Chromosomal Microarray Analysis (CMA) is a high-resolution genetic diagnostic tool used to analyze an individual’s complete set of chromosomes. This technology detects subtle, genome-wide variations in DNA that were previously undetectable with older methods. CMA provides precise diagnostic information and is now standard practice for evaluating individuals with unexplained developmental and congenital conditions.
What is Chromosomal Microarray Analysis
Chromosomal Microarray Analysis is a laboratory technique that systematically scans the entire genome to identify sections of DNA that are either missing or extra. The test uses a microchip platform containing thousands of probes, which are small, known sequences of DNA. Patient DNA is labeled with a fluorescent dye and mixed with a control DNA sample labeled with a different color. By comparing the intensity of the two colors across the array, the system quantifies the relative amount of DNA at each location.
This process serves as a molecular karyotype, offering far greater resolution than traditional G-banded karyotype analysis. Conventional karyotyping is limited to detecting large changes, typically in the 5 to 10 megabase (Mb) size range. In contrast, CMA can detect imbalances as small as 500 kilobases (kb), allowing for the identification of submicroscopic deletions and duplications.
Clinical Scenarios Requiring CMA
CMA is widely recommended as the first-line genetic test for children and adults presenting with a range of unexplained neurodevelopmental and physical issues. The primary indications include unexplained developmental delay or intellectual disability, which affect cognitive and adaptive skills. The test is also frequently ordered for individuals diagnosed with autism spectrum disorder (ASD).
CMA is also utilized when a patient presents with multiple congenital anomalies, which are birth defects not specific to a recognized genetic syndrome. In the prenatal setting, CMA is employed when a fetal ultrasound reveals structural abnormalities, providing a higher diagnostic yield than traditional testing. Finding a significant genetic change provides a definitive diagnosis, allowing for more informed clinical management and family planning.
Decoding Copy Number Variations
The specific genetic changes that Chromosomal Microarray Analysis is designed to detect are known as Copy Number Variations (CNVs). A CNV is a segment of DNA that is present in a number of copies that differs from the standard two copies (one inherited from each parent). These variations are categorized as either deletions, where a segment of DNA is missing, or duplications, where an extra segment of DNA is present.
These gains or losses of genetic material disrupt gene dosage, which is the number of copies of a gene in a cell. If a deletion removes a functional gene or a duplication causes protein overproduction, the normal biological process can be altered, leading to a condition. CMA focuses on these structural changes and does not detect single-nucleotide variants (point mutations involving a change in one DNA base pair). While CNVs are a normal part of human variation, large or rare CNVs encompassing genes can have significant clinical consequences.
Navigating Test Outcomes
The results of a Chromosomal Microarray Analysis are typically grouped into three main classifications, which determine the clinical significance of any detected CNV. A CNV is classified as pathogenic (or likely pathogenic) if it is a known cause of disease and explains the patient’s symptoms. Conversely, a CNV is deemed benign (or likely benign) if it is a common variation found in the healthy population and is not associated with any known disorder.
The most challenging result for clinicians and families is the Variant of Unknown Significance (VUS). A VUS is a CNV for which there is currently insufficient scientific evidence to classify it as definitively harmful or harmless.
When a VUS is identified, the CNV is not considered clinically actionable. The next step often involves testing the patient’s parents to determine if the VUS was inherited or occurred spontaneously. If the variant is present in a healthy parent, it is more likely to be reclassified as benign. A spontaneous, or de novo, variant is more suspicious. Clinicians continuously re-evaluate VUS results as new information is added to genetic databases, and a VUS can be reclassified later.
Practical Aspects of the Testing Process
Chromosomal Microarray Analysis requires a biological sample, which can be obtained through a blood draw, saliva collection, or, in the prenatal setting, from amniotic fluid or chorionic villi. Once the sample reaches the laboratory, the DNA extraction and analysis process typically takes two to four weeks.
Genetic counseling is recommended both before and after the CMA test. Pre-test counseling ensures the patient or family understands the scope of the test, its limitations, and the possibility of complex results like a VUS. Post-test counseling explains the findings in detail, discusses the implications for the patient’s health, and addresses the risk of recurrence for family members.