Description of Procedure or Service

Chromosomal microarray (CMA) testing refers to the use of comparative genomic hybridization (CGH) arrays to detect small (10 to 100kb) duplications or deletions of chromosomal DNA (copy number variants or CNVs), similarity in single nucleotide sequences (homozygosity), and triploidy when chromosomal abnormality is suspected based on clinical presentation. Genetic counseling is strongly recommended for individuals being considered for chromosomal microarray testing. Low-pass whole genome sequencing (low-pass WGS) is a method of WGS that is less expensive and has lower coverage than standard WGS. Low-pass WGS maintains a high accuracy for detecting single nucleotide sequences by using imputation algorithms.

For guidance on exome sequencing, please see AHS-M2032 - Genome and Exome Sequencing.

Related Policies:

Prenatal Screening for Fetal Aneuploidy AHS-G2055

Prenatal Screening (Genetic) AHS-M2179

Genome and Exome Sequencing AHS-M2032

Genetic Testing for Epilepsy AHS-M2075

Testing for Developmental Delay AHS-M2176

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for chromosomal microarray testing and low-pass whole genome sequencing  when it is determined the medical criteria below is met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When chromosomal microarray testing and low-pass whole genome sequencing is covered

1. Chromosomal microarray (CMA) testing or low-pass whole genome sequencing (low-pass WGS) of the products of conception (e.g., fetal tissue and/or the fetus) is considered medically necessary to evaluate any second-trimester or later pregnancy loss or the second consecutive first-trimester pregnancy loss.
2. Prenatal CMA testing or low-pass WGS is considered medically necessary when any one of the following is met: 
   1. When diagnostic testing for fetal aneuploidy is needed for pregnant individuals undergoing invasive prenatal testing (i.e., amniocentesis, chorionic villus sampling or fetal tissue sampling)
   2. When non- invasive prenatal screening (NIPS) results require confirmation
   3. As a follow-up test for any smaller copy-number changes that were reported as positive by NIPS, OR
   4. When ultrasound examination reveals one or more structural abnormalities
   5. When, regardless of gestational age, fetal growth restriction is detected and a fetal malformation or polyhydramnios (or both) are also present.
   6. When unexplained isolated fetal growth restriction is diagnosed at <32 weeks of gestation.
   7. When there is intrauterine fetal demise or stillbirth in the third trimester and CMA is indicated to determine the potential cause.
   8. When the fetus is at high risk for a chromosome abnormality detectable by CMA, based on family history.
3. Evaluation with CMA testing or low-pass WGS is considered medically necessary in any of the following situations:
   1. For individuals with multiple congenital anomalies that are not specific to a well-delineated genetic condition and cannot be identified based on clinical evaluation alone
   2. For individuals with non-syndromic developmental delay/intellectual delay, OR
   3. For individuals with autism spectrum disorder, OR
   4. For individuals with a suspected inherited seizure disorder.
   5. When sex determination by NIPS is discordant with physical examination or clinical findings suggestive of a disorder of sexual differentiation, OR
   6. For individuals with proportionate short stature with other physical or structure defects.
4. Maternal cell contamination (MCC) analysis is considered medically necessary when performed in parallel with fetal diagnostic testing.
5. CMA testing for central nervous system (CNS) tumors and pediatric solid and soft tissue tumors is considered medically necessary.

When chromosomal microarray testing and low-pass whole genome sequencing is not covered

Postnatal CMA testing is considered not medically necessary when a chromosomal trisomy is suspected.

Co-testing CMA and low-pass WGS is considered not medically necessary.

All other CMA testing not listed above is considered not medically necessary.

Policy Guidelines

Chromosomal abnormalities are associated with a variety of disorders including developmental delay (DD), intellectual disability (ID), and congenital anomalies (Miller et al., 2010), as well as pregnancy loss.

Chromosomal microarray (CMA) testing to detect copy number variations (CNVs), homozygosity, and triploidy has replaced karyotyping as the first-tier diagnostic tool for many cases where chromosomal abnormality is suspected. CMA is significantly more sensitive (10 to 100 kb) than traditional karyotyping (5 to 10 Mb); additionally, CMA does not require cell culture, which reduces the turnaround time for results, and provides an alternative to karyotyping when dividing cells are not available for analysis. This technique may be used for several different purposes, such as identifying a cause of pregnancy loss or identifying other aneuploid conditions, such as Down Syndrome. “Emerging studies suggest that low-pass genome sequencing (GS) provides additional diagnostic yield of clinically significant copy-number variants (CNVs) compared with chromosomal microarray analysis (CMA). However, a prospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of low-pass GS compared with CMA is warranted.”

Chromosomal microarray (CMA) uses comparative genomic hybridization (CGH) to compare the DNA of a patient with a normal control using standard sets of DNA probes immobilized on a glass slide or glass beads. CGH arrays have been designed to cover the entire genome, for targeted analysis of known microdeletion/microduplication syndromes, and for known loci of inherited mutations. Array sensitivity varies based on the size and type of probes used. Oligonucleotide probes (~60 base pairs) or single nucleotide polymorphism (SNP) probes (32-40 base pairs) are most common. Oligonucleotide probes can be used to cover the entire genome at an average resolution of about 35 kb. Current arrays generally use a combination of copy number probes (oligonucleotide) to detect copy gains and losses and single nucleotide polymorphism (SNP) probes to detect similarity in single nucleotide sequences (homozygosity). The combination of probes detect runs of homozygosity between the maternal and paternal copy of each chromosome, enabling diagnosis of triploidy, uniparental disomy, and consanguinity as well as improving the detection of low levels of mosaicism.

Chromosomal microarray (CMA), as all genetic tests, can have variable clinical sensitivity due to the numerous types of genetic abnormalities that can impact gene expression. Some genetic conditions are caused by a change in copy number and/or a sequence change in the gene that is undetectable by CMA. If a genetic condition in which a subset of cases are caused by sequence changes, then other testing should be considered either in place of, or in addition to, CMA.

Low-pass WGS is a less expensive but lower coverage method of standard WGS. Low-pass WGS typically has less than 1x coverage, while standard WGS has a depth of 30x to 50x. Alternatively, compared to traditional low-cost microarrays, low-pass WGS results have over ten times the amount of information. Low-pass WGS maintains accuracy with reduced coverage by using imputation algorithms, a statistical analysis method that assigns values to missing data based on known information. With imputation algorithms, the low-pass WGS method uses known genetic variants within a representative population to genotype an individual without measurements from every locus.

CMA and Seizures

A seizure occurs due to erroneous electrical activity in the brain and may strike for many reasons including a brain injury or infection, abnormal sodium or glucose levels in the blood, congenital brain defects, epilepsy, and electric shock.

Epilepsy is a neurological disorder associated with abnormal electrical brain activity. CMA is often the first genetic tool used to obtain more information about a patient’s epilepsy and has a diagnostic yield of approximately 8% with several studies reporting higher values (Dubbs, 2022). Testing a specific gene may be appropriate in some epileptic cases as more than 80 genes have been associated with epilepsy and hundreds more associated with disorders that are accompanied by seizures. However, if results are negative, CMA or gene testing should commence as this is likely more appropriate than testing several more genes individually. If CMA testing is negative, gene panel and exome testing are appropriate.

Olson, et al. (2014) have found that in many patients, CNVs identified through CMA were able to explain an epileptic phenotype. The authors concluded that “Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.”

