • Congenital or early onset epilepsy (before age 3 years) without suspected environmental causes
  • Autism spectrum disorder with no identifiable cause (idiopathic)
  • Developmental delay or intellectual disability with no identifiable cause (idiopathic)
Prenatal evaluation

Chromosomal microarray analysis is considered medically necessary for the prenatal evaluation of a fetus for ANY of the following:

  • Structural fetal anomaly noted on ultrasound
  • Fetal demise or history of 2 or more miscarriages
  • Individuals undergoing invasive diagnostic testing based on advanced maternal age or positive findings on other screening tests

Cytogenetic microarray (CMA) platforms are designed for the detection of DNA copy number gains and losses associated with unbalanced chromosomal aberrations, known as copy number variations (CNVs). The benefits of this technique include the ability to analyze DNA from nearly any tissue, better definition and characterization of abnormalities detected by standard chromosomal study, and the ability to detect copy neutral absence of heterozygosity with platforms incorporating single nucleotide polymorphisms (SNP) probes. The utility of this technology for detection of gains and losses in patients with intellectual disabilities, autism, and/or congenital anomalies, as well as applicability in prenatal specimens, has been well documented.6 In samples with a normal karyotype, microarray analysis has been shown to identify clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening for Down’s syndrome.7 In addition to other professional organizations, the Canadian College of Medical Geneticists recently reinforced the recommendation of using CMA as a first-tier test for patients with neurodevelopmental disorders, such as global developmental delay, intellectual disability, and/or autism spectrum disorder—thus reserving exome sequencing and comprehensive gene panels for second-tier testing.8 There are also limitations with CMA. It will not detect all pathogenic variants associated with a given syndrome or detect genetic events that do not affect relative copy number. For example, it is unable to detect molecularly balanced chromosomal rearrangements. Also, CMA does not always elucidate the chromosomal mechanism of genetic imbalance.6


1. Burke W. Genetic tests: clinical validity and clinical utility. Curr Protoc Hum Genet. 2014;81:9.15.1-9..8.

2. Resta R, Biesecker BB, Bennett RL, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns. 2006;15(2):77-83.

3. CDC. How Accessible are Genetics Providers and How Can Access be Increased? 2020.

4. Borno HT, Rider JR, Gunn CM. The Ethics of Delivering Precision Medicine-Pretest Counseling and Somatic Genomic Testing. JAMA Oncol. 2020;6(6):815-6.

5. Patch C, Middleton A. Genetic counselling in the era of genomic medicine. Br Med Bull. 2018;126(1):27-36.

6. Shao L, Akkari Y, Cooley LD, et al. Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(10):1818-29.

7. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84.

8. Carter MT, Srour M, Au PB, et al. Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG). J Med Genet. 2023;60(6):523-32.


The following code list is not meant to be all-inclusive. Authorization requirements will vary by health plan. Please consult the applicable health plan for guidance on specific procedure codes.

Specific CPT codes for services should be used when available. Nonspecific or not otherwise classified codes may be subject to additional documentation requirements and review.


CPT® (Current Procedural Terminology) is a registered trademark of the American Medical Association (AMA). CPT® five-digit codes, nomenclature and other data are copyright by the American Medical Association. All Rights Reserved. AMA does not directly or indirectly practice medicine or dispense medical services. AMA assumes no liability for the data contained herein or not contained herein.

May Be Medically Necessary When Criteria are Met
Code May Be Medically Necessary When Criteria are Met
81228 Cytogenomic (genome-wide) analysis for constitutional chromosomal abnormalities; interrogation of genomic regions for copy number variants, comparative genomic hybridization (CGH) microarray analysis
81229 Cytogenomic (genome-wide) analysis for constitutional chromosomal abnormalities; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants, comparative genomic hybridization (CGH) microarray analysis
81349 Cytogenomic (genome-wide) analysis for constitutional chromosomal abnormalities; interrogation of genomic regions for copy number and loss-of-heterozygosity variants, low-pass sequencing analysis
81405 Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)
0209U Cytogenomic constitutional (genome-wide) analysis, interrogation of genomic regions for copy number, structural changes and areas of homozygosity for chromosomal abnormalities
0252U Fetal aneuploidy short tandem–repeat comparative analysis, fetal DNA from products of conception, reported as normal (euploidy), monosomy, trisomy, or partial deletion/duplications, mosaicism, and segmental aneuploidy
0318U Pediatrics (congenital epigenetic disorders), whole genome methylation analysis by microarray for 50 or more genes, blood
S3870 Comparative genomic hybridization (CGH) microarray testing for developmental delay, autism spectrum disorder and/or intellectual disability
Not Medically Necessary
Code Not Medically Necessary
0454U Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping

ICD-10 Diagnosis

Refer to the ICD-10 CM manual


Status Review Date Effective Date Action
Revised 01/23/2024 10/20/2024 Independent Multispecialty Physician Panel (IMPP) review. Clarified recommendations for genetic counseling. Clarified requirements for postnatal evaluation: individuals with congenital or early onset epilepsy (before age 3) without suspected environmental causes and those with autism spectrum disorder, developmental delay, or intellectual disability with no identifiable cause (idiopathic). Added references.
Updated codes 07/01/2024 n/a Unchanged Added CPT code 0454U (NMN).
Updated codes 03/17/2024 n/a Unchanged Added CPT code 0252U. Added required language to General Clinical Guideline per new Medicare regulations.
Created 09/21/2022 02/12/2023 IMPP review. Original effective date.

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