Basic Genetics of Chromosome 15 Duplications

Special thanks to our professional advisors Brenda Finucane, MS, CGC and Chantell Wolpert, MBA, PA-C, CGC for the following information:

Genetics Overview
There is no way around it: In order to understand the implications of chromosome 15 duplications, you will need to have a basic understanding of genes, chromosomes, and heredity.

Genes
Genes are tiny body chemicals which come in pairs and contain information about the way our bodies grow and develop. Each of our body cells contains around 30,000 genes which make up larger structures known as chromosomes.

What is a Chromosome?
Just as genes come in pairs, chromosomes also come in pairs. For most people each cell in their body has 23 pairs of chromosomes (for a total of 46); one member of each pair is inherited from the mother and the other is inherited from the father. The first 22 pairs (numbered 1 through 22) are called autosomes and they determine most of our features. The last pair is called the sex chromosomes and they determine if we are male or female. Females have two X chromosomes and males have one X chromosome and one Y chromosome.

It is possible to tell the chromosomes apart by their size and their "banding pattern." The banding pattern is a result of a chemical staining process used in the laboratory to help researchers see the chromosomes more easily. Each chromosome is divided into two sections or "arms." The short arm is called the "p" arm and the long arm is called the "q" arm. The bands on each arm are numbered. When researchers study the chromosomes (a process called chromosome analysis) they try to determine if there are any missing or extra pieces of the chromosomes.

What is Isodicentric Chromosome 15
Isodicentric chromosome 15 is the scientific name for a specific type of chromosome abnormality. Individuals with isodicentric chromosome 15, or "idic(15)", have 47 chromosomes instead of the typical 46 chromosomes. Occasionally, a person may have 2 extra idic(15) pieces(48 chromosomes) or 3 extra idic(15) pieces (49 chromosomes) in all or some of their cells.  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. Most commonly, the region called 15q11-q13 is the portion of chromosome 15 duplicated. Individuals with idic(15) usually have a total of four copies of this chromosome 15 region instead of the typical two copies (1 copy each on the maternal and paternal chromosomes and 2 copies on the idic(15)).

Some children and adults with idic(15) are said to have 'mosaicism', meaning that their extra 15th chromosome is present in some, but not all, of their body cells.  Mosaicism occurs by chance in this and many other chromosomal disorders.

What is interstitial duplication chromosome 15?
People born without an extra chromosome but who have a segment of duplicated material within chromosome 15 are said to have an interstitial duplication chromosome 15, abbreviated int dup(15).  Most often this is the same section (15q11-13) 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.  For both conditions, there is a wide range of severity from one person to the next; as a group however, people with interstitial duplication 15 tend to have milder symptoms than those with idic(15).

How often do duplications of chromosome 15 occur?
Researchers think that approximately 1 in 8,000 babies are born with an extra chromosome that came from chromosome 15. The most common type of marker chromosome 15 is very small and does not cause any problems. We don’t know the frequency of the larger ones, that cause the symptoms seen in idic(15) and int dup(15) but one researcher estimates they occur in about 1 in 15,000 – 20,000 births.

Generally, people with idic(15) do not have family members with the chromosome abnormality. The idic(15) usually forms by chance in one person in the family. Children with idic(15) are born to parents of every socioeconomic, racial, and ethnic background.  There is no known link between idic(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 idic(15).

How are duplications of Chromosome 15 diagnosed?
The diagnosis of idic(15) is made through a blood test called a chromosome study, with FISH (Fluorescence In Situ Hybridization) confirming the diagnosis, by distinguishing idic(15) from other supernumerary marker chromosomes.  Interstitial duplications of chromosome 15 can be more difficult to detect on routine chromosome analysis but are clearly identifiable using a 15q FISH study.  Families should always discuss the results of chromosome and FISH studies with a genetic counselor or other genetics professional to ensure accurate interpretation.  Additionally, studies on all family members can be done and questions regarding recurrence can be explored with the genetic counselor or other genetics professional.