CMA and Short Stature

Short stature is a general term used to describe individuals whose height is two standard deviations or more below the mean compared to peers of the same age and racial-ethnic group (Richmond & Rogol, 2024). The most common causes of short stature are genetic and delayed growth; these are considered normal or nonpathologic variants of growth.

Intrauterine growth restriction (IUGR) is a condition which describes when an unborn baby is growing abnormally slow in the womb; this could be due to either genetic or environmental factors and may cause significant morbidity and mortality in infants. CMA has been used for diagnostic purposes in fetuses due to IUGR.

Idiopathic short stature (ISS) describes individuals whose height falls below two standard deviations of the mean for age, but no metabolic, endocrine, or other diagnosis has been identified to cause the height disorder. Regarding the genetic evaluation of short stature, some researchers suggest that for patients with ISS, patients born small for gestational age, or patients with growth hormone deficiency, “Targeted evaluation of a single gene or panels of genes is recommended... For those patients who do not fit into a distinct subgroup or for whom initial genetic testing is inconclusive, we recommend consideration of genome-wide evaluation through exome sequencing and chromosomal microarray to detect both sequence variants and CNVs.” An association has been identified between CNVs and short stature, and many report that CMA is a promising tool to identify pathogenic CNVs in patients with ISS.

Proprietary Testing

The only FDA-approved commercial CMA test is CytoScan^® by ThermoFisher. This test helps identify the underlying genetic causes of developmental delay, intellectual disability, congenital anomalies, or dysmorphic features in children. CytoScan^® detects chromosomal CNVs in genomic DNA from peripheral whole blood.

Several other commercial CMA tests are available including the GenomeDx CMA by GeneDx. The GenomeDx is able to confirm clinical diagnoses, differentiate between de novo and familial cases, and assist with prenatal diagnoses in at-risk pregnancies. This test has a three-week turnaround time and may utilize both blood (preferred) and buccal swabs (cheek swabs) as the tested specimen. The GenomeDx is a whole-genome CMA, containing 118,000 oligonucleotide probes that detect CNVs.

Quest Diagnostics has developed the ClariSure^® Postnatal CMA Test; the ClariSure^® consists of over 2.6 million probes that detect 1,900,000 CNVs and 750,000 SNPs. With a 10- to 15-day turnaround time, this test can help to determine the genetic cause of developmental delay or mental retardation. Blood is the preferred specimen for this test, but saliva may also be used.

LabCorp has developed Reveal^®, an SNP microarray aimed for pediatric purposes. This test uses a blood or salivary sample to detect chromosomal abnormalities that may be associated with congenital anomalies or developmental delay. Results are provided in 14-17 days.

The Invitae Chromosomal Microarray Analysis test is used too diagnosis chromosomal abnormalities associated with developmental disorders, multiple congenital anomalies, dysmorphic features, autism spectrum disorders, seizures, and epilepsy. The turnaround time is 10-12 days and samples can include whole blood or post birth cord blood. This test can detect whole and segmental aneuploidies, submicroscopic copy CNVs that cannot be detected by conventional karyotype, size and gene content of CNVs, regions of homozygosity, and uniparental isodisomy.

Analytical Validity

Although chromosomal microarray testing can vary widely in technology, resolution, and the likelihood of producing results of unknown significance, studies have demonstrated that CMA provides chromosomal evaluation at a much higher resolution than karyotyping. Miller, et al. (2010) noted that most clinical CMA platforms available in 2010 could detect copy number changes at a resolution of 400 kb; this was considered at least a “10-fold” improvement over G-banded karyotyping.

In a retrospective study, Zhu, et al. (2021) compared the utility of non‐invasive prenatal screening (NIPS) with chromosomal microarray analysis (CMA) for the detection of chromosomal abnormalities in high‐risk pregnancies. Of the 774 high risk pregnancies, 550 (71.1%) had a positive NIPS result, while 308 (39.8%) had a positive CMA result. The rate of full or partial concordance was 82.2% between NIPS and CMA. CNV's were more often detected by CMA, with an incidence of 7.9% by CMA and 3.1% by NIPS. In addition, a genetic aberration was detected by CMA in 1 in 17 high risk pregnancies that had a negative NIPS result. Overall, the authors conclude that "CMA should be offered instead of expanded NIPS for high‐risk pregnancies.”

Chaubey, et al. (2020) compared the diagnostic utility of low-pass genome sequencing (LP-GS) to chromosomal microarrays (CMAs) in its ability to detect copy number variants (CNVs). 409 DNA samples were studied for CNV accuracy, precision, specificity, and sensitivity using both techniques. The LP-GS test accurately detected 40 positive control samples with clinically relevant CNVs, absence of heterozygosity, deletions and duplications, and translocations and accurately reported 38 control samples without any clinically significant CNVs. In addition, 331 clinical specimens were tested for developmental delay, autism, intellectual disability, congenital anomalies, and dysmorphic features. Of the 331 cases, pathogenic CNVs were detected in 57 cases relating to microdeletion/microduplication syndromes, intragenic deletions and intragenic duplications, uniparental isodisomy, triploidy, and whole chromosome aneuploidies. The other cases were classified as variants of unknown significance or did not have a reportable CNV finding. The authors conclude that "LP-GS was able to reliably detect absence of heterozygosity, microdeletion/microduplication syndromes, and intragenic CNVs with higher coverage and resolution over the genome.”

Mazzonetto, et al. (2024) preformed a study evaluating the performance of low-pass whole genome sequencing (LP-WGS) to detect copy number variants (CNVs) in clinical cytogenetics. The DNA samples selected for this study were obtained from 44 unrelated individuals previously referred to molecular investigation in clinical cytogenetics. The patients were investigated by CMA (either array-CGH or SNP-array), currently considered the gold standard diagnostic test for CNV analysis DNA panel, with 12 prenatal and 32 postnatal samples, comprising a total of 55 genomic imbalances. The CNVs were chosen to represent a wide range of clinically relevant CNVs detected by CMA in diagnostic routine, being the vast majority of them associated with intellectual disability or recognizable syndromes. The selected CNVs contained at least one coding sequence. They were mapped to a variety of chromosomes ranging in copy number state from zero to 3/4, and ranging in genomic size from 75 kb to 90.3 Mb, including aneuploidies and two mosaic cases. Particularly, for methodology evaluation and quality control metrics, we used DNA extracted from several types of biological samples. The data shows “the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection.”

Clinical Utility and Validity

A review of 33 studies, comparing traditional karyotyping to CMA, has shown that CMA increases the detection rate for chromosomal abnormalities in individuals with DD/ID (developmental disability/intellectual disability) or autism spectrum disorder (ASD). CMA detected pathogenic genomic imbalances with an average diagnostic yield of 12.2% across all studies in this patient population, which is about 10% more than karyotyping alone.

Hillman, et al. (2013) performed both a meta-analysis and cohort study evaluating CMA’s detection rate of chromosomal abnormalities. The authors investigated 243 pregnant individuals who had both a CMA and karyotype performed, and the meta-analysis included 25 primary studies. Overall, CMA was found to detect 4.1% more abnormalities compared to karyotyping in the cohort study and 10% more in the meta-analysis.

Reddy, et al. (2012) compared the detection rates of microarray and traditional karyotyping. A total of 532 stillbirths were examined. The authors found that microarrays provided more results than karyotyping (87.4% compared to 70.5%) and identified more genetic abnormalities (8.3% vs 5.8%). Microarray analysis also found more genetic abnormalities among 443 antepartum stillbirths (8.8% vs 6.5%) and among 67 stillbirths with congenital abnormalities (29.9% vs 19.4%). Overall, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies compared to karyotyping.

Coulter, et al. (2011) assessed impact of CMA results on clinical decision making. A total of 1792 patients were examined, and 235 of them had either an “abnormal” result (n = 131) or a “variant of possible significance” (VPS) (n = 104). Clinical action was recommended for 54% of the patients in the “abnormal” cohort and 34% of the patients in the VPS cohort.

Brady, et al. (2013) performed a prospective study of fetuses with abnormalities detected on ultrasound. A total of 383 prenatal samples were examined. Causal imbalances were found in 37 samples, submicroscopic CNVs were found in 10 of the 37 samples, and arrays added “valuable information” over conventional karyotyping in 15 of 37 samples. The authors concluded that there was added value of chromosomal microarrays for prenatal diagnosis in the presence of ultrasound anomalies.

Borrell, et al. (2017) performed a meta-analysis of literature to estimate the incremental yield of CMA over karyotyping in fetal growth restriction (FGR). The authors identified ten studies and found a 4% incremental yield of CMA over karyotyping in “nonmalformed growth-restricted fetuses” and a 10% incremental yield in FGR when associated with fetal malformations.

Robson, et al. (2017) compared karyotyping and CMA in fetuses with ultrasound anomalies. Out of 629 cases with structural anomalies, CMA detected copy number variants (CNVs) and more pathogenic CNVs than karyotyping. CMA was also found to have a turnaround time of five days quicker than karyotyping. Finally, CMA was found to be £113 more expensive per patient than karyotyping. The authors conclude, “CMA is a robust, acceptable and probably cost-effective method to detect more clinically significant chromosomal imbalances in the anomalous fetus. The results suggest that CMA should replace karyotyping in these care pathways.”

Li, et al. (2018)  performed a study investigating the cost effectiveness of karyotyping, CMA, and NGS in genetic diagnosis of unexplained global developmental delay. The authors found that: “CMA testing results in more genetic diagnoses at an incremental cost of US $2692 per additional diagnosis compared with karyotyping, which has an average cost per diagnosis of US $11,033.” The authors also found that performing both tests sequentially result in the same number of diagnoses but costs less when CMA testing is done first and karyotyping second. The authors also analyzed the cost-effectiveness of a variant of unknown significance. When CMA testing yields a variant of unknown significance, additional genetic diagnoses can be obtained “at an incremental cost of US $4220 by CMA testing of both parents, and when parents are not available or the patient had a normal CMA result, targeted NGS of the patient can add diagnoses at a further incremental cost of US $12,295.” The authors concluded that “These results provide a cost effectiveness rationale for the use of CMA as the first-tier test for the genetic diagnosis of unexplained GDD/ID [global developmental delay/intellectual disability] and further indicate that testing of both parents may be cost effective when a variant of unknown significance is detected in the patient.”

Hydrops fetalis occurs when fluid accumulates in fetal serous cavities and soft tissues; nonimmune hydrops fetalis (NIHF) develops when red cell alloimmunization does not cause the hydrops fetalis case in question. A retrospective study by Mardy, et al. (2020) looked at prenatally diagnosed NIHF cases identified at the University of California, San Francisco from 2008 to 2018 was performed. A total of 131 cases were identified. The researchers found that “In 43/44 cases with a CMA performed, results were categorized as normal or likely benign. One case was found on CMA to have a large pathogenic duplication.” This shows that CMA is not an effective diagnostic tool for NIHF.

Pasternak, et al. (2020) aimed to assess the diagnostic capabilities of CMA among pregnancies terminated due to fetal malformations identified with ultrasounds. CMA was performed on 71 pregnancies using fetal DNA or placental DNA. The authors noted that “Findings were abnormal in 17 cases (23.9%), of which 13 were detectable by karyotype. The incremental yield of CMA was 4/71 (5.6%); 1/32 (3.1%) for cases with an isolated anomaly and 3/39 (7.7%) for cases with nonisolated anomalies.” CMA identified more chromosomal abnormalities than karyotype and did not require dividing cells, making it a more practical option after termination.

Rodriguez-Revenga, et al. (2020) studied the diagnostic yield of CMA in prenatal diagnosis where 2905 prenatal samples with a normal rapid aneuploidy detection test were referred for CMA testing. The study revealed pathogenic CNVs associated with syndromic disorders in 4.8% of the 2905 cases, adding a 2.8% diagnostic value of CMA over karyotyping. This study shows that "CMA increases 2‐fold the diagnostic yield achieved by conventional karyotyping." Therefore, "chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result.”

Bajaj Lall, et al. (2021) valuated the diagnostic yield and clinical utility of CMA by comparing it to karyotyping results. CMA and karyotyping were performed on consecutive referrals of 370 prenatal samples of amniotic fluid (n = 274) and chorionic villi (n = 96) from Indian pregnant individuals with high maternal age (n = 23), biochemical screen positive (n = 61), previous child abnormal (n = 59), abnormal fetal ultrasound (n = 205) and heterozygous parents (n = 22). The overall diagnostic yield of abnormal results was higher via CMA than by karyotyping (9.18% vs. 5.40%, respectively). As such, the authors argue that “CMA must be used as the first tier test in all cases with abnormal fetal ultrasound and if cost is not an issue, it can be offered to all pregnant [individuals] undergoing the invasive test, as the test results are faster and the diagnostic yield is higher by CMA than by karyotyping even in other groups.”

Monier, et al. (2021) evaluated the use of chromosomal microarray analysis as compared to karyotyping in these cases of isolated fetal growth restriction. Both karyotyping and chromosomal microarray analysis were performed in 146 fetuses, and the researchers found that the detection rate of genetic abnormalities by CMA was 7.5%, with an incremental yield of 3.6% as compared to karyotyping. Moreover, CMA was able to identify a variant of unknown significance in three fetuses boasting normal karyotypes. Consequently, the level of granularity of CMA in “these results support the use of chromosomal microarray analysis in addition to karyotype for isolated fetal growth restriction.”

Zhang, et al. (2021) investigated the incidence and clinical significance of chromosomal mosaicism (CM) in a single-center retrospective study of invasive prenatal diagnosis of CM. From a sample of 5758 G-band karyotyping results and 6066 CMA results, the authors deduced that their findings “demonstrate that increased risk in genetic counselling is due to discordant CM from different specimens or testing methods” and so “It is highly recommended to use more comprehensive assays such as a combination of CMA, FISH [fluorescence in situ hybridization analysis] and karyotyping to detect mosaicism in AF [amniotic fluid] and CB [cord blood] before any irreversible decision is made in regard to the pregnancy.

Chau, et al. (2020) conducted a retrospective back-to-back comparison study of “low-pass GS versus routine CMA for 532 prenatal, miscarriage, and postnatal cases, the overall diagnostic yield was 22.4% (119/532) for CMA and 23.1% (123/532) for low-pass GS. Thus, the overall relative improvement of the diagnostic yield by low-pass GS versus CMA was ~ 3.4% (4/119). Identification of cryptic and clinically significant CNVs among prenatal, miscarriage, and postnatal cases demonstrated that CNV detection at higher resolutions is warranted for clinical diagnosis regardless of referral indications. Overall, [the] study supports low-pass GS as the first-tier genetic test for molecular cytogenetic testing.”

Guidelines and Recommendations

American College of Medical Genetics and Genomics (ACMG)

In the Clinical Practice Resource for Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities, the ACMG recommends CMA testing “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 nonsyndromic DD/ID.” 
3. “Autism spectrum disorders.” 

