Clinical UM Guideline
Subject: Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability (Intellectual Developmental Disorder) and Congenital Anomalies
Guideline #: CG-GENE-10 Publish Date: 10/01/2020
Status: Reviewed Last Review Date: 05/14/2020
Description

This document addresses chromosomal microarray analysis (CMA) as a diagnostic tool for congenital anomalies as well as for individuals with unexplained developmental delay (DD), autism spectrum disorder (ASD) or intellectual disability (intellectual developmental delay).  This document does not provide clinical indications for karyotyping or fluorescence in situ hybridization (FISH).

For information on prenatal testing for fetal aneuploidies (including fetal sex chromosome aneuploidies), fetal sex determination and microdeletions using cell-free fetal DNA isolated from a maternal blood sample, see GENE.00026 Cell-Free Fetal DNA-Based Prenatal Testing.

Clinical Indications

Medically Necessary:

Chromosomal microarray analysis (CMA) is considered medically necessary 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; or
  2. Apparently non-syndromic developmental delay/intellectual disability; or
  3. Autism spectrum disorders.

As an alternative to fetal karyotyping, CMA is considered medically necessary for the evaluation of a fetus for ANY of the following:

  1. Abnormal fetal anatomic findings which are characteristic of a genetic abnormality; or
  2. Fetal demise with congenital anomalies; or
  3. In individuals with a structurally normal fetus undergoing invasive prenatal diagnostic testing; or
  4. The individual is considered at high risk for fetal aneuploidy due to ANY of the following:
    1. The expectant mother will be 35 years of age or older at the time of delivery; or
    2. The expectant mother has a history of a prior pregnancy with a trisomy; or
    3. The expectant mother has a positive first or second-trimester standard biomarker screening test.

* In this document, the term “postnatal” is not specifically defined in terms of a time frame.  The intent is that aCGH be done during the initial evaluation once a problem is detected.  This means that sometimes, the test may not be done until a number of years after birth.

Not Medically Necessary:

Chromosomal microarray analysis (CMA) is considered not medically necessary for all indications when the above criteria are not met.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CPT

 

81228

Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (eg, bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)

81229

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

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) [when specified as the following]:

  • Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities

0209U

Cytogenomic constitutional (genome-wide) analysis, interrogation of genomic regions for copy number, structural changes and areas of homozygosity for chromosomal abnormalities
CNGnome, PerkinElmer Genomics, PerkinElmer Genomics

 

 

HCPCS

 

S3870

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

 

 

ICD-10 Diagnosis

 

F70-F79

Intellectual disabilities

F80.0-F80.9

Specific developmental disorders of speech and language

F81.0-F81.9

Specific developmental disorders of scholastic skills

F82

Specific developmental disorder of motor function

F84.0

Autistic disorder

F84.2

Rett’s syndrome

F84.3

Other childhood disintegrative disorder

F84.5

Asperger’s syndrome

F84.8

Other pervasive developmental disorders

F84.9

Pervasive developmental disorder, unspecified

F88

Other disorders of psychological development

F89

Unspecified disorder of psychological development

 

And all other diagnoses related to chromosomal abnormalities, including but not limited to the following:

O35.1XX0-O35.1XX9

Maternal care for (suspected) chromosomal abnormality in fetus

O35.2XX0-O35.2XX9

Maternal care for (suspected) hereditary disease in fetus

Q00.0-Q89.9

Congenital malformations and deformations

Discussion/General Information

CMA is a high-resolution whole-genome screening which allows for the detection of small genetic alterations, including submicroscopic abnormalities that are too small to be identified by conventional karyotyping or FISH.  While conventional karyotypes primarily detect genetic abnormalities resulting from large changes in the structure or number of chromosomes (translocations, aneuploidy, large deletions or duplications), CMA identifies genomic copy number variations (CNVs), which are deletions and/or duplications that are smaller than the resolution of karyotyping.  CMA does not detect balanced chromosome rearrangements in which there is no gain or loss of DNA (balanced inversions or balanced translocations). 

Postnatally, CMA is used as a diagnostic tool for individuals with unexplained DD, ASD and intellectual disability (ID).  Prenatally, CMA is used a technique to identify chromosomal abnormalities in the fetus to assist in reproductive decisions.  When used as a prenatal test, CMA requires an invasive procedure to collect intact fetal cells (for example, amniocentesis or chorionic villous sampling).  CMA may be used as an alternative to karyotyping.

CMA collectively describes two different laboratory techniques: comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays.  While both of these techniques detect CNVs, they identify different types of genetic variation. 

Microarray-based Comparative Genomic Hybridization (aCGH)
aCGH comparative genomic hybridization compares the genomes of two individuals (the subject and a normal control) to detect genome-wide microscopic and submicroscopic copy number variants (CNVs) less than 100 kb.  aCGH detects copy number variation for relatively large deletions or duplications, including whole-chromosome duplications (for example, trisomy), but aCGH cannot detect triploidy (ACOG, 2013; Babkina, 2014).

