GENETIC COUNSELING FOR ANGELMAN
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
To begin, a review of basic genetics may be helpful.
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
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
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
The mechanisms are each discussed in more detail below, in order
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.
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%.
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.
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.
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
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
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
Mutation - a permanent transmissible change in the genetic
Pedigree - an ordered drawing showing a family's genetic
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
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.