The ACMG also recommends “further determination of the use of CMA testing for the evaluation of the child with growth retardation, speech delay, and other less well-studied indications…, particularly by prospective studies and after- market analysis.” Additionally, ACMG recommends “appropriate follow-up … in cases of chromosome imbalance identified by CMA, to include cytogenetic/FISH studies of the patient, parental evaluation, and clinical genetic evaluation and counseling.” These statements were reaffirmed in 2020 by the ACMG Board of Directors. 

An update from ACMG states that a stepwise or tiered approach to the clinical genetic diagnostic evaluation of autism spectrum disorder is recommended, with the recommendation being for first tier to include fragile X syndrome and chromosomal microarray analysis (CMA).

In 2017 the ACMG published a laboratory practice resource outlining an algorithm for diagnostic cytogenetic testing following positive noninvasive prenatal screening results which recommends:

• “CMA testing on either CVS or amniotic fluid may be used as confirmatory diagnostic testing in cases with positive NIPS results, or as reflex testing in cases with initial normal results from chromosome analysis.”
• CMA is recommended as follow-up testing for any smaller copy-number changes that are reported as positive by NIPS.
• They also suggest that when “prenatal diagnostic testing may not be performed due to loss of the pregnancy before testing is possible. In such instances, testing of the products of conception and/or the fetus by either chromosome analysis or CMA should be considered on a case-by-case basis.”
• In newborns for whom the screen is suggestive of aneuploidy, but further testing is declined a genetics consultation with physical examination is sufficient for neonates, however, “if the neonate has an abnormal physical examination that is not suggestive of the trisomy in question, CMA is recommended.”

CMA is also recommended when the sex determination by NIPS is discordant with physical examination, or clinical findings suggestive of a disorder of sexual differentiation. Following a Systematic Evidence Review in 2023, the ACMG now recommends “ACMG strongly recommends NIPS over traditional screening methods for all pregnant patients with singleton and twin gestations for fetal trisomies 21, 18, and 13 and strongly recommends NIPS be offered to patients to screen for fetal sex chromosome aneuploidy.”

In 2009, the ACMG published guidelines on the genetic evaluation of short stature. These guidelines provide recommendations for genes associated with short stature and intrauterine growth restriction (IUGR) and state that high resolution chromosome analysis and/or array CGH can be used to evaluate IUGR.

In 2018, the ACMG published a clinical practice report on genetic testing after CMA for the diagnosis of neurodevelopmental disability and congenital anomalies. These guidelines state that “CMA may not detect balanced cytogenomic abnormalities or uniparental disomy (UPD), and deletion/duplications and regions of homozygosity may require additional testing to clarify the mechanism and inform accurate counseling.”

In 2025 the ACMG published an addendum to their 2018 clinical practice guidelines on the use of CMA for screening neurodevelopmental disability and congenital anomalies. The update largely reaffirms the 2018 guidelines with a few with a few additions “microarray is no longer the sole first-tier go-to test per ACMG evidence-based clinical guidelines… Additional testing after chromosomal microarray remains clinically relevant for disease-specific testing (eg, testing for an autosomal recessive pathogenic variant or uniparental disomy after detection of homozygosity), as well as more general testing recommendations (eg, balanced translocations and insertions).”

In 2020, the ACMG published guidelines on the use of fetal exome sequencing in prenatal diagnosis. These guidelines recommend that “Exome sequencing may be considered for a fetus with ultrasound anomalies when standard CMA and karyotype analysis have failed to yield a definitive diagnosis. If a specific diagnosis is suspected, molecular testing for the suggested disorder (with single-gene test or gene panel) should be the initial test.”

The ACMG Technical Standards for Clinical Genetics Laboratories (2021 Revision) state, “the contamination of both direct and cultured cells from AF and CVS with maternal cells is well documented and therefore represents a potential source of error in prenatal diagnosis. Prenatal samples should be examined in parallel with a maternal sample to rule out error due to maternal cell contamination (MCC). Laboratories should understand how their testing methods are affected by the presence and the amount of MCC. For example, prenatal detection of a deletion using PCR, as is the case in testing for DMD and SMA, is expected to be more sensitive to maternal contamination, since a normal maternal allele could mask the deletion. A prenatal test using an allele-specific PCR reaction to detect a paternal RhD gene in the fetus of a RhD-negative mother is much less sensitive to maternal contamination.”

American Academy of Pediatrics (AAP)

The 2014 AAP guidance for the comprehensive evaluation of children with intellectual disability or global developmental delays noted that “chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology.” They further add that “CMA is now the standard for diagnosis of patients with GDD/ID, as well as other conditions, such as autism spectrum disorders or multiple congenital anomalies.”

Another clinical report published by the AAP on the identification of infants and young children with developmental disorders states that “The child with suspected global developmental delay or intellectual disability should have laboratory testing done, including chromosomal microarray and fragile X testing.” The authors also note that “The initial genetic workup of the child with suspected ASD is evolving; current recommendations also include chromosomal microarray and fragile X testing.”

The AAP has an epilepsy webpage overview and on the genetic testing for epilepsy page states that “The genetic tests most utilized in the evaluation of children with epilepsy include chromosomal microarray (CMA), epilepsy gene panels, and whole-exome sequencing (WES). Each test has its own specific benefits and limitations, and the utility of different tests may vary for a given individual. Decisions regarding testing need to consider the clinical indication including associated symptoms, turn-around time, insurance coverage, and cost.” The AAP published guidelines on the evaluation of children with autism spectrum disorder. According to the guidelines, CMA is recommended if the etiology for developmental disability is not known. Since Fragile X Syndrome increases the risk for autism spectrum disorder, DNA testing for Fragile X should be recommended in all children with ASD, especially for boys and children with a family history of intellectual disability. “The cytosine-guanine-guanine trinucleotide repeat expansion that is responsible for fragile X syndrome is not detected on CMA and must be ordered as a separate test. When the history and physical examination, CMA, and fragile X analysis do not identify an etiology, the next step at this time in the etiologic evaluation for [autism spectrum disorder] is whole-exome sequencing (WES).” AAP does not recommend the use of commercially marketed tests as they do not provide a molecular etiologic diagnosis.

American Academy of Neurology (AAN)

The AAN published coverage policies for chromosomal microarray analysis for intellectual disabilities in 2015. The policy document notes the criteria do not represent a binding standard of care and that the criteria are proposed as clinical contexts that readily support the use of microarray testing. The authors note that chromosomal microarray analysis is reasonable and medically necessary for diagnosing a genetic abnormality when all of the following conditions are met:

• “In children with developmental delay/intellectual disability (DD/ID) or an autism spectrum disorder (ASD) according to accepted Diagnostic and Statistical Manual of Mental Disorders-IV criteria;
  AND 
• If warranted by the clinical situation, biochemical testing for metabolic diseases has been performed and is negative; 
• Targeted genetic testing, (for example: FMR1 gene analysis for Fragile X), if or when indicated by the clinical and family history, is negative; 
• The results for the testing have the potential to impact the clinical management of the patient; 
• Face-to-face genetic counseling with an appropriately trained and experienced healthcare professional has been provided to the patient (or legal guardian(s) if a minor child). Patient or legal guardians have given their consent for testing. Cognitively competent adolescent patients have given their assent for testing as well.”

The document notes the presence of major and minor congenital malformations and dysmorphic features should be considered evidence that microarray testing will be more likely to yield a diagnosis. However, dysmorphic and syndromic features are not required for testing.

American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM)

Originally published 2013 reaffirmed in 2020, the ACOG and SMFM issued joint guidelines recommending the following use of CMA for prenatal diagnosis:

• “Most genetic changes identified by chromosomal microarray analysis that typically are not identified on standard karyotype are not associated with increasing maternal age; therefore, the use of this test can be considered for all women, regardless of age, who undergo prenatal diagnostic testing.
• Prenatal chromosomal microarray analysis is recommended for a patient with a fetus with one or more major structural abnormalities identified on ultrasonographic examination and who is undergoing invasive prenatal diagnosis. This test typically can replace the need for fetal karyotype.
• In a patient with a structurally normal fetus who is undergoing invasive prenatal diagnostic testing, either fetal karyotyping or a chromosomal microarray analysis can be performed.
• Chromosomal microarray analysis of fetal tissue (i.e., amniotic fluid, placenta, or products of conception) is recommended in the evaluation of intrauterine fetal death or stillbirth when further cytogenetic analysis is desired because of the test’s increased likelihood of obtaining results and improved detection of causative abnormalities.
• Comprehensive patient pretest and posttest genetic counseling from an obstetrician–gynecologist or other health care provider with genetics expertise regarding the benefits, limitations, and results of chromosomal microarray analysis is essential. Chromosomal microarray analysis should not be ordered without informed consent, which should include discussion of the potential to identify findings of uncertain significance, nonpaternity, consanguinity, and adult-onset disease.
• The routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published.”

ACOG and SMFM do not recommend use of CMA for evaluation of first- and second-trimester pregnancy loss due to limited clinical utility information. Additionally, they recommend pre- and post-test genetic counseling “from qualified personnel such as a genetic counselor or geneticist regarding the benefits.”

A 2018 study of these guidelines analyzed 3223 prenatal samples undergoing CMA. Cases were categorized into two groups: those that met ACOG guidelines for CMA versus those that met ACOG guidelines for either CMA or karyotype. They found that “in patients who could have elected either CMA or karyotype, 2.5% had clinically significant chromosomal abnormalities (CSCA) that would have been missed if the patient had elected to pursue karyotype.”

American Society for Reproductive Medicine (ASRM)

In 2012, ASRM published a committee opinion on evaluation and treatment of recurrent pregnancy loss with clinical practice recommendations. ASRM recommended to proceed with the evaluation of recurrent pregnancy loss after two consecutive clinical pregnancy losses. This definition of recurrent pregnancy loss was reaffirmed in 2013. The recommended assessment of recurrent pregnancy loss included screening for genetic, hormonal and metabolic factors in addition to other factors. They have stated that “karyotypic analysis of products of conception may be useful in the setting of ongoing therapy for recurrent pregnancy loss.”

In 2023, the Practice Committee and Genetic Counseling Professional Group (GCPG) of the ASRM published their opinion on the clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts. Defining prenatal diagnostic testing as including chorionic villus sampling or amniocentesis, the group recommends the following:

• “Analyses on prenatal testing samples beyond a standard karyotype may be considered, depending on the specific PGT-A result and at the discretion of the ordering provider. These may include:
  • Chromosomal microarray, when partial chromosome aneuploidy is involved
  • Additional cell counts with a traditional karyotype or fluorescent in situ hybridization to identify lower-level mosaicism
  • Uniparental disomy studies, depending on the chromosome involved
• Genetic counseling is strongly recommended for any patient pregnant after the transfer of a mosaic-result embryo and should include a discussion of the risks, benefits, and limitations of prenatal testing options.”

Society of Obstetricians and Gynaecologists of Canada (SOGC)- Canadian College of Medical Geneticists (CCMG) Joint Technical Update

The 2018 joint guideline supersedes the 2011 iteration.

• “Offer of chromosomal microarray analysis (in addition to any other relevant diagnostic testing) is recommended in cases with multiple fetal anomalies identified by a comprehensive obstetric ultrasound (II-1A). Other diagnostic testing may include specific single gene, multigene panels or other genetic tests if the pattern of anomalies suggests a specific genetic condition not identified by array.”
•  “Single structural defects in association with other abnormal ultrasound findings (eg, intrauterine growth restriction (IUGR), oligohydramnios) should not be considered isolated, and thus array should be offered if RAD is normal.” 
• “In cases with a single fetal anomaly, prenatal CMA should be considered for those malformations associated with a high frequency of abnormal results. Its use in cases where the diagnostic yield is lower may be considered, if resources are available.” 
• “In fetuses with a nuchal translucency ≥3.5 mm, prenatal CMA should be offered.”

For “analysis of fetal loss prior to 20 weeks gestation”:

• “In cases of congenital anomalies and/or IUGR, in any fetal loss prior to 20 weeks gestation, if QF-PCR methodologies and/or other directed diagnostic inquiries do not provide a diagnosis and further cytogenetic analysis is intended, it is recommended that karyotype be replaced with chromosomal microarray analysis.”

For fetal deaths ≥20 weeks gestation:

• “Aneuploidy is the most common abnormal chromosomal finding in stillbirths. If RAD and/or other directed diagnostic inquiries are uninformative, it is recommended that in cases complicated by congenital anomalies and/or IUGR, karyotype be replaced with CMA when further cytogenetic analysis is desired.” 
• “In stillbirths without structural fetal anomalies, CMA may be considered in the context of local resource availability and site-based postmortem protocol (whether complete, limited or external only).”

Society of Obstetricians and Gynaecologists of Canada (SOGC)

The SOGC published a 2024 guideline on prenatal screening for fetal chromosomal anomalies where they cover the following recommendations:

• “All pregnant persons, regardless of age, should be offered, through an informed counselling process with shared decision-making, the option of a prenatal screening test for the most common fetal aneuploidies and for major fetal anomalies
• Prenatal screening programs should be implemented with resources that support audited screening and laboratory services, ultrasound services, genetic counselling, and patient and health care provider education.
• Regardless of aneuploidy screening choice, all pregnant persons should be offered a first-trimester fetal ultrasound, (optimally between 11- and 14-weeks gestation), to assess viability, gestational age, number of fetuses, chorionicity in multiples, early fetal anatomy, and nuchal translucency. Maternal serum screening (with or without nuchal translucency measurement for aneuploidy risk estimation) should not be performed if cell-free DNA screening is performed or planned
• If a fetal structural abnormality (not a soft marker) is identified during the first- or second-trimester ultrasound, regardless of previous screening test results, genetic counselling and invasive diagnostic testing should be offered, with rapid aneuploidy detection and reflex microarray analysis or exome/genome sequencing, if rapid aneuploidy detection is normal or inconclusive. The diagnostic role of fetal exome/genome sequencing is a rapidly evolving area, and maternity care providers should be aware of this technology.”

Association for Molecular Pathology (AMP)

The MCC [maternal cell contamination] Guidelines Working Group of the AMP Clinical Practice Committee issued laboratory guidelines for detecting MCC in 2011. They state, “To determine the pure fetal origin of all prenatal specimens undergoing genetic analysis, it is recommended that MCC analysis be performed in parallel with diagnostic testing, regardless of the genetic disorder or its mode of inheritance.”

The Association for Molecular Pathology Training and Education Committee published a series of quick reference cards called Molecular-in-My-Pocket^™ for trainees and anyone looking to quickly reference molecular diagnostics information.

In their oncology subdivision, the AMP summarize assays and techniques for molecular biomarkers for various cancers. Below are summaries of their syntheses.

When testing for primary and recurrent tumors for the KIT biomarker in cutaneous melanoma, “NGS, pyrosequencing, Sanger sequencing, PCR-based assays, microarray” are applicable for therapeutic indications.

