mitochondrial inheritance (http://www.genetics.edu.au/Information/Genetics-FactSheets/Mitochondial-Inheritance-Complex-Patterns-of-Inheritance-2-FS12).
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What are reduced penetrance and variable expressivity?
Reduced penetrance and variable expressivity are factors that influence the effects
of particular genetic changes. These factors usually affect disorders that have an
autosomal dominant pattern of inheritance, although they are occasionally seen in
disorders with an autosomal recessive inheritance pattern.
Reduced penetrance
Penetrance refers to the proportion of people with a particular genetic change (such
as a mutation in a specific gene) who exhibit signs and symptoms of a genetic
disorder. If some people with the mutation do not develop features of the disorder,
the condition is said to have reduced (or incomplete) penetrance. Reduced
penetrance often occurs with familial cancer syndromes. For example, many people
with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their
lifetime, but some people will not. Doctors cannot predict which people with these
mutations will develop cancer or when the tumors will develop.
Reduced penetrance probably results from a combination of genetic, environmental,
and lifestyle factors, many of which are unknown. This phenomenon can make it
challenging for genetics professionals to interpret a person’s family medical history
and predict the risk of passing a genetic condition to future generations.
Variable expressivity
Although some genetic disorders exhibit little variation, most have signs and
symptoms that differ among affected individuals. Variable expressivity refers to the
range of signs and symptoms that can occur in different people with the same
genetic condition. For example, the features of Marfan syndrome vary widely—
some people have only mild symptoms (such as being tall and thin with long, slender
fingers), while others also experience life-threatening complications involving the
heart and blood vessels. Although the features are highly variable, most people
with this disorder have a mutation in the same gene (FBN1).
As with reduced penetrance, variable expressivity is probably caused by a
combination of genetic, environmental, and lifestyle factors, most of which have
not been identified. If a genetic condition has highly variable signs and symptoms,
it may be challenging to diagnose.
For more information about reduced penetrance and variable expressivity:
The PHG Foundation offers an interactive tutorial on penetrance
(http://www.phgfoundation.org/tutorials/penetrance/index.html) that explains the
differences between reduced penetrance and variable expressivity.
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A more in-depth explanation of these concepts is available from the textbook Human
Molecular Genetics 2 in chapter 3.2, Complications to the Basic Pedigree Patterns
(http://www.ncbi.nlm.nih.gov/books/NBK7573/?redirect-on-error=__HOME__#A286).
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What do geneticists mean by anticipation?
The signs and symptoms of some genetic conditions tend to become more severe
and appear at an earlier age as the disorder is passed from one generation to the
next. This phenomenon is called anticipation. Anticipation is most often seen with
certain genetic disorders of the nervous system, such as Huntington disease,
myotonic dystrophy, and fragile X syndrome.
Anticipation typically occurs with disorders that are caused by an unusual type of
mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence
of three DNA building blocks (nucleotides) that is repeated a number of times in a
row. DNA segments with an abnormal number of these repeats are unstable and
prone to errors during cell division. The number of repeats can change as the gene
is passed from parent to child. If the number of repeats increases, it is known as a
trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand
until the gene stops functioning normally. This expansion causes the features of
some disorders to become more severe with each successive generation.
Most genetic disorders have signs and symptoms that differ among affected
individuals, including affected people in the same family. Not all of these differences
can be explained by anticipation. A combination of genetic, environmental, and
lifestyle factors is probably responsible for the variability, although many of these
factors have not been identified. Researchers study multiple generations of affected
family members and consider the genetic cause of a disorder before determining
that it shows anticipation.
For more information about anticipation:
The Merck Manual for Healthcare Professionals provides a brief explanation of
anticipation as part of its chapter on nontraditional inheritance
(http://www.merckmanuals.com/professional/special_subjects/general_principles_
of_medical_genetics/unusual_aspects_of_inheritance.html?qt=&sc=&alt=#
v1123535).
