Chromosomal microarray analysis enables detection of microdeletions/duplications and has become the standard for clinical diagnostic testing in individuals with congenital abnormalities and developmental disorders. In the era of genomic arrays, the value of traditional chromosomal analysis needs to be reassessed.
The development and implementation of genomic microarray technology has opened a new era in clinical genetics. Previously, G-banded chromosomal analysis has been the clinical standard for diagnosing chromosomal abnormalities for over 35 years. Chromosomal analysis detects numerical and structural chromosomal abnormalities by counting chromosomes and analyzing chromosomal banding patterns in metaphase cells. To be detected by chromosomal analysis, structural changes must be > 3-10 Mb in size. Fluorescence in situ hybridization (FISH) can also detect chromosomal abnormalities, including those beyond the resolution of chromosome analysis, by examining metaphase or interphase cells. A disadvantage of FISH is that it requires prior knowledge of specific areas that may be abnormal and thus has limited utility as a first-tier test for clinical diagnosis. Chromosomal microarray analysis (CMA), one of the most commonly used microarray techniques in clinical laboratories, detects chromosomal losses and gains across the genome by comparing the strength of hybridization between patient DNA and normal control DNA. FISH analysis, chromosomal analysis, or molecular techniques are often performed after CMA to confirm results and identify translocations or insertions associated with copy number changes.
An advantage of CMA is its ability to detect submicroscopic loss and/or gain of chromosomal material, i.e. too small to be detected by conventional G-banded chromosome analysis, which results in a significant increase in diagnostic yield of approximately 10% for those with unexplained development higher for people with disabilities or congenital anomalies. In addition, CMA analysis of DNA extracted from all different types of uncultured cells requires fewer experimental requirements for sample quality than chromosomal analysis and often results in shorter reporting times. Although detection of somatic mosaicism missed by chromosomal analysis by CMA has been reported, CMA cannot reliably detect mosaicism <30%. Furthermore, CMA was unable to detect apparently balanced rearrangements.
Chromosomal analysis and CMA are clinically useful diagnostic tools for the detection of chromosomal abnormalities throughout the human genome. Currently, CMA is recommended as a primary test for intellectual disability and congenital defects, replacing the previous role of chromosomal analysis.
The detection of mosaicism by CMA differs from that by chromosome analysis because the technique and the cell population analyzed are different. CMA analysis of DNA extracted from all nucleated cells in peripheral blood including multiple cell lineages. In contrast, chromosomal analysis was performed primarily on phytohemagglutinin-stimulated T lymphocytes. Research suggests that CMA may be more sensitive when abnormal cells do not respond to mitogens and/or abnormalities are rare or absent in T cells, such as in Pallister-Killian syndrome.
Almost all chromosomal abnormalities detectable by chromosomal analysis can be detected by CMA, supporting the recommendation to use CMA as a primary test. However, traditional cytogenetic analysis remains useful for the detection of chimeras and the characterization of structural rearrangements.
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