What problems are caused by duplications of Chromosome 15?
Since chromosomes carry genes that determine how our bodies grow and develop, having extra chromosomal material can alter a person’s physical and mental development. Unlike many other chromosomal syndromes, there are few characteristic physical findings associated with idic(15) and int dup(15).  There is also a wide range of severity, so that two children with the same chromosome pattern may be very different in terms of their abilities.  In general, the following features are found in most people with idic(15) and int dup(15) to varying degrees: 

• Poor Muscle Tone (hypotonia) particularly in babies, with delayed milestones (although the vast majority will walk independently),
• Cognitive disabilities/learning disabilities
• Autism spectrum disorders
• Seizure Disorders
• Speech/Language Delay
• Sensory Processing Disorders
• Attention Deficit Disorders (ADD/ADHD)
• Anxiety Disorders
• Small size for age
• Minor unusual physical features, including wide-spaced eyes with skin folds at the inner corners (epicanthal folds); noticeable unfolding of the edge of the ears; short, upturned nose with a low or flattened nasal bridge; and full lips.

As with any chromosomal syndrome, there can be differences in the way their hearts, kidneys, or other body organs are formed.  Parents should check with their genetics specialist for specific recommendations regarding medial evaluations.
At the present time, there is no specific treatment that can undo the genetic pattern seen in people with idic(15) or int dup(15).  Although the fundamental genetic differences cannot be reversed, children and adults have been known to benefit from some of the following:

1. Early Intervention (speech, physical, occupational, and sensory integration therapies)
2. Ongoing Special Education
3. Total Communication Systems (a combination of speech, sign, gestures and picture exchange)
4. Behavioral Strategies
5. Sensory Integration Strategies
6. Medical Management of Symptoms
7. Vocational Training
   

Isodicentric Chromosome 15 and Autism
For more than 12 years, scientists have noticed that some individuals with autism also have idic(15). In fact, idic(15) is the most frequently identified chromosome problem in individuals with autism. (A chromosome anomaly involves extra or missing chromosomal material, not changes within the genes such as Fragile X syndrome). There are now over 20 reports in the literature of individuals with both autism and idic(15). The frequency of these reports suggest that the co-occurrence of autism and idic(15) is not by chance. There may be a gene or genes in the 15q11-q13 region that is/are related to the development of autism in some individuals.

Genetic research studies of individuals without chromosome anomalies also support this idea that an autism-related gene may be present in 15q11-q13. Specifically, research studies found that certain DNA markers from the 15q11-q13 region were found more often in individuals with autism than in individuals without autism. Although these DNA markers are too small to be genes, they suggest that researchers may be getting close to finding an autism gene in this region. Researchers are currently focusing on genes in this region called the GABA receptor genes, known as GABRB3, GABRA5, and GABRG3. They are good candidates for being related to autism not just because of their location, but also because of their function. The GABA genes make proteins that carry messages between nerve cells. Several studies have found associations between GABRB3 and autism (Buxbaum et al., 2002; Shao et al., 2003; Cook et al., 1998), but further study is needed.

Isodicentric Chromosome 15 and Seizures
Seizures represent an important medical feature of idic(15) syndrome. Over half of people with idic(15) will have at least one seizure. The vast majority of those will experience their first seizure before age 5.

In a survey of 90 parents of children with idic(15), the following preliminary picture of the relationship of idic(15) to seizures emerged:

• 54% of the group surveyed had experienced at least one seizure. Age of onset of the first seizure ranged from birth through 18 years, with a mean age of 2.8 years.
• 55% of those with seizures had onset by 1 year of age, with 82% having onset prior to age 5.
• Parents reported multiple seizure types in their children, including generalized tonic clonic (18%), absence (12%), and myoclonic seizures (11%). Sixteen percent of the group, accounting for 29% of those with seizures, had a history of infantile spasms. Many children experienced more than one seizure type, and several had severe, intractable epilepsy.
• When surveyed about the impact of the child's seizures on his / her quality of life and functioning, 51% of parents reported a minor impact, 16% a moderate impact, and 33% a major impact.

Abnormal GABA receptor gene expression is a likely contributor to seizures in people with idic(15). Additional studies are needed to further characterize seizures in idic(15) and to study the effectiveness of medications which influence the brain's GABA receptor system.