Additional information about anticipation is available from the textbook Human
Molecular Genetics 2 in chapter 3.2, Complications to the Basic Pedigree Patterns
(http://www.ncbi.nlm.nih.gov/books/NBK7573/?redirect-on-error=__HOME__#A286).
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What are genomic imprinting and uniparental disomy?
Genomic imprinting and uniparental disomy are factors that influence how some
genetic conditions are inherited.
Genomic imprinting
People inherit two copies of their genes—one from their mother and one from their
father. Usually both copies of each gene are active, or “turned on,” in cells. In some
cases, however, only one of the two copies is normally turned on. Which copy is
active depends on the parent of origin: some genes are normally active only when
they are inherited from a person’s father; others are active only when inherited from
a person’s mother. This phenomenon is known as genomic imprinting.
In genes that undergo genomic imprinting, the parent of origin is often marked, or
“stamped,” on the gene during the formation of egg and sperm cells. This stamping
process, called methylation, is a chemical reaction that attaches small molecules
called methyl groups to certain segments of DNA. These molecules identify which
copy of a gene was inherited from the mother and which was inherited from the
father. The addition and removal of methyl groups can be used to control the activity
of genes.
Only a small percentage of all human genes undergo genomic imprinting.
Researchers are not yet certain why some genes are imprinted and others are not.
They do know that imprinted genes tend to cluster together in the same regions of
chromosomes. Two major clusters of imprinted genes have been identified in
humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another
on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13).
Uniparental disomy
Uniparental disomy (UPD) occurs when a person receives two copies of a
chromosome, or part of a chromosome, from one parent and no copies from the
other parent. UPD can occur as a random event during the formation of egg or
sperm cells or may happen in early fetal development.
In many cases, UPD likely has no effect on health or development. Because most
genes are not imprinted, it doesn’t matter if a person inherits both copies from one
parent instead of one copy from each parent. In some cases, however, it does make
a difference whether a gene is inherited from a person’s mother or father. A person
with UPD may lack any active copies of essential genes that undergo genomic
imprinting. This loss of gene function can lead to delayed development, mental
retardation, or other medical problems.
Several genetic disorders can result from UPD or a disruption of normal genomic
imprinting. The most well-known conditions include Prader-Willi syndrome, which
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is characterized by uncontrolled eating and obesity, and Angelman syndrome, which
causes mental retardation and impaired speech. Both of these disorders can be
caused by UPD or other errors in imprinting involving genes on the long arm of
chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a
disorder characterized by accelerated growth and an increased risk of cancerous
tumors), are associated with abnormalities of imprinted genes on the short arm of
chromosome 11.
For more information about genomic imprinting and UPD:
The University of Utah offers a basic overview of genomic imprinting
(http://learn.genetics.utah.edu/content/epigenetics/imprinting/).
Additional information about genomic imprinting (http://www.genetics.edu.au/
Information/Genetics-Fact-Sheets/Genetic-Imprinting-Epigenetics-2-FS15) is
available from the Centre for Genetics Education.
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Are chromosomal disorders inherited?
Although it is possible to inherit some types of chromosomal abnormalities, most
chromosomal disorders (such as Down syndrome and Turner syndrome) are not
passed from one generation to the next.
Some chromosomal conditions are caused by changes in the number of
chromosomes. These changes are not inherited, but occur as random events during
the formation of reproductive cells (eggs and sperm). An error in cell division called
nondisjunction results in reproductive cells with an abnormal number of
chromosomes. For example, a reproductive cell may accidentally gain or lose one
copy of a chromosome. If one of these atypical reproductive cells contributes to the
genetic makeup of a child, the child will have an extra or missing chromosome in
each of the body’s cells.
Changes in chromosome structure can also cause chromosomal disorders. Some
changes in chromosome structure can be inherited, while others occur as random
accidents during the formation of reproductive cells or in early fetal development.
