Array Comparative Genomic Hybridization (aCGH) is a powerful genetic test that detects alterations within a person’s genomic DNA sequence. This technique identifies extra or missing segments of genetic material, offering a comprehensive way to understand various genetic conditions. It is widely utilized in clinical research across areas such as constitutional cytogenetics, rare diseases, cancer, and reproductive health.
Understanding How aCGH Works
The aCGH process compares a patient’s DNA to a normal reference DNA. Both samples are labeled with different fluorescent dyes, typically green and red. These labeled DNA samples are then mixed and applied to a microarray. This microarray contains tens of thousands of short DNA sequences, called probes, which represent specific regions across the human genome.
The labeled DNA samples hybridize to the corresponding probes on the microarray. After hybridization, a scanner detects the fluorescent signals from both dyes. The relative intensity of the green and red signals at each probe indicates whether there is more or less of the patient’s DNA compared to the reference. A higher green signal suggests a gain of genetic material in the patient, while a higher red signal indicates a loss.
Genetic Changes Identified by aCGH
aCGH identifies Copy Number Variations (CNVs). CNVs are segments of DNA that are duplicated (extra copies) or deleted (missing copies) in an individual’s genome compared to a reference. These variations can range in size from small deletions or duplications to larger changes involving entire chromosomes.
Even small CNVs can have significant effects by altering the number of copies of specific genes. This change in gene dosage can disrupt normal gene function, potentially leading to various health or developmental conditions. For instance, if a gene is duplicated, there might be an excess of the protein it produces, or if it’s deleted, there might be too little or none at all.
Key Applications of aCGH
aCGH is a standard genetic test in several clinical scenarios due to its high resolution and genome-wide analytical capabilities. It is frequently employed in cases of developmental delays and intellectual disabilities, helping uncover underlying genetic causes not visible with traditional chromosome analysis.
The test is also widely used in the investigation of congenital anomalies, which are birth defects present at birth. By detecting subtle genetic gains or losses, aCGH can pinpoint the chromosomal changes responsible for these structural abnormalities. For children diagnosed with autism spectrum disorder, aCGH can identify specific genetic factors contributing to the condition, as certain CNVs are found with increased frequency in individuals with autism.
aCGH plays a role in prenatal diagnosis, particularly when ultrasound examinations reveal abnormalities in a developing fetus or other concerns arise during pregnancy. It offers a detailed look at fetal chromosomes to detect potential genetic imbalances. In cases of recurrent miscarriages, aCGH can be applied to the products of conception or parental samples to identify chromosomal aberrations that may be contributing to pregnancy losses.
What aCGH Does Not Detect
While aCGH is a powerful tool for detecting copy number variations, it has limitations regarding the types of genetic changes it can identify. The test does not detect single gene changes, such as point mutations where a single DNA building block (nucleotide) is altered. These changes require different sequencing technologies.
aCGH also cannot detect balanced rearrangements of genetic material. In these rearrangements, such as balanced translocations or inversions, segments of DNA are rearranged within or between chromosomes, but no genetic material is gained or lost. Since aCGH relies on detecting differences in the amount of DNA, these types of rearrangements remain undetected. Additionally, aCGH does not analyze epigenetic changes, which involve modifications to DNA or its associated proteins that affect gene activity without altering the DNA sequence itself, nor does it detect mutations in mitochondrial DNA.
Interpreting aCGH Test Results
Interpreting aCGH test results involves categorizing detected genetic changes based on their likely impact on health. A “Normal” or “Negative” result indicates no clinically significant copy number variations were found. This means the DNA copy number profile is consistent with a typical reference genome.
Conversely, a “Pathogenic” or “Abnormal” result signifies a copy number variation was detected that is known to cause a specific genetic condition. This classification is based on established scientific evidence linking the particular CNV to a recognized disease or syndrome. Genetic counselors and medical professionals then discuss the implications of such a finding with the individual and their family.
A “Variant of Uncertain Significance” (VUS) result means a CNV was found, but there is not enough scientific evidence to definitively classify it as either benign or pathogenic. VUS results can be challenging because their clinical impact is not yet fully understood, and they may require further investigation, such as testing of parents or other family members to see if the variant segregates with a condition within the family. Over time, as more research is conducted, a VUS may be reclassified as pathogenic or benign. A “Benign Variant” indicates a CNV was detected, but it is considered a common variation in the population and is not associated with any known health problems.