Charles A. Williams, M.D.
7/4/97GENETICS 101 OF ANGELMAN SYNDROME
I. Definitions:
Chromosome 15 - The chromosome that is abnormal in Angelman syndrome. We have 23 pairs of chromosomes, one derived from each parent. There are 22 pairs that are numbered numerically from 1 to 22, the final pair is an X and Y. We receive one chromosome 15 from our mother and one chromosome 15 from our father. Chromosomes contain millions of molecules that are condensed together at the time of cell division and thus are able to be seen under the microscope.
15qll-13 Region - Chromosomes are divided into short arms and long arms
and have a central segment called a centromere. The short arm is call "P" and
the long arm is called "q". The "q" region is divided numerically into
several segments and the q11 - 13 segment refers to an area that is toward the middle of
the number 15 chromosome. It spans about 5-10 million nucleic acid molecules so this
region includes many genes. It is the
region that is crucial in Angelman syndrome but also contains other genes such as those
causing the PraderWilli syndrome.
15q11-13 Deletion - This usually refers to a spontaneous chromosome defect whereby a large common region spanning between 5-10 million nucleic acid molecules is missing from chromosome 15. Deletions can also be microdeletions and involve even smaller segments, but this is unusual in Angelman syndrome. Very tiny deletions can affect small regions such as the imprinting center or the region where the UBE3A gene is located.
Gene - A gene is a small piece of the genetic code that contains
sufficient information to produce a protein. Genes are located within chromosomes and are
composed of molecules of nucleic acid hooked together in a specific sequence. Thousands of
these sequences form the DNA code and it is the main component of chromosomes. Four
nucleic acids are used in the DNA code and are designated C, G, A and T. They can be
changed into a second code termed RNA which uses the code sequences U, C, A and G. RNA can
then be used
by the cell to directly translate the code into a series of amino acids which ultimately
form proteins.
Imprinting - A process (not completely understood) whereby a gene is inactivated or silenced. The result is that only one of the normal two genes is active. Imprinting occurs during development of the egg and sperm. The Angelman syndrome chromosome region is imprinted meaning that some genes are only active on the chromosome derived from the mother They are silenced on the chromosome derived (inherited) from the father.
Imprinting Center - This is a small area of DNA on chromosome 15 within the 15q11-13 region. It is believed to have control over large regions of 15q11-13. When the AS gene is inherited from your father it is believed to be in a turned off state but when inherited from your mother it is in the turned on state. This requires that the gene change it's active status as it passes through generations. In a way that is yet unknown1 the Imprinting Center is able to imprint as well as "unimprint" the 15q11-13 region, thereby allowing it to undergo it's normal turning on and turning off process.
Meiosis - This process occurs in germ cells (testes, ovaries) whereby a parent's normal dose of DNA is processed and reduced to a half dose. The half dose is needed during the time of conception when two parental half doses come together to make the usual normal dose of genetic material. Meiosis occurs during the time of sperm and egg development. This is also the time when some genes are evidently imprinted, thus establishing their active and inactive status.
Methylation - This term is often used to describe DNA which has methyl (CH3) groups attached to certain regions of it. The extent of methylation can be associated with gene inactivation, so it may play an improtant role in the imprinting process.
Mutation - Any condition which causes a detrimental change in DNA. This can involve a change in a single molecule or involve large deletions and other abnormalities. The net affect of a mutation is that it ultimately changes the way the protein is made, sometimes preventing its production or creating an abnormal protein which does not function properly.
UBE3A Gene - A gene that has been shown to be disrupted in some children with Angelman syndrome. The precise function of this gene is not yet known but it is presumed to affect the function of ubiquitin in the brain.
Ubiquitin - A small molecule that is present inside all cells. It can be attached to molecules that are old and ready to be degraded or that need rem ovE for whatever reason. This removal system is called the ubiquitin degradation pathway. The Angelman gene, UBE3A, is a component of this ubiquitin pathway but it remains unclear exactly how or if this gene helps degrade proteins in the brain.
