4.1
Introduction to Clinical Genetics. Clinical genetics is becoming an increasingly vital part of
healthcare, as the science of genetics provides an underpinning for virtually
all clinical topic areas. The modern prediction, diagnosis, analysis and
evaluation of disease is increasingly relying on genetic science. Clinical genetics is particularly important in reproductive
medicine, as well as in paediatrics, midwifery and nursing. Clinical genetic
data is vital in disease epidemiology, and offers great potential for the
avoidance and prevention of disease. As genetic science progresses, it is likely that more and more
patients/clients will benefit from an increased understanding of the genetic
basis of disease pathology and the utilization of genetic tests and even
possibly therapies. Such an important clinical area deserves study by all healthcare
practitioners. Here we offer a starting point for your endeavours. For most people, the term pedigree is best known for the reporting
of the blood line of animals, a sign of excellence in horses, dogs and cats
etc. However pedigree analysis is also a vital part of clinical genetics,
as the accurate documentation of family history can give vital clues to the
hereditary nature of disease as well as the patterns of inheritance for a
wide range of conditions. Family histories are normally obtained through a process of
interview with a patient/client who has been referred to the genetic services.
The person who has been referred and is seeking advice from the clinical
geneticist is termed the consultand. It is from the consultand that the pedigree
is normally started. As the documentation of a family history and the drawing of
a pedigree are important clinical tools, it is important that as much relevant
information is gathered as is possible. Full names and dates of birth of
relatives for instance, will allow the retrieval of appropriate medical records.
The specifics of the condition under study are also important, so that data
such as the symptoms and the age that the condition arose in relatives is
needed. Specific questions about multiple marriages, abortions, stillbirths
and factors such as consanguinity, whilst difficult to ask, are vital. This
type of information, due to its sensitivity is not always volunteered. Pedigrees are drawn using a number of symbols to represent
individuals, their relationships and the presence or absence of disease.
A selection of these can be seen in figure 4.2 (below). Figure 4.2. : Commonly used symbols for genetic pedigree analysis As mentioned previously, the pedigree is normally started with
the consultand and then details of the first degree relatives such as children,
sib,siblings and parents can be added. Next the second degree relatives including
grandparents, aunts, uncles, nieces and nephews can be added if possible.
If the person seeking advice is married or has a partner, a pedigree for
their family may be needed if the data is to be used for preconception or
antenatal advice. A completed pedigree drawing can be
seen in Figure 4.2.1 below. Figure 4.2.1: Completed pedigree drawing The risk of developing or passing on a genetic condition
is probably the most important piece of information for an individual, couple
or family seeking help from genetic services. For the majority of single
gene disorders where the mutation can be identified and analyzed, this risk
can be identified accurately. However, most risk is expressed as a probability
that has been calculated from pedigree analysis or risk figures standardised
from a number of research studies. For many common conditions such as cancer and heart disease,
it is difficult to calculate risk because of the additional factors
involved. Conditions with a Mendelian inheritance and due to mutant genes,
generally have a high risk of recurrence in families. Chromosomal disorders
have a generally lower risk. The nature of risk is also influenced by how serious a condition
is and the availability of effective care and treatment. So all aspects of
the condition need to be taken into account when patients/clients are given
information. An example of this can be given where there is a high risk of
transmitting a mild, treatable condition versus a low risk of transmitting
a disabling and life-shortening disorder. The perception of risk in these
cases takes on a deeply personal perspective for the patient(s)/client(s).
Cultural, moral and religious factors are also influential and the personal
beliefs of individuals must be respected at all times. The aim of genetic counselling is to help families who have
higher genetic risk than others to live as normally as possible. The genetic
counsellor acts both as an educator and a psychotherapist. The counselling given to individuals and families requires
that an accurate risk assessment and diagnosis has been performed, but ultimately
it is the way that the information is given and the consideration of the
impact of this information on individuals and families which identifies the
competent practitioner. The process of genetic counselling is guided by the general
principles that the patient/client should be helped to understand a genetic
disorder in terms of its diagnosis, possible outcomes and available care
and treatment. Patients/clients will also be given insight into the genetic
basis of the condition and the chances of it future recurrence. In addition,
the counsellor will address the options available, such as testing. The counsellor has an important role in allowing patients to
make an informed choice that is appropriate for them and their family according
to situation and circumstance. Counsellors should also use all their skill
to aid patients and clients to adjust to any impact, whether physical, psychological
or sociological, of having a named and identified condition in the family. Genetic counselling is an integral part of the genetic testing
process. The counsellor acts to support the patient/client through the testing
"journey" Chromosomal analysis plays an important role in clinical genetics,
through the determination of numerical and structural abnormalities that
result in genetic disorders. The chromosomes of the client/patient under study are obtained
from cells gathered from that person. The most common type of cells taken
are white blood cells and these are grown in the laboratory and treated to
optimize the presence of chromosomes in dividing cells. Cells may also be
taken from the skin, the bone marrow or from the chorionic villi or amnion
of the developing fetus. Originally, chromosomes could only be analyzed in terms of
size, shape and number, but an expansion of cellular and molecular biological
techniques make it possible to identify changes at finer and finer scales.
In fact, the most modern techniques can detect changes at the level of individual
genes. The complement of chromosomes found in the cell is termed the
karyotype and the way that karyotypes are described and reported
is set down by international convention. The short arm of each chromosome is designated "p" from the
french petit, whilst the long arm is termed "q" for queue. The centromere
is designated "cen" and the tips of the chromosome called the telomeres represented
as "ter". A number of specific staining protocols result in the detection
of chromosome "bands", these banding patterns are used to further subdivide
each arm of the chromosome. Fine banding techniques can be used to detect
structural abnormalities such as deletions. One of the most modern chromosome analysis techniques is called
F.I.S.H. (fluorescent in situ hybridization). A single strand of DNA is labelled
with a fluorescent dye and is allowed to hybridise (stick to) with prepared
chromosomes. the DNA is then used as a "probe" to detect the presence (or
absence) of specific DNA sequences within the chromosome. In addition, whole
chromosomes may be labelled in this way, enabling detection of both structural
and numerical (aneuploidy) abnormalities. An example of fluorescent labelling of chromosomes can be seen
in Figure 4.5 below. Figure 4.5: Fluorescent labelling of a human
chromosome: note bright green and yellow labelled chromosome and grey unlabelled
chromosomes Karyotypes are reported in a standard format giving the
total number of chromosomes first, followed by the sex
chromosome complement. Additional or web links: For a very detailed view of human chromosomes, try the human
chromosome viewer at NCBI - click
here. Genetic tests are performed for a number of reasons. Firstly
they may be diagnostic, being used to confirm a diagnosis of a condition
in an individual. Secondly they may be used to predict whether an individual
will develop a condition in the future or is at an increased risk of developing
the condition. Carrier testing identifies healthy people who may pass a condition
to their children. Prenatal testing is used to diagnose an affected fetus. Testing for a genetic condition is carried out using a range
of biochemical, cytological and molecular biological methods. It is important
to understand that not all genetic disorders require sophisticated testing
methods. Perhaps the oldest genetic screening test in the U.K, is the heel
prick test used on new-born babies. This test, employed to detect individuals
affected by the single gene disorder phenylketonuria (PKU), relies on the
biological assay of a metabolic by-product of the amino acid phenylalanine. Chromosome analysis, as described in section 4.5 (above) is
a major method of genetic testing. However the rapid expansion of molecular
genetics techniques over the past two decades, means that rapid and accurate
analysis of genetics at the single-gene level is becoming more and more prevalent
in the clinical genetics laboratory. web links:
missing chromosomes are indicated by + or - for whole
chromosomes. Any structural defects are reported indicating the p or q arm
and
any band position.
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