Isodicentric 15

Isodicentric 15, or idic(15), is a chromosome abnormality in which a child is born with extra genetic material from chromosome 15. People with idic(15) are typically born with 47 chromosomes in their body cells, instead of the normal 46. The extra chromosome is made up a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Individuals with idic(15) have a total of four copies of this chromosome 15 region instead of the normal two copies (1 copy each on the maternal and paternal chromosomes.

The extra chromosome is usually found in mosaic state, i.e. some of the cells carry the marker chromosome. However, mostly because of the marker's instability and tendency to be lost during cell division (mitosis), some cells are completely normal with 46 chromosomes. Occasionally, cells may have more than one idic(15), resulting in 48 or 49 chromosomes in all or some of their cells. The same clinical picture could be expected in individuals that have the extra chromosome 15 material as an interstitial duplication; not as a marker chromosome; thus having 46 chromosomes.

Signs and symptoms

Iindividuals with idic(15) have delays in language development and motor skills such as walking or sitting up. Other traits may include low muscle tone (hypotonia), seizures, short stature, and mental retardation. Distinctive facial features associated with idic(15) may include epicanthal folds (skin folds at the inner corners of the eyes), a flattened nasal bridge, button nose, and a high arched palate (roof of the mouth). Some individuals with idic(15) also have features of autism, such as problems with communication, social interactions, and repetitive and stereotyped behaviors (e.g., lining up toys, playing with a toy in the same manner over and over again, hand flapping, rocking back and forth).

Epidemiology

About half of all marker chromosomes are idic(15) but idic (15) in itself is one of the rare chromosome abnormalities. It is estimated that 1 out of 8000 babies are affected. This number includes the children with a large IDIC (15) marker as well as children with a small marker (without negative phenomena). There are organizations for families with idic(15) children that offer extensive information and support.

Genetics

Generally, idic(15) is not inherited; it is said to appear de novo; in one member of the family, by chance. In most cases, the abnormal chromosome is generated in the mother's germ cells; oocytes. This finding is due to ascertainment bias; i.e. cases with maternally derived idic(15) usually have clinical findings and attract attention but those with paternally derived idic(15) usually do not. Thus, established cases are usually patients with maternally inherited idic (15).

People with idic(15) have extra genetic material that has developed from chromosome 15. The material usually exists as a little extra chromosome 15; which is called marker chromosome or extra structurally abnormal chromosome (ESAC). The marker usually exists as an isodicentric chromosome; i.e. 2 copies of a specific part of the long arm of chromosome 15 (most commonly, 15q11-q13) that is mirrored and doubled, with 2 centromeres and 2 satellites. The smallest markers appear to be harmless and they may go undetected. However, if they are large enough to contain a number of important genes, they may result in "idic(15) syndrome" which is characterized by mental retardation, autism and other neurological symptoms. One of the regions responsible for the symptoms of idic(15)syndrome is the critical PWS/AS-region named after the Prader-Willi and/or Angelman syndromes.

idic(15) is also referred to as partial tetrasomy 15q or inverted duplication 15 (inv dup 15).

Diagnosis/Testing

The extra chromosome in people with idic(15) can be easily detected through chromosome analysis (karyotyping). Additional tests are usually required. FISH (Fluorescent in situ hybridization) is used to confirm the diagnosis by distinguishing idic(15) from other supernumerary marker chromosomes. Array CGH could be used to determine the gene content and dosage so that clinical picture could be foreseen. 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. Families should always discuss the results of chromosome and FISH studies with a genetic counselor or other genetics professionals to ensure accurate interpretation.

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). It is suggested 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.

Prognosis/Management

At the present time, there is no specific treatment that can undo any chromosomal abnormality, nor the genetic pattern seen in people with idic(15). The extra chromosomal material in those affected was present at or shortly after conception, and its effects on brain development began taking place long before the child was born. Therapies are available to help address many of the symptoms associated with idic(15). Physical, occupational, and speech therapies along with special education techniques can stimulate children with idic(15) to develop to their full potential.

In terms of medical management of the symptoms associated with dup15q syndrome, families should be aware that individuals with chromosome 15 duplications may tolerate medications differently and may be more sensitive to side effects for some classes of medications, such at the serotonin reuptake inhibitor type medications (SSRI). Thus, these should be used with caution and any new medication should be instituted in a controlled setting, with slow titration of levels and with a clear endpoint as to what the expected outcome for treatment is.

Genetic Counseling

In general, idic(15) occurs de novo but the parents must be karyotyped to make sure it is not inherited, mostly because this will affect the course of genetic counseling given to the family. If the abnormality is found prenatally and one of the parents harbour the marker, the child has a chance of being normal. Further tests should however be done to prove the marker has not been rearranged while being inherited. This information is also necessary for counseling of future pregnancies. Each family is unique and should therefore be handled individually.