Uniparental Disomy - This occurs when both of the chromosomes from a particular pair are inherited from the same parent. In Angelman syndrome, the presence of two of the paternally derived number 15 chromosomes results in Angelman syndrome (i.e., uniparental disomy of chromosome is or UPD15).
II. Genetic Testing Definitions:
High Resolution Chromosome (Karyotype) - This was a term applied to a chromosome analysis which examined the number 15 chromosome under high resolution in order to detect large deletions of 15q11-13. This test is rarely used today because some large deletions were actually missed using this method.
FISH - This test uses the process of fluorescent in situ hybridization which means that chromosomes are directly visualized under the microscope while a molecular fluorescent probe is used. The probes are specific for areas within 15q11-13 and when a small area is missing the probe fails to light up. In the normal state each chromosome fluoresces with the probe, but in Angelman syndrome, due to a large common deletion, only the paternal chromosome shows fluorescence.
DNA Methylation - This test detects changes in the methylation status of
nucleic acids in the 15q11-13 Angelman region. Within this area the paternal region
contains a different number of methyl (CH3) molecules
than the maternal region. When this region is then chopped up using enzymes that cut DNA,
it creates different size fragments. Normal individuals show two distinct fragments, one
from each of their parent's 15q11-13
region. If something disturbs the methylation status or the methylated region is
completely missing, then the methylation pattern is abnormal. In about 70% of Angelman
syndrome children, only the methylation pattern from the father's chromosome is seen
indicating that the 15q11-13 region is either missing due to a large maternal deletion, or
has two paternal 15 chromosomes or has a defect in the imprinting center.
UBE3A Direct Mutation Analysis - This involves examining DNA sequences inside the UBE3A gene. This test is not available at present and is currently in the research phase. Preliminary studies indicate that a small percentage of Angelman children who are normal by the above three tests may have mutations within this gene.
Normal Genetic Tests - This is not a test but represents a situation
where a chfld is believed to have the clinical manifestations of Angelman syndrome but
typically has normal high resolution chromosome, FISH and methylation studies. Most
children with normal genetic studies have not had UBE3A mutation testing but it
appears that most would still be normal even with this testing today. Accordingly, there
remains a group of
"genetically negative" children who show all the classical features of Angelman
syndrome.
III. Inheritance of Angelman Syndrome:
(Note: estimating recurrence risk In AS can be very complicated and professional genetic counseling is advised)
Large Common Deletion q11-13 - This is almost uniformly a sporadic occurrence without apparent increased risk in fliture offspring. Large common deletions occur in about 70% of cases of AS and are usually diagnosed by FISH tests using probes that map to region q11 - 13.
Microdeletion in 15q11-13 (molecular microdeletion) - This can occur in several molecular regions of 15q11-13 including the imprinting center and the area where the UBE3A gene resides. These microdeletions can either be sporadic (non-inherited) or they can be inherited from an apparently normal mother. If these microdeletions are also present in the mother then there is a 50% theoretical recurrence risk in future offspring.
UBE3A Mutations - This is a newly described group that has mutations within the putative AS gene. It appears that most of these mutations are sporadic and non-inherited although there is a risk, not yet well defined, that UBE3A mutations can be inherited from an apparently normal mother. If so, the theoretical risk would be 50%.
Uniparental Disomy for 15 - These appear to be sporadic. Recurrence risk for this disorder appears very low at less than 1%.
Normal Genetic Studies - This is a group that has completely normal genetic studies induding negative studies for the UBE3A gene. Sometimes affected siblings are included in this group and when this occurs, the theoretical recurrence risk is 50%. Accurate recurrence risks are difficult to establish for the overall group because of the varied nature of patients in this category.
Other Categories - There are a few AS individuals with unusual chromosome 15 rearrangements. In these cases, recurrence risk is variable depending on the chromosomal findings in the parents.
Pages provided as a public service by: Harold Anderson
Revised: December 20, 2000.