When testing for primary and recurrent tumors for 1p/19q co-deletion in tumors of the central nervous system, “FISH, array, NGS” are approved for diagnosis and prognosis. Moreover, when testing for EGFR amplification, gain of chromosome 7, and loss of chromosome 10, “FISH, array, NGS” are applicable for diagnosis.

Similarly, in their pediatric molecular pathology section, the AMP summarizes assays and techniques for pediatric brain tumors. The following table, adapted from the oncology Molecular-in-my-Pocket^™ card, lists the assays and techniques mentioning CMA and their corresponding tumor types:

Regarding pediatric solid tumors, the following table, adapted from the oncology Molecular-in-my-Pocket^™ card,  lists the assays and techniques mentioning CMA and their corresponding tumor types:

Regarding pediatric soft tissue tumors, the following table, adapted from the oncology Molecular-in-my-Pocket^™ card, lists the assays and techniques mentioning CMA and their corresponding tumor types:

Society for Maternal-Fetal Medicine (SMFM)

The SMFM recommends chromosomal microarray for evaluation of mild fetal ventriculomegaly and nonimmune hydrops fetalis.

SMFM released guidelines on the diagnosis and management of fetal growth restriction. The following recommendations were made:

• SMFM recommends that pregnant individuals “be offered fetal diagnostic testing, including chromosomal microarray analysis, when fetal growth restriction is detected and a fetal malformation, polyhydramnios, or both are also present regardless of gestational age.”
• They also recommend that pregnant individuals “be offered prenatal diagnostic testing with chromosomal microarray analysis when unexplained isolated fetal growth restriction is diagnosed at <32 weeks of gestation.”

International Standard Cytogenomic Array (ISCA) Consortium

The ISCA (an international group of experts in the field) assembled to “address mutual concerns about standardization and collaboration for clinical CMA testing.” After much research, the ISCA has stated that “Our recommendation based on current evidence is to offer CMA as the first-tier genetic test, in place of G-banded karyotype, for patients with unexplained DD/ID, ASD, or MCA [multiple congenital anomalies].”

International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF)

Joint guidelines on the use of genome-wide sequencing for fetal dianosis were published by the ISPD, SMFM and PQF. However, these guidelines also mention CMA quite frequently because “The use of diagnostic sequencing is currently being introduced for evaluation of fetuses for whom standard diagnostic genetic testing, such as chromosomal microarray analysis (CMA), has already been performed and is uninformative or is offered concurrently according to accepted practice guidelines, or for whom expert genetic opinion determines that standard genetic testing is less optimal than sequencing for the presenting fetal phenotype.”

Fetal sequencing is recommended in several scenarios, including the following which also mention CMA:

• “A current pregnancy with a fetus with a single major anomaly or with multiple organ system anomalies that are suggestive of a possible genetic etiology, but no genetic diagnosis was found after CMA; or in select situations with no CMA result, following a multidisciplinary review and consensus, in which there is a fetus with a multiple anomaly ‘pattern’ that strongly suggests a single gene disorder. 
• A personal (maternal or paternal) history of a prior undiagnosed fetus (or child) affected with a major single anomaly or multiple anomalies suggestive of a genetic etiology, and a recurrence of similar anomalies in the current pregnancy without a genetic diagnosis after karyotype or CMA.
• In families with a history of recurrent stillbirths of unknown etiology after karyotype and/or CMA, where the fetus in the current pregnancy has a recurrent pattern of anomalies.”

These recommendations show that CMA should be used as an initial strategy (before fetal sequencing) to determine the genetic causation during pregnancy of the aforementioned cases.

Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration

These guidelines focus on clinical genetic testing for patients with autism spectrum disorders (ASDs). The authors note that “CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.” Further, the guidelines later state that “our results suggest that CMA with whole genome coverage should be adopted as a national standard of care for genetic testing among patients with ASDs.”

Endocrine Society (ES)

The Endocrine Society published guidelines on the diagnosis and treatment of children with idiopathic short stature (ISS) in 2008. These guidelines state that “In situations where a specific genetic diagnosis associated with short stature is expected (such as Noonan syndrome or GH insensitivity syndrome), the genes of interest should be examined.” These guidelines do not mention CMA.

The National Fragile X Foundation

The National Fragile X Foundation’s statement on genetic testing for Fragile X Syndrome and associated disorders includes within its recommendations the use of chromosomal microarray analysis and exome sequencing for the diagnosis of “the underlying cause of a child’s developmental delays, autism, or intellectual disability”. However, though the above are viable options for genetic testing in general, “Currently, Fragile X testing must be ordered as a separate test since expansions of the FMR1 gene cannot be detected through microarray or exome sequencing”, and as such a specific DNA test for Fragile X Syndrome via PCR and Southern Blot analysis will need to be used.

State and Federal Regulations, as applicable

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

In 2014 the FDA approved CytoScan^® Dx Assay as a “qualitative assay intended for the postnatal detection of copy number variations (CNV) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. CytoScan^® Dx Assay is intended for the detection of CNVs associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features.”

In 2017 the FDA approved GenetiSure Dx Postnatal Assay as a “qualitative assay intended for the postnatal detection of copy number variations (CNV) and copy-neutral loss of heterozygosity (cnLOH) in genomic DNA obtained from peripheral whole blood in patients referred for chromosomal testing based on clinical presentation. GenetiSure Dx Postnatal Assay is intended for the detection of CNVs and cnLOH associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81228, 81229, 81265, 81349, 0209U, 0252U, 0469U, S3870

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. 

Scientific Background and Reference Sources

Schrijver I, Zehnder JL. Tools for genetics and genomics: Cytogenetics and molecular genetics. Updated August 10, 2023. https://www.uptodate.com/contents/tools-for-genetics-and-genomics-cytogenetics-and-molecular-genetics

Gencove. Low-pass sequencing and imputation for evaluating genetic variation. 2023;

Mandy GT. Infants with fetal (intrauterine) growth restriction. Updated Feb 10, 2025. https://www.uptodate.com/contents/infants-with-fetal-intrauterine-growth-restriction

Miller D. Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray. Updated Jul 31, 2024. https://www.uptodate.com/contents/use-of-chromosomal-microarray-in-obstetrics

Reddy UM, Page GP, Saade GR, et al. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med. Dec 6 2012;367(23):2185-93. doi:10.1056/NEJMoa1201569

ACOG. Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstetrics and gynecology. Dec 2016;128(6):e262-e268. doi:10.1097/aog.0000000000001817

Wang H, Dong Z, Zhang R, et al. Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis. Genet Med. Mar 2020;22(3):500-510. doi:10.1038/s41436-019-0634-7

Aradhya S, Cherry AM. Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs. Genet Med. Sep 2007;9(9):553-9. doi:10.1097/gim.0b013e318149e354

Illumina. Coverage depth recommendations. https://www.illumina.com/science/technology/next-generation-sequencing/plan-experiments/coverage.html

Dubbs H. National Coordinating Center For Epilepsy Epilepsy Overview. https://www.aap.org/en/patient-care/epilepsy/diagnosing-pediatric-epilepsy/genetic-testing-for-epilepsy/

Poduri A, Sheidley BR, Shostak S, Ottman R. Genetic testing in the epilepsies—developments and dilemmas. Nature Reviews Neurology. 2014/05/01 2014;10(5):293-299. doi:10.1038/nrneurol.2014.60

Mefford HC. Clinical Genetic Testing in Epilepsy. Epilepsy Curr. Jul-Aug 2015;15(4):197-201. doi:10.5698/1535-7511-15.4.197

Olson H, Shen Y, Avallone J, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. Jun 2014;75(6):943-58. doi:10.1002/ana.24178

Richmond Padilla EJ, Rogol AD. Diagnostic approach to children and adolescents with short stature. Updated June 09, 2023. https://www.uptodate.com/contents/5834

Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. J Clin Endocrinol Metab. Sep 2014;99(9):3080-92. doi:10.1210/jc.2014-1506

Collett-Solberg Paulo F, Ambler G, Backeljauw Philippe F, et al. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective. Hormone Research in Paediatrics. 2019;92(1):1-14. doi:10.1159/000502231

ThermoFisher. CytoScan cytogenetics suite. https://assets.thermofisher.com/TFS-Assets/LSG/brochures/CytoScan-Comprehensive-Brochure.pdf

GeneDx. Chromosomal Microarray (GenomeDx^®). https://providers.genedx.com/tests/detail/chromosomal-microarray-718

Quest. Chromosomal Microarray, Postnatal, ClariSure^® Oligo-SNP. Quest Diagnostics. Updated April 2023. https://testdirectory.questdiagnostics.com/test/test-guides/TS_Postnatal_ClariSure_Oligo-SNP/chromosomal-microarray-postnatal-clarisure-oligo-snp?p=td

LabCorp. SNP Microarray−Pediatric (Reveal^®). https://www.labcorp.com/tests/510002/snp-microarray-pediatric-reveal

Invitae. Invitae Chromosomal Microarray Analysis (CMA) Test code: 56033. https://www.invitae.com/us/providers/test-catalog/test-56033

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. 2010:749-64. vol. 5.

Zhu X, Chen M, Wang H, et al. Clinical utility of expanded non-invasive prenatal screening and chromosomal microarray analysis in high-risk pregnancy. Ultrasound Obstet Gynecol. Mar 2021;57(3):459-465. doi:10.1002/uog.22021

Chaubey A, Shenoy S, Mathur A, et al. Low-Pass Genome Sequencing: Validation and Diagnostic Utility from 409 Clinical Cases of Low-Pass Genome Sequencing for the Detection of Copy Number Variants to Replace Constitutional Microarray. J Mol Diagn. Jun 2020;22(6):823-840. doi:10.1016/j.jmoldx.2020.03.008

Mazzonetto PC, Villela D, da Costa SS, et al. Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting. Ann Hum Genet. Mar 2024;88(2):113-125. doi:10.1111/ahg.12532

Hillman SC, McMullan DJ, Hall G, et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology. 2013;41(6):610-620. doi:10.1002/uog.12464

Coulter ME, Miller DT, Harris DJ, et al. Chromosomal microarray testing influences medical management. Genet Med. Sep 2011;13(9):770-6. doi:10.1097/GIM.0b013e31821dd54a

Brady PD, Chiaie BD, Christenhusz G, et al. A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors. Genetics in Medicine. [2013-10-31] 2013;16:469-476. doi:doi:10.1038/gim.2013.168

Borrell A, Grande M, Pauta M, Rodriguez-Revenga L, Figueras F. Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis. Fetal diagnosis and therapy. Sep 9 2017;doi:10.1159/000479506

Robson SC, Chitty LS, Morris S, et al. Efficacy and Mechanism Evaluation. Evaluation of Array Comparative genomic Hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation. 2017;doi:10.3310/eme04010

Li Y, Anderson LA, Ginns EI, Devlin JJ. Cost Effectiveness of Karyotyping, Chromosomal Microarray Analysis, and Targeted Next-Generation Sequencing of Patients with Unexplained Global Developmental Delay or Intellectual Disability. Molecular diagnosis & therapy. Feb 2018;22(1):129-138. doi:10.1007/s40291-017-0309-5

Mardy AH, Rangwala N, Hernandez-Cruz Y, et al. Utility of chromosomal microarray for diagnosis in cases of nonimmune hydrops fetalis. Prenat Diagn. Jan 25 2020;doi:10.1002/pd.5617

Pasternak Y, Daykan Y, Tenne T, et al. The yield of chromosomal microarray analysis among pregnancies terminated due to fetal malformations. J Matern Fetal Neonatal Med. Jan 23 2020:1-5. doi:10.1080/14767058.2020.1716722

Rodriguez-Revenga L, Madrigal I, Borrell A, et al. Chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result. Clinical Genetics. 2020;98(4):379-383. doi:10.1111/cge.13810

Bajaj Lall M, Agarwal S, Paliwal P, et al. Prenatal Diagnosis by Chromosome Microarray Analysis, An Indian Experience. J Obstet Gynaecol India. Apr 2021;71(2):156-167. doi:10.1007/s13224-020-01413-6

Monier I, Receveur A, Houfflin-Debarge V, et al. Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study. Am J Obstet Gynecol. Dec 2021;225(6):676.e1-676.e15. doi:10.1016/j.ajog.2021.05.035

Zhang Y, Zhong M, Zheng D. Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis. J Cell Mol Med. Jan 2021;25(1):358-366. doi:10.1111/jcmm.16080

Chau Matthew HW, Yunli Lai, Yanyan Zhang, Fuben Xu, Yanqing Tang, Yanfang Wang, Zihan Chen, Tak Yeung Leung, Jacqueline Pui Wah Chung, Yvonne K Kwok, Shuk Ching Chong, Kwong Wai Choy, Yuanfang Zhu, Likuan Xiong, Weihong Wei, Zirui Dong. Low-pass genome sequencing: a validated method in clinical cytogenetics. Human Genetics. 2020;doi:10.1007/s00439-020-02185-9

Chau MHK, Wang H, Lai Y, et al. Low-pass genome sequencing: a validated method in clinical cytogenetics. Hum Genet. Nov 2020;139(11):1403-1415. doi:10.1007/s00439-020-02185-9

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):742-5. doi:10.1097/GIM.0b013e3181f8baad

Cherry AM, Akkari YM, Barr KM, et al. Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. Aug 2017;19(8):845-850. doi:10.1038/gim.2017.91

Dungan JS, Klugman S, Darilek S, et al. Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2023;25(2)doi:10.1016/j.gim.2022.11.004

Seaver LH, Irons M. ACMG practice guideline: genetic evaluation of short stature. Genet Med. Jun 2009;11(6):465-70. doi:10.1097/GIM.0b013e3181a7e8f8

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. Oct 2018;20(10):1105-1113. doi:10.1038/s41436-018-0040-6

Ting W, Rudd MK, Melanie AM. Addendum: 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). Genetics in Medicine. 2025;27(3):101335. doi:10.1016/j.gim.2024.101335

Monaghan KG, Leach NT, Pekarek D, et al. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2020/04/01 2020;22(4):675-680. doi:10.1038/s41436-019-0731-7

ACMG. ACMG Technical Standards for Clinical Genetics Laboratories (2021 Revision): Clinical Molecular Genetics (Section G). https://www.acmg.net/PDFLibrary/ACMG%20Technical%20Lab%20Standards%20Section%20G.pdf

Moeschler JB, Shevell M. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. Sep 2014;134(3):e903-18. doi:10.1542/peds.2014-1839

Lipkin PH, Macias MM. Promoting Optimal Development: Identifying Infants and Young Children With Developmental Disorders Through Developmental Surveillance and Screening. Pediatrics. Jan 2020;145(1)doi:10.1542/peds.2019-3449

Hyman SL, Levy SE, Myers SM. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. Jan 2020;145(1)doi:10.1542/peds.2019-3447