Because the inheritance of these changes can be complex, people concerned about
this type of chromosomal abnormality may want to talk with a genetics professional.
Some cancer cells also have changes in the number or structure of their
chromosomes. Because these changes occur in somatic cells (cells other than
eggs and sperm), they cannot be passed from one generation to the next.
For more information about how chromosomal changes occur:
As part of its fact sheet on chromosome abnormalities, the National Human Genome
Research Institute provides a discussion of how chromosome abnormalities happen.
(http://www.genome.gov/11508982#6)
The Chromosome Deletion Outreach fact sheet Introduction to Chromosomes
(http://www.chromodisorder.org/CDO/General/IntroToChromosomes.aspx) explains
how structural changes occur.
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Why are some genetic conditions more common in
particular ethnic groups?
Some genetic disorders are more likely to occur among people who trace their
ancestry to a particular geographic area. People in an ethnic group often share
certain versions of their genes, which have been passed down from common
ancestors. If one of these shared genes contains a disease-causing mutation, a
particular genetic disorder may be more frequently seen in the group.
Examples of genetic conditions that are more common in particular ethnic groups
are sickle cell anemia, which is more common in people of African, African-American,
or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur
among people of Ashkenazi (eastern and central European) Jewish or French
Canadian ancestry. It is important to note, however, that these disorders can occur
in any ethnic group.
For more information about genetic disorders that are more common in certain
groups:
The National Coalition for Health Professional Education in Genetics offers Some
Frequently Asked Questions and Answers About Race, Genetics, and Healthcare
(http://www.nchpeg.org/index.php?option=com_content&view=article&id=
142&Itemid=64).
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Chapter 5
Genetic Consultation
Table of Contents
What is a genetic consultation?
Why might someone have a genetic consultation?
What happens during a genetic consultation?
How can I find a genetics professional in my area?
What is the prognosis of a genetic condition?
How are genetic conditions diagnosed?
How are genetic conditions treated or managed?
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What is a genetic consultation?
A genetic consultation is a health service that provides information and support to
people who have, or may be at risk for, genetic disorders. During a consultation, a
genetics professional meets with an individual or family to discuss genetic risks or
to diagnose, confirm, or rule out a genetic condition.
Genetics professionals include medical geneticists (doctors who specialize in
genetics) and genetic counselors (certified healthcare workers with experience in
medical genetics and counseling). Other healthcare professionals such as nurses,
psychologists, and social workers trained in genetics can also provide genetic
consultations.
Consultations usually take place in a doctor’s office, hospital, genetics center, or
other type of medical center. These meetings are most often in-person visits with
individuals or families, but they are occasionally conducted in a group or over the
telephone.
For more information about genetic consultations:
MedlinePlus offers a list of links to information about genetic counseling
(http://www.nlm.nih.gov/medlineplus/geneticcounseling.html).
Additional background information is provided by the National Genome Research
Institute in its Frequently Asked Questions About Genetic Counseling
(http://www.genome.gov/19016905).
Information about genetic counseling, including the different types of counseling,
is available from the National Society of Genetic Counselors and the Genetic Alliance
in their booklet Making Sense of Your Genes: A Guide to Genetic Counseling
(http://www.geneticalliance.org/sites/default/files/ksc_assets/publications/
guidetogcfinal.pdf).
The Centre for Genetics Education also offers an introduction to genetic counseling
(http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/Genetic-Counselling-
FS3).
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Why might someone have a genetic consultation?
Individuals or families who are concerned about an inherited condition may benefit
from a genetic consultation. The reasons that a person might be referred to a genetic
counselor, medical geneticist, or other genetics professional include:
•
A personal or family history of a genetic condition, birth defect,
chromosomal disorder, or hereditary cancer.
•
Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who
died.
•
A child with a known inherited disorder, a birth defect, mental retardation,
or developmental delay.
•
A woman who is pregnant or plans to become pregnant at or after age
35. (Some chromosomal disorders occur more frequently in children born
to older women.)
