There are many highly publicised controversies in genetics,
including the use of modern genetic technologies in genetic
testing, embryo research, gene therapy and the potential
application of cloning techniques. In everyday clinical practice,
however, the legal and ethical issues faced by professionals
working in clinical genetics are generally similar to those in
other specialities. Certain dilemmas are more specific to
clinical genetics, for example, the issue of whether or not
genetic information belongs to the individual and/or to other
relatives remains controversial. Public perception of genetics is
made more sensitive by past abuses, often carried out in the
name of scientific progress. Whilst professionals have learnt
lessons from history, the public may still have anxieties about
the purpose of genetic services.
Saturday, April 11, 2009
Informed consent
Competent adults can give informed consent for a procedure
when they have been given appropriate information by
professionals and have had the chance to think about it. With
regard to genetic tests, the information given needs to include
the reason for the test (diagnostic or predictive), its accuracy
and the implications of the result. It may be difficult to ensure
that consent is truly informed when the patient is a child, or
other vulnerable person, such as an individual with cognitive
impairment. This is of most concern if the proposed genetic
test is being carried out for the benefit of other members of the
family who wish to have a genetic disorder confirmed in order
to have their own risk assessed.
when they have been given appropriate information by
professionals and have had the chance to think about it. With
regard to genetic tests, the information given needs to include
the reason for the test (diagnostic or predictive), its accuracy
and the implications of the result. It may be difficult to ensure
that consent is truly informed when the patient is a child, or
other vulnerable person, such as an individual with cognitive
impairment. This is of most concern if the proposed genetic
test is being carried out for the benefit of other members of the
family who wish to have a genetic disorder confirmed in order
to have their own risk assessed.
Genetic tests in childhood
In the UK the professional consensus is that a predictive
genetic test should be carried out in childhood only when it is
in the best interests of the child concerned. It is important to
note that both medical and non-medical issues need to be
considered when the child’s best interests are being assessed.
There may be a potential for conflict between the parents’
“need to know” and the child’s right to make his or her own
decisions on reaching adulthood. In most cases, genetic
counselling helps to resolve such situations without predictive
genetic testing being carried out during childhood, since
genetic tests for carrier state in autosomal recessive disorders
only become of consequence at reproductive age, and physical
examination to exclude the presence of clinical signs usually
avoids the need for predictive genetic testing for late-onset
dominant disorders.
genetic test should be carried out in childhood only when it is
in the best interests of the child concerned. It is important to
note that both medical and non-medical issues need to be
considered when the child’s best interests are being assessed.
There may be a potential for conflict between the parents’
“need to know” and the child’s right to make his or her own
decisions on reaching adulthood. In most cases, genetic
counselling helps to resolve such situations without predictive
genetic testing being carried out during childhood, since
genetic tests for carrier state in autosomal recessive disorders
only become of consequence at reproductive age, and physical
examination to exclude the presence of clinical signs usually
avoids the need for predictive genetic testing for late-onset
dominant disorders.
Confidentiality
Confidentiality is not an absolute right. It may be breached, for
example, if there is a risk of serious harm to others. In practice,
however, it can be difficult to assess what constitutes serious
harm. There is the potential for conflict between an
individual’s right to privacy and his or her genetic relatives’
right to know information of relevance to themselves.
Occasionally patients are reluctant to disclose a genetic
diagnosis to other family members. In practice the individual’s
sense of responsibility to his or her relatives means that, in
time, important information is shared within most families.
There may also be conflict between an individual’s right to
privacy and the interests of other third parties, for example
employers and insurance companies.
example, if there is a risk of serious harm to others. In practice,
however, it can be difficult to assess what constitutes serious
harm. There is the potential for conflict between an
individual’s right to privacy and his or her genetic relatives’
right to know information of relevance to themselves.
Occasionally patients are reluctant to disclose a genetic
diagnosis to other family members. In practice the individual’s
sense of responsibility to his or her relatives means that, in
time, important information is shared within most families.
There may also be conflict between an individual’s right to
privacy and the interests of other third parties, for example
employers and insurance companies.
Unsolicited information
Problems may arise where unsolicited information becomes
available. Non-paternity may be revealed either as a result of a
genetic test, or through discussion with another family member.
Where this would change the individual’s genetic risk, the
professional needs to consider whether to divulge this
information and to whom. In other situations a genetic test,
such as chromosomal analysis of an amniocentesis sample for
Down syndrome, may reveal an abnormality other than the one
being tested for. If this possibility is known before testing, it
should be explained to the person being tested.
available. Non-paternity may be revealed either as a result of a
genetic test, or through discussion with another family member.
Where this would change the individual’s genetic risk, the
professional needs to consider whether to divulge this
information and to whom. In other situations a genetic test,
such as chromosomal analysis of an amniocentesis sample for
Down syndