TOPIC
Chromosomal microarray testing
CLINICAL BOTTOM LINE
Chromosomal microarray testing (CMA) uses molecular probes to detect gains or losses of segments of DNA (copy number variations [CNVs]) or copy neutral changes, such as loss of heterozygosity or uniparental disomy, depending on the type of microarray.
CMA testing offers a significant improvement over routine chromosomal studies in detecting clinically significant chromosomal deletions and duplications that are not visible by routine chromosome studies (G-banded karyotype).1,2
Recent guidelines and publications have recommended that CMA should replace G-banded karyotyping for the evaluation of children with autism spectrum disorders, developmental delay/intellectual impairment, and/or multiple congenital anomalies. Deletions and duplications found in these children have been published in recent papers.1,3,4
Primary care management pearls
– Genetic counseling should be provided prior to ordering CMA testing to ensure that patients and families understand the types of information that may be reported.
– If a child has clinical symptoms of a known genetic syndrome, such as Down syndrome, testing for that specific condition should be considered first.1
– Providing clinical information to the laboratory along with the sample will increase the ability of the laboratory to interpret unique CNVs.2
– Clinicians and patients should be aware that they may receive results indicating a "variant of unknown significance" (VOUS). This means that there is not enough information at this time to report the CNV as pathogenic or benign. As additional information is obtained, a VOUS may be reclassified.2,5
– In general, clinically significant findings include known microdeletion or microduplication syndromes, deletions of genes that are known to be associated with disease due to loss of one copy (haploinsufficiency), and large deletions or duplications involving multiple genes.5
WHAT IS CMA TESTING?
• A CMA test uses molecular markers spaced along the chromosomes to detect deletions, duplications, or unbalanced rearrangements of DNA; or loss of heterozygosity or uniparental disomy (in the case of a single nucleotide polymorphism [SNP]-based array).
• The markers are most dense in areas of known clinical significance, so that even very small deletions and duplications in these regions can be detected.
• Most CMA tests also include backbone coverage (the regions outside the areas of known clinical significance) to detect deletions or duplications of 100 to 500 kilobases in the rest of the genome. Comparatively, traditional G-banded karyotypes can detect deletions or duplications of 5 to 10 megabases in size.5
• CMA testing cannot detect point mutations or very small deletions or duplications in genes.
• CMA will find a pathogenic deletion or duplication in 15% to 20% of children tested for autism spectrum disorder, developmental delay/intellectual impairment, and/or congenital anomalies. G-banded karyotype will detect an abnormality in 3% to 5% of the same population.1,2
• To determine pathogenicity of a CNV, laboratories will consider the size of the deletion or duplication, the particular genes in the area, whether the deletion or duplication is inherited from one of the parents, reports of similar deletions or duplications in published literature and databases, and the symptoms displayed by the patient.3,5
LIMITATIONS/CAUTIONS
• Different laboratories offer different types and levels of coverage for CMA tests. Discussion with the laboratory about each patient is important to ensure that the appropriate test is ordered.5,6
• CMA cannot detect low-level mosaicism, inversions, balanced chromosome translocations, or point mutations in genes. In couples with a history of multiple miscarriages and a child with autism, developmental delay, and/or multiple congenital anomalies, a G-banded karyotype may be needed.
• Some laboratories use SNP-based arrays, which may identify incest or consanguinity.
• Currently, CMA is not considered a first-line test for epilepsy or neuropsychiatric disorders.
• Identification of small CNVs is common; most have no known clinical significance at this time.
CMA TESTING
• CMA testing requires a blood sample—usually both an EDTA (purple top) and a sodium heparin (green top) tube.
• Samples should be shipped at room temperature and not be refrigerated or frozen.
• Parental samples may be requested to help determine the clinical significance of some findings. JAAPA
W. Andrew Faucett is director of policy and education for the Genomic Medicine Institute at Geisinger Health System in Danville, Pennsylvania. Melissa Savage is a research coordinator at Columbia University in New York, New York. The authors have indicated no relationships to disclose related to the content of this article.
Michael A. Rackover, PA-C, MS; Constance Goldgar, MS, PA-C, department editors
REFERENCES
1. 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.
2. Coulter ME, Miller DT, Harris DJ, et al. Chromosomal microarray testing influences medical management. Am J Hum Genet. 2011;13(9):770-776.
3. Kaminsky EB, Kaul V, Paschall J, et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011;13(9):777-784.
4. Manning M, Hudgins L; Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12(11):742-745.
5. 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. 2011;13(7):680-685.
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. 2011;13(7):676-679.