Many genetic disorders and conditions first manifest as physical abnormalities at the fetal stage or in early childhood. These can be serious and life-threatening illnesses such as phenylketonuria and Tay-Sachs disease, or life-changing differences such as Down syndrome and intersex conditions. All of these situations benefit from early detection, so that parents can prepare the best life possible for their children, particularly for the more serious conditions that are the dominant cause of infant death in the United States. Distinguishing and even detecting these conditions can be surprisingly difficult, requiring more information than typical research methods can provide.
This is where newer testing methods come in. Chromosomal microarray testing has helped fill in the gaps of our understanding of fetal abnormalities. According to the research of Dr. Brynn Levy of the Columbia University Medical Center, these tests find significant genetic imbalances, indicative of gene duplication or deletion events, in 6% of tested fetuses whose karyotypes are otherwise normal. Whole-exome sequencing (WES) is another method that stands to dramatically improve these statistics. Most deleterious genetic abnormalities, including copy number variations, manifest in the exome, where they can directly impact the shape and function of proteins. Copy-number variations (CNVs) in particular can lead to overproduction of proteins with widespread downstream effects similar to those associated with unusual chromosome numbers. Dr. Levy’s research shows that WES is a sensitive-enough procedure on its own; it reveals an additional 14% of abnormalities that do not show on a karyotype, helping explain conditions that otherwise may remain unexplained.
The real strength of this method is in combination with microarray testing. With WES and other tests guiding the effort, chromosomal microarrays with whole-exome coverage using assays like like Applied Biosystems™ CytoScan™ XON Assay can focus their impressive coverage and resolution exactly where it’s most needed. Where other arrays might have one or two probes in relevant areas, these arrays offer 20 or 30, giving an exceptionally clear picture of a gene that reveals CNVs and changes to the area of the genome surrounding it. This is particularly important for conditions that can follow from changes at multiple possible sites in the genome, or that are potentially symptoms of very different diseases, enabling researchers to accurately determine the nature of the problem and direct their efforts accordingly.
One of the most interesting possibilities afforded by expanded prenatal testing using these new technologies is collecting more complete information about human development and the ways it can surprise us. Numerous genetic conditions do not have well-characterized signs at the prenatal level are outright lethal in uteroor or in early childhood. Whole-exome testing can reveal the workings of these conditions before they would otherwise be visible. This kind of information helps scientists understand these conditions and develop new treatments and interventions that would not be possible later in life, as well as providing insight into the complex process of human development.
For the full story on Dr. Brynn Levy’s research, watch the video in the CytoScan Suite Resource Library. You can also go to our website to get more information about the Applied Biosystems™ CytoScan™ XON Assay Kit.