Single nucleotide polymorphism (SNP)
SNP microarrays allow genotyping based on allele frequency.  SNP arrays have additional oligonucleotide probes which analyze thousands of SNPs throughout the genome in order to identify deletions and duplications.  SNPs provide more even genome coverage and improved detection of CNVs compared to aCGH.  When SNPs are used in the prenatal setting, only fetal DNA is hybridized to the array platform, and the absence or presence of specific known DNA sequence variants is evaluated by signal intensity to provide a genome-wide copy number analysis.  SNP microarrays are able to detect homozygosity or heterozygosity (identical or different stretches of DNA) and may be used to demonstrate the extent of consanguinity (shown as regions of homozygosity), as well as triploidy and uniparental disomy (ACOG, 2013; Babkina, 2014).

In general, CMA offers the following advantages over karyotyping:

Postnatal Diagnosis (Developmental Delay, Autism Spectrum Disorder and Intellectual Disability)
The use of CMA in the postnatal setting to diagnose individuals suspected of having DD, ASD or ID has evolved rapidly from a promising technology (ACOG 2009; Johnson, 2007) to an accepted diagnostic technique.

The ACMG (American College of Medical Genetics) guidelines were updated in 2010 to address the utility and limitations of array-based technology for utilization in medical genetics practice for detection of chromosome abnormalities.  The guidelines make the following recommendations:

In 2010, the International Standard Cytogenomic Array (ISCA) Consortium convened two international workshops and conducted a literature review of 33 studies, including 21,698 individuals who underwent CMA.  The evidence-based summary of clinical cytogenetic testing compared CMA to G-banded karyotyping with respect to the technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation.  The authors concluded that CMA offers a much higher diagnostic yield (15%–20%) for genetic testing of individuals with unexplained DD/ID, ASD or multiple congenital anomalies (MCA) than a G-banded karyotype (~3%, excluding Down syndrome and other recognizable chromosomal syndromes).  The ISCA Consortium recommends the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for individuals with DD/ID, ASD, or MCA.  G-banded karyotype analysis should be reserved for individuals with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.  The ISCA notes that geneticists, pediatric neurologists, and developmental pediatricians are increasingly ordering CMA to obtain a genetic diagnosis for children with unexplained DD/ID, ASD, and MCA.  A specific genetic diagnosis facilitates comprehensive medical care and accurate recurrence risk counseling for the family (Miller, 2010). 

In keeping with the consensus opinion that CMA is a first-tier test for individuals with congenital anomalies and developmental disabilities, the ACMG practice guidelines titled “Clinical genetics evaluation in identifying the etiology of autism spectrum disorders” consider CMA to be a first-tier test in place of a karyotype (Schaefer, 2013).

A 2015 Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Special Report evaluated the evidence on CMA testing to identify CNVs in children with global developmental delay (GDD), ASD and ID.  The authors found “consistent evidence that the diagnostic yield obtained from CMA testing is higher than with karyotyping in children with GDD/ID or ASD, with or without congenital anomalies.”  The authors indicated that although data supporting analytic validity are readily available only for the Affymetrix CytoScan Dx assay; it is expected that laboratories meeting Clinical Laboratory Improvement Amendments (CLIA) standards but using other platforms will achieve adequate technical performance.  The report also acknowledged that:

A particular challenge when considering the evidence and methods used to determine variant pathogenicity is that, outside the more common syndromes, diagnoses include a large number of rare disorders a clinician, even a specialist, might not encounter during a lifetime.  Identifying a pathogenic variant can: (1) impact the search for a diagnosis, (2) inform follow-up that can benefit a child by reducing morbidity, and (3) affect reproductive planning for parents and potentially the affected patient” (BCBSA, 2015).

Prenatal Diagnosis (Invasive Prenatal Testing and Fetal Demise)
In clinical prenatal testing, at least two types of chromosomal microarrays are used: comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays.  While both of these techniques detect CNVs, they identify different types of genetic variation. 

A 2013 Committee Opinion of the American College of Obstetricians and Gynecologists (ACOG) addressed the use of CMA in prenatal diagnosis, prompted by the results of a study of 4406 women undergoing prenatal diagnosis using both CMA and karyotyping (Wapner, 2012).  The authors reported that in samples with normal karyotypes, CMA revealed deletions or duplications in 6% with a structural anomaly and in 1.7% of those whose indication for testing was advanced maternal age or positive maternal serum screening, validating the increased sensitivity of CMA.  The technique used in this study was aCGH.  The 2013 ACOG recommendations were replaced in 2016 by an ACOG and Society for Maternal-Fetal Medicine (SMFM) Committee Opinion on Microarrays and Next-Generation Sequencing Technology, which includes the following recommendations and conclusions regarding the use of CMA:  

Similar to the recommendations above, in a separate document the SMFM recommends “that chromosomal microarray analysis be offered when genetic analysis is performed in cases with fetal structural anomalies and/or stillbirth and replaces the need for fetal karyotype in these cases (GRADE 1A)” (SMFM, 2016).

