Diagnosing Dup15q Syndrome
How are duplications of chromosome 15 diagnosed?
Genetic tests look for abnormalities in DNA such as deleted or extra material. Each chromosome has unique regions or bands that contain genes, and each band is labeled numerically. This is where genetic tests look for missing or extra bands. Several kinds of tests are used to examine the chromosomes or look for evidence of an extra dosage of DNA from the region.
Genetic tests that are used to help diagnose dup15q syndrome:
A microarray cannot tell the difference between an isodicentric (idic) duplication and an interstitial triplication (2 extra copies adjacent to one another). On some microarray reports it may list the total number of copies; if it is listed as 3 total copies, it may be reasonable to assume that it is interstitial. In order to be idic, there would typically need to be the two normal copies and two mirrored copies to create the extra chromosome. So, it would be highly unlikely to have an idic with 3 total copies of the region. Diagnosis is confirmed by standard cytogenetic techniques and FISH analysis, which confirms the diagnosis by distinguishing the dup15q from other supernumerary marker chromosomes. Interstitial duplications of chromosome 15 can be more difficult to detect on a routine chromosome analysis but are clearly identifiable using a 15q FISH study or clinical microarray/array CGH. Molecular studies, such as microsatellite analysis on parental DNA or methylation analysis on the affected child’s DNA, are required in order to detect the parent-of-origin of the dup15q.
Standard of practice is still to do a FISH or karyotype to confirm all cases, though, because chromosomes can sometimes act in unexpected ways.
Microarrays are DNA tests that measure the “copy number” of the chromosomes. They screen for duplications or deletions, termed “copy number variations,” for all the chromosomes and are typically able to determine how many total copies of a chromosomal region are present. Although they give more precise boundaries for the duplicated region than chromosomal studies, they cannot always distinguish int dup(15) and idic(15) chromosomes. Chromosomal studies are also typically performed if the microarray shows a duplication.
Karyotype or Chromosome Study
A chromosome study or karyotype is done typically from blood or at an amniocentesis. With this study, the chromosomes are counted, and the pairs are matched up, the sex chromosomes are identified, and then the banding pattern is examined to look for signs that there could be lost, extra, or rearranged chromosomes.
A second test called FISH, which stands for Fluorescence In Situ Hybridization, is used to give more precise information about the DNA included in a duplication. This test uses a fluorescent piece of DNA that marks a specific spot on chromosome 15 to determine whether it is found in the duplication and, if so, how many copies there are. Interstitial duplications of chromosome 15 can be more difficult to detect on routine chromosomal analysis but are clearly identifiable using a 15q FISH study.
The methylation assay uses a chemical modification of the DNA to distinguish whether the duplication is on a chromosome that came from the mother or the father. The test was developed for use in Prader Willi and Angelman syndromes, so one or both of those names are often in the name of the test.
Copy Number and Severity
There is a wide range of severity in the developmental problems experienced by individuals with dup15q syndrome. Two children with the same dup15q chromosome pattern may be very different in terms of their abilities. Reviews of the scientific literature do not show an obvious correlation between the size of the duplication region and the severity of the symptoms. The genetic risks for the different types of chromosome 15 duplications are not the same. Additional information is provided on the page for each type of duplication. Families should always discuss the results of their genetic studies with a genetics professional to ensure accurate interpretation.