•
Abnormal test results that suggest a genetic or chromosomal condition.
•
An increased risk of developing or passing on a particular genetic disorder
on the basis of a person’s ethnic background.
•
People related by blood (for example, cousins) who plan to have children
together. (A child whose parents are related may be at an increased risk
of inheriting certain genetic disorders.)
A genetic consultation is also an important part of the decision-making process for
genetic testing. A visit with a genetics professional may be helpful even if testing
is not available for a specific condition, however.
For more information about the reasons for having a genetic consultation:
An overview of indications for a genetics referral (http://www.ncbi.nlm.nih.gov/books/
NBK115554/) is available from The Genetic Alliance booklet “Understanding
Genetics: A Guide for Patients and Professionals.”
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What happens during a genetic consultation?
A genetic consultation provides information, offers support, and addresses a patient’s
specific questions and concerns. To help determine whether a condition has a
genetic component, a genetics professional asks about a person’s medical history
and takes a detailed family history (a record of health information about a person’s
immediate and extended family). The genetics professional may also perform a
physical examination and recommend appropriate tests.
If a person is diagnosed with a genetic condition, the genetics professional provides
information about the diagnosis, how the condition is inherited, the chance of passing
the condition to future generations, and the options for testing and treatment.
During a consultation, a genetics professional will:
•
Interpret and communicate complex medical information.
•
Help each person make informed, independent decisions about their
health care and reproductive options.
•
Respect each person’s individual beliefs, traditions, and feelings.
A genetics professional will NOT:
•
Tell a person which decision to make.
•
Advise a couple not to have children.
•
Recommend that a woman continue or end a pregnancy.
•
Tell someone whether to undergo testing for a genetic disorder.
For more information about what to expect during a genetic consultation
The National Society of Genetic Counselors offers information about what to expect
from a genetic counseling session as part of its FAQs About Genetic Counselors
(http://nsgc.org/p/cm/ld/fid=144).
EuroGentest explains what a person can expect during a visit with a genetic
specialist (http://www.eurogentest.org/index.php?id=620) and offers frequently
asked questions that may be helpful during an appointment
(http://www.eurogentest.org/index.php?id=615).
Information about the role of genetic counselors and the process of genetic
counseling (http://www.ncbi.nlm.nih.gov/books/NBK115552/) are available from the Genetic Alliance publication “Understanding Genetics: A Guide for Patients and
Professionals.”
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How can I find a genetics professional in my area?
To find a genetics professional in your community, you may wish to ask your doctor
for a referral. If you have health insurance, you can also contact your insurance
company to find a medical geneticist or genetic counselor in your area who
participates in your plan.
Several resources for locating a genetics professional in your community are
available online:
•
The National Society of Genetic Counselors offers a searchable
directory of genetic counselors in the United States and Canada
(http://nsgc.org/p/cm/ld/fid=164). You can search by location, name, area
of practice/specialization, and/or ZIP Code.
•
The National Cancer Institute provides a
Cancer Genetics Services Directory (http://www.cancer.gov/cancertopics/
genetics/directory), which lists professionals who provide services related
to cancer genetics. You can search by type of cancer or syndrome,
location, and/or provider name.
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What is the prognosis of a genetic condition?
The prognosis of a genetic condition includes its likely course, duration, and
outcome. When health professionals refer to the prognosis of a disease, they may
also mean the chance of recovery; however, most genetic conditions are life-long
and are managed rather than cured.
Disease prognosis has multiple aspects, including:
•
How long a person with the disorder is likely to live (life expectancy)
•
Whether the signs and symptoms worsen (and how quickly) or are stable
over time
•
Quality of life, such as independence in daily activities
•
Potential for complications and associated health
The prognosis of a genetic condition depends on many factors, including the specific
diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and an individual’s particular signs and symptoms. Sometimes the associated genetic change, if known,
can also give clues to the prognosis. Additionally, the course and outcome of a