Definitions

Autism Spectrum Disorders: A collection of associated developmental disorders that affect the parts of the brain that control social interaction, verbal and non-verbal communication.

Balanced Reciprocal Translocations: An equal exchange of material between chromosomes.

Chromosomal microarray analysis (CMA): A method used to measure the gains and losses of DNA throughout the human genome. CMA includes both single nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays.

Comparative Genomic Hybridization (CGH): A molecular technique that is used to detect chromosome gain or loss by hybridizing DNA from a target cell and a normal cell.

Congenital Anomaly: A defect that is present at birth and may be the result of either environmental or genetic factors, or both.

Copy Number Variants (CNVs): An alteration of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

Cytogenetics: A branch of genetic science that focuses on the study of the structure and function of the cell, especially the chromosomes. Cytogenetics includes but is not limited to G-banded karyotyping, fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).

G-banded Karyotyping: A molecular chromosome analysis technique which employs Giemsa dye to stain DNA strands.

Karyotypes: The number and appearance of chromosomes under a light microscope.

Sequence Inversions: The same sequence is present in reverse base pair order.

Single nucleotide polymorphisms (SNP): DNA sequence variations that occur when a single nucleotide in the genome sequence is altered.  

References

Peer Reviewed Publications:

  1. Babkina N, Graham JM Jr. New genetic testing in prenatal diagnosis. Semin Fetal Neonatal Med. 2014; 19(3):214-219.
  2. Coulter ME, Miller DT, Harris DJ, et al. Chromosomal microarray testing influences medical management. Genet Med. 2011; 13(9):770-776.
  3. Hillman SC, McMullan DJ, Williams D, et al. Microarray comparative genomic hybridization in prenatal diagnosis: a review. Ultrasound Obstet Gynecol. 2012; 40(4):385-391.
  4. Hillman SC, Pretlove S, Coomarasamy A, et al. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2011; 37(1):6-14.
  5. 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. 2009; 52(4):161-169.
  6. 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. 2011a; 13(7):676-679.
  7. 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. 201lb; 13(7):680-685.
  8. Lee CN, Lin SY, Lin CH, et al. Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies. BJOG. 2012; 119(5):614–625.
  9. Sagoo GS, Butterworth AS, Sanderson S, et al. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med. 2009; 11(3):139-146.
  10. Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010; 125(4):e727-735.
  11. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367(23):2175-2184.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Obstetricians and Gynecologists (ACOG). ACOG Committee opinion no.446: array comparative genomic hybridization in prenatal diagnosis. Obstet Gynecol. 2009; 114(5):1161-1163.
  2. American College of Obstetricians and Gynecologists (ACOG). Committee opinion no. 545: noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012; 120(6):1532-1534.
  3. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122(6):1374-1377.
  4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. DSM-5. American Psychiatric Association. Washington, DC.
  5. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). TEC Special Report: Chromosomal microarray for the genetic evaluation of patients with global developmental delay, intellectual disability, and autism spectrum disorder. Technol Eval Cent Assess Program Exec Summ. 2015; 30(2):1-4.
  6. Committee on Genetics and the Society for Maternal-Fetal Medicine. Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol. 2016; 128(6):e262-e268.
  7. Duncan A, Langlois S.; SOGC Genetics Committee; CCMG Prenatal Diagnosis Committee. Use of array genomic hybridization technology in prenatal diagnosis in Canada. J Obstet Gynaecol Can. 2011; 33(12):1256-1259.
  8. Johnson CP, Myers SM.; American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007; 120(5):1183-1215.
  9. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010; 12(11):742-745. 
  10. 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. 2011; 77(17):1629-1635.
  11. 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. 2010; 86(5):749-764.
  12. Moeschler JB, Shevell M.; American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics. 2006; 117(6):2304-2316.
  13. Moeschler JB, Shevell M.; American Academy of Pediatrics Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134(3):e903-918.
  14. Schaefer GB, Mendelsohn NJ. Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. 2013; 15(5):399-407.
  15. Society for Maternal-Fetal Medicine (SMFM), Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016; 215(4):B2-B9.
  16. Waggoner D, Wain KE, Dubuc AM, et al. Yield of additional genetic testing after chromosomal microarray for diagnosis of neurodevelopmental disability and congenital anomalies: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018; 20(10):1105-1113.
Websites for Additional Information
  1. Center for Disease Control and Prevention (CDC).
Index

Array comparative genomic hybridization (aCGH)
Chromosomal microarray analysis (CMA)
Comparative genomic hybridization (CGH) microarray
Cytogenetic microarray analysis (CMA)
Microarray-based comparative genomic hybridization
Single nucleotide polymorphism (SNP)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

  10/01/2020

Updated Coding section with 10/01/2020 CPT changes; added PLA code 0209U.

Reviewed

05/14/2020

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Websites for Additional Information.

New

06/06/2019

MPTAC review. Initial document development. Moved content of GENE.00021 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability (Intellectual Developmental Disorder) and Congenital Anomalies to new clinical utilization management guideline document with the same title.

 

 

 


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