Satya-Murti S, Cohen, B.H., and Michelson, D. Chromosomal microarray analysis for intellectual disabilities. American Academy of Neurology. https://www.aan.com/siteassets/home-page/tools-and-resources/practicing-neurologist--administrators/billing-and-coding/model-coverage-policies/15microarrayanalysismodel_tr.pdf

Hay SB, Sahoo T, Travis MK, et al. ACOG and SMFM guidelines for prenatal diagnosis: Is karyotyping really sufficient? Prenat Diagn. Jan 9 2018;doi:10.1002/pd.5212

ASRM. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertility and Sterility. 2012;98(5):1103-1111. doi:10.1016/j.fertnstert.2012.06.048

ASRM. Clinical management of mosaic results from preimplantation genetic testing for aneuploidy of blastocysts: a committee opinion. Updated November 2023. https://www.asrm.org/practice-guidance/practice-committee-documents/clinical-management-of-mosaic-results-from-preimplantation-genetic-testing-for-aneuploidy-pgt-a-of-blastocysts-a-committee-opinion/

Armour CM, Dougan SD, Brock JA, et al. Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. Journal of medical genetics. Apr 2018;55(4):215-221. doi:10.1136/jmedgenet-2017-105013

Audibert F, Wou K, Okun N, De Bie I, Wilson RD. Guideline No. 456: Prenatal Screening for Fetal Chromosomal Anomalies. Journal of Obstetrics and Gynaecology Canada. 2024;46(11)doi:10.1016/j.jogc.2024.102694

Nagan N, Faulkner NE, Curtis C, Schrijver I. Laboratory guidelines for detection, interpretation, and reporting of maternal cell contamination in prenatal analyses a report of the association for molecular pathology. J Mol Diagn. Jan 2011;13(1):7-11. doi:10.1016/j.jmoldx.2010.11.013

AMP. "Molecular in My Pocket^™" Reference Card Series. Association for Molecular Pathology. https://www.amp.org/education/amp-review-resources/molecular-in-my-pocket-guides/

Fox NS, Monteagudo A, Kuller JA, Craigo S, Norton ME. Mild fetal ventriculomegaly: diagnosis, evaluation, and management. Am J Obstet Gynecol. Jul 2018;219(1):B2-b9. doi:10.1016/j.ajog.2018.04.039

Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. Feb 2015;212(2):127-39. doi:10.1016/j.ajog.2014.12.018

Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction: (Replaces Clinical Guideline Number 3, April 2012). Am J Obstet Gynecol. Oct 2020;223(4):B2-b17. doi:10.1016/j.ajog.2020.05.010

ISPD. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. Jan 2018;38(1):6-9. doi:10.1002/pd.5195

Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. Apr 2010;125(4):e727-35. doi:10.1542/peds.2009-1684

Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. Nov 2008;93(11):4210-7. doi:10.1210/jc.2008-0509

National FragileX Foundation. Fragile X Syndrome Testing & Diagnosis. https://www.fragilex.org/understanding-fragile-x/fragile-x-101/testing-diagnosis/

FDA. Affymetrix^® CytoScan^® Dx Assay. https://www.accessdata.fda.gov/cdrh_docs/reviews/K130313.pdf

FDA. GenetiSure Dx Postnatal Assay. https://www.accessdata.fda.gov/cdrh_docs/pdf16/K163367.pdf.

Medical Director review 7/2022

Medical Director Review 7/2023

Medical Director Review 7/2024

Medical Director Review 7/2025

Policy Implementation/Update Information

For Policy Titled: Chromosomal Microarray

1/1/19 New policy developed. BCBSNC will provide coverage for chromosomal microarray testing when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (an)

9/10/19 Medical Director review 8/2019. Reviewed by Avalon 2nd Quarter 2019 CAB. References and policy guidelines updated. Coding table removed, added code 81265. For clarity, the term “Postnatal” was added to when not covered section so it now states that Postnatal chromosomal microarray testing. Maternal cell contamination (MCC) analysis performed in parallel with fetal diagnostic testing is medically necessary (based on both AMP and ACMG guidelines). Added to when not covered section “except for microarray for neoplasia.” (eel)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (gm)

3/31/20 Specialty Matched Consultant Advisory Panel 3/18/20. No change to policy statement. (eel)

7/28/20 Medical Director review 7/2020. Reviewed by Avalon 2nd Quarter CAB. Coding section updated with 81479. When Not Covered section clarified with low-pass investigational statement. Description, Policy Guidelines and Resources sections updated. When Covered section updated with item 4->E. No change to policy statement. (eel)

10/1/20 Coding section updated with new code 0209U effective 10/1/20. (eel) 

3/31/21 Specialty Matched Consultant Advisory Panel 3/9/21. (bb)

8/24/21 Reviewed by Avalon 2nd Quarter 2021 CAB. Medical Director review 7/2021. Under Billing/Coding section, added PLA code 0252U, deleted 0209U. Updated Policy Guidelines and References. Under “When Covered” section, added “for evaluation of 2nd consecutive clinical first trimester pregnancy loss” to statement #2. Under “When Covered” section for statement #3 also added: “When fetal growth restriction is detected and a fetal malformation, polyhydramnios, or both are also present regardless of gestational age, OR for item F and “When unexplained isolated fetal growth restriction is diagnosed at <32 weeks of gestation, OR” for item G. Notification given 8/24/21 for effective date 11/2/21. (lpr)

12/30/21 The following code was added to the Billing/Coding section: 81349 effective 1/1/2022. (tt)

9/13/22 Reviewed by Avalon 2nd Quarter 2022 CAB. Related policies added. Description, policy guidelines, and references updated. Updated existing medical necessity language to reflect reimbursement language. When Covered section updated for clarity. Removed investigational statement and added coverage for low-pass whole genome sequencing (low-pass WGS). #3E updated to reflect “Due to family history or other indications as documented in the patient’s medical record, the fetus is at high risk for a chromosome abnormality, detectable by CMA”. Added #6 Reimbursement is allowed for CMA testing for central nervous system (CNS) tumors and pediatric solid and soft tissue tumors. Added following statements to When not covered: “Reimbursement is not allowed for co-testing CMA and low-pass WGS” and “Reimbursement is not allowed for all other CMA testing.” Removed 81479 from Billing/Coding section. Medical Director review 7/2022. (tt)

8/15/23 Reviewed by Avalon 2nd Quarter 2023 CAB. Related policies added. Description, policy guidelines, and references updated. When Covered section updated for clarity. Medical director review 7/2023. (tt)

10/24/23 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Reimbursement to Medical Necessity. (tt)

7/17/24 Updated Billing/Coding section to add PLA code 0469U. (tt)

For Policy Titled: Chromosomal Microarray and Low-pass Whole Genome Sequencing

9/4/24 Reviewed by Avalon 2nd Quarter 2024 CAB. Description, Related Policies, Policy Guidelines, and References updated. Removed “Postnatal” from when covered #3 for clarity. Added 3.D to when covered: “For individuals with a suspected inherited seizure disorder”. Updated when not covered as follows for clarity: “Postnatal CMA testing is considered not medically necessary when a chromosomal trisomy is suspected.” Removed 96040 and S0265 from Billing/Coding section. Medical Director review 7/2024. (tt)

10/15/25 Reviewed by Avalon 3rd Quarter 2024 CAB.  Description, Related Policies, Policy Guidelines, and References updated. Added 0209U to Billing/Coding section. No change to policy statement. Medical Director review 7/2025.