GENETIC COUNSELING FOR ANGELMAN SYNDROME (AS)
by Jill E. Hendrickson, MS, MSSW (CGC)

Genetic counseling is the process of assisting patients or other family members at risk for a disorder that may be hereditary to understand the consequences of the disorder, the probability of developing or transmitting it, and ways it might be treated or prevented. This information helps families to better understand the disorder and its implications, helping them to make the best possible adjustment.

During a genetic counseling session, the counselor first reviews the reason for the consultation and discusses what the counselee expects from the session. Next the patient and counselor collaborate to construct a pedigree, or diagram of the family tree. The counselor will ask for details about any family member with birth defects, mental retardation, or identified genetic disorders. The counselor will then address issues surrounding the reason for the referral and address any other issues the pedigree or patient have identified. Such things as the genetic mechanism causing the disorder in the affected family member will be discussed to ensure a basic understanding. Recurrence risk information is discussed in light of the information supplied from the family and from records available at the time of consultation.

Genetics 101

To begin, a review of basic genetics may be helpful.

KARYOTYPE
Humans normally have 23 pairs, or 46 total chromosomes. Each of us receives chromosome pairs at conception, normally one of each pair from our mothers via the egg and one from our fathers via the sperm.

EGGS AND SPERM PRODUCED
When our bodies produce eggs and sperm, one from each of our pairs usually goes into producing each egg or sperm made. This process is called meiosis. When the egg and sperm unite, children then receive genetic information from both of their parents, normally the same number of chromosomes from each.

GENES, CHROMS, DNA
By convention, chromosomes are arranged in pairs from largest to smallest and numbered in that order. Humans have 22 pairs of autosomes with a 23rd pair, the sex chromosomes, either XX in females or XY in males. Genes are the individual bits of information that code for specific traits, for example, eye color, blood type, and disorders such as cystic fibrosis, PKU, muscular dystrophy, color blindness, or sickle cell disease. It is estimated that the human genome contains 30,000 to 50,000 gene pairs, usually one form each parent. Genes are composed of strands of DNA, the actual coding sequences of the genes.

The genetics of Angelman syndrome
Genetic counseling for Angelman syndrome has greatly changed in the years since 1987 when it was first reported that a small deletion in the long arm of chromosome 15 was found in a majority of AS patients. The diagnosis of AS still relies on the presence of clinical features (see consensus clinical diagnostic criteria) to initially suspect the diagnosis, followed by laboratory studies.

Genetic counseling is most accurate when an exact diagnosis is known, and for Angelman syndrome, only after a more precise genetic defect has been identified.

The deletion or other genetic change that disrupts information is always found on the maternally contributed #15 chromosome while the same apparent deletion or change on the paternally derived #15 may result in Prader-Willi syndrome, a distinctively different disorder.

AS subgroups To date 5 different types of genetic mechanisms that may lead to features of what has been termed AS have been identified. As children differ, so does presence or absence of some of the features seen in Angelman individuals. Some of these differences may be due to the nature of the deletion or mutation; thus the genes involved, but also are modified by other inherited familial traits.

The basic genetic mechanism that causes AS is the loss of the maternally imprinted contribution of key DNA in the 15q11-q13 region. This occurs in several different ways. Genetic counseling to assess risks to siblings and other family members is based upon knowing the mechanism involved in causing the loss of expression of this genetic region at the molecular level. Recurrence risks to parents and extended family members vary from a negligible risk of recurrence to a possible 50% risk.

The mechanisms are each discussed in more detail below, in order of frequency.

15q deletion

Approximately 70-80% of individuals with AS have a deletion in 15q11-q13. This deletion is visible by high-resolution chromosome analysis or may be found by FISH (fluorescent in situ hybridization) analysis. Recurrence risk for parents with an affected child is less than 1%, as this is considered a sporadic occurrence. The risk is never zero since a similar event might happen by chance or a (rare) possibility that one of the parents may harbor other cells with similar mutations in their reproductive organs (called gonadal mosaicism).

Prenatal diagnosis by chorionic villus sampling or amniocentesis is possible for these families, as the mutation is easily identifiable. The risk of prenatal testing probably outweighs the risk of recurrence, but may be elected to provide reassurance.

UBE3A

Up to 25% of patients clinically diagnosed with AS may have a presumed mutation in the UBE3A gene. Recurrence risk may be as high as 50%.

Imprinting mutation

Found in up to 5% of cases. Recurrence risk may be as high as 50% in some families. This test is not done in every center and may be more research based.

Uniparental disomy

5% or fewer individuals with AS have a double paternal contribution of chromosome #15 and none from the mother. Recurrence risk for siblings is less than 1%.

Other structural rearrangements

Found in less than 1% of patients. Recurrence risk depends on the nature of the chromosomal rearrangement and whether it has been inherited from either of the parents.

Glossary

Amniocentesis - withdrawal of a small amount of amniotic fluid, the water surrounding a developing baby, from the uterus. This procedure is done in a doctor's office, usually when the woman is about 16 weeks pregnant, counting from the first day of the last menstrual period. This is performed under ultrasound guidance by inserting a very thin needle through the abdomen into the uterus, removing an ounce or less of fluid.

Autosomes - any of the chromosomes excluding the sex chromosomes; in humans there are 22 pairs.

Chorionic villus sampling (CVS) -- a procedure for prenatal diagnosis where a small amount of tissue from the developing placenta is withdrawn. The chorionic villi are made up of cells that develop from the same fertilized egg cell as the fetus. This test is usually performed at 10-12 weeks, counting from the first day of the last menstrual period, and may be done in a doctor's office or hospital setting. CVS is an earlier alternative to amniocentesis but the risk for complications is slightly higher.

Chromosomes - structures found in the nucleus of cells that are composed of threads of DNA, which transmit genetic information. During cell division, the DNA strands become tightly coiled, and when appropriately stained, the chromosomes are visible under a microscope. Humans have 46 chromosomes with 23 pairs.

Deletion - a loss of genetic material from a chromosome; this loss may or may not be grossly visible and may result in mutational changes.

DNA (deoxyribonucleic acid) - found in all living cells, it is the carrier of genetic information from generation to generation; its molecular building blocks are adenine, guanine, cytosine, and thymine.

FISH (fluorescent in situ hybridization) - a chromosome analysis technique that uses small known DNA segments which have been fluorescently labeled to selectively attach to specific DNA sequences and light them up under the microscope. Presence or absence of the glow indicates presence or absence of a specific sequence.

Genes - the biologic unit of heredity; genes are reproduced and passed from generation to generation and are located at specific positions of particular chromosomes.

High-resolution chromosome analysis - provides a more sensitive analysis of the chromosomes by treating them in a way to optimize the appearance of smaller sub-bands. Chromosomes to be analyzed are stained before analysis to reveal a horizontally striped pattern that is similar in all humans but variable from chromosome to chromosome.

Imprinting - a recently described phenomenon in mammals involving particular genes which are not equally expressed, depending on the sex of the parent of origin. AS represents one of the first classical examples of imprinting.

Imprinting mutation - a change, or mutation, in the mechanism that resets the imprinting pattern during gametogenesis (production of eggs or sperm).

Karyotype - an ordered picture of the chromosome pairs, arranged largest to smallest by convention.

Meiosis - a special cell division during the production of eggs or sperm which results in each daughter nucleus having only one of each pair of chromosomes; when the egg and sperm then unite, pairs are restored.

Mosaicism - presence in an individual of two or more separate cell lines which are distinct from one another but arose from the same source.

Mutation - a permanent transmissible change in the genetic material

Pedigree - an ordered drawing showing a family's genetic relationships

Prader Willi syndrome - a syndrome distinct from AS which occurs from chromosomal deletion in the same area as AS; although the same apparent genetic region is involved, the differences may be due to imprinting as individuals with PWS inherit the deleted chromosome from their fathers (rather than the mother for AS), and maternal UPD may also result in PWS (paternal UPD for AS).

UBE3A - a gene found to have mutations in some individuals with AS

Uniparental disomy (UPD)- a term used when an offspring received both members of a chromosome pair from one parent and none from the other. Angelman syndrome may occur when both #15 chromosomes are paternal, because chromosome #15 has imprinted regions.