When the duplicated piece of chromosome 15 is included within the long arm of one of the two copies of chromosome 15, rather than as an extra chromosome, it is called an interstitial duplication of chromosome 15, or int dup(15). The duplicated segment is usually adjacent to the normal copy and can be oriented in the same direction (tandem) or inverted. Sometimes the direction is mentioned on the chromosome report. Interstitial triplications, int trp(15) have two extra copies of part of chromosome 15q inserted. These different forms can be distinguished by combinations of molecular and chromosomal tests.
People born with the typical 46 chromosomes, but who have a segment of duplicated material within chromosome 15, are said to have an interstitial duplication chromosome 15. Most often this is the same section (15q11-q13) that makes up the extra chromosome in idic(15). For this reason, people with interstitial duplications of 15q and those with idic(15) share similar characteristics. When the extra genetic material comes from the paternal chromosome, a child may have normal development. However, when the duplicated material comes from the maternal chromosome, developmental problems are often the result. In most cases of chromosome 15q11.2-13.1 duplication syndrome, the chromosome duplication is not inherited, but occurred as a random event during the formation of reproductive cells (eggs and sperm).
Advances in the technology of genetic testing, such as array comparative genomic hybridization (aCGH), have enabled the detection of ever more subtle genetic anomalies including different forms of int dup(15) chromosomes.
Int dup(15) chromosomes that include the core PWS/AS critical region that lies at coordinates 15q11.2-q13.2 were the first ones described and therefore the ones that we know the most about. The boundaries for the duplicated piece of DNA can vary resulting in two common forms of int dup(15) chromosomes that differ in whether they include the 8 known genes in the edge region “E”. A study published in 2013 found no major difference in severity of symptoms based on this feature of the duplication.
This diagram shows two of the most common forms of int dup(15) chromosomes that vary by whether or not they include the “E” region. They both contain one additional copy of the PWS/AS critical region so when paired with another chromosome 15 in a cell, there are 3 total copies of genes from the duplicated piece of the chromosome.
When an int dup(15) chromosome is found, studies are performed to determine whether it is a duplication of the maternal or paternal chromosome. Why? This is because the stretch of DNA in the PWS/AS region undergoes an unusual process (called imprinting) that results in differences in activity of several genes based on whether they are on the chromosome that came from the mother or the father. For most genes, the copies on both the maternal and paternal chromosomes are used equally. However, a select group of genes on chromosome 15 are activated on the maternal chromosome and silenced on the paternal chromosome or vice versa. The activity levels of these genes must be tightly regulated, and the additional copy in the duplication segment throws off this balance. For this particular set of genes, this regulatory process is particularly important in brain cells.
Knowing whether it is a duplication of the maternal or the paternal chromosome is important because it affects the clinical outcome. If the duplication occurred in the chromosome 15 that came from the mother, then there is a high risk for developmental problems. When the duplication is paternal, there may be no symptoms or they may be very mild; however, there are also some individuals who have been found to have developmental disorders, including autism, who carried a paternal int dup(15). The number of individuals with paternal duplications that have been identified is relatively small, so the spectrum of symptoms is not fully known.
When you know whether the duplication is maternal or paternal, it can help determine whether or not there are other relatives who may want to undergo genetic testing. In most cases, int dup(15) occurs sporadically and both parents have normal chromosome studies. However, in some families, the duplication can be inherited from a parent who has little to no symptoms. You should work with your genetics professional to identify other family members to test and to discuss the specifics of your family’s situation.
Children with all forms of int dup(15) chromosomes are born to parents of every socioeconomic, racial, and ethnic background. There is no known link between int dup(15) and environmental or lifestyle factors. In other words, there is nothing that parents did before or during pregnancy to cause their child to be born with int dup(15). This is general information. Families should always seek the advice of a genetics specialist to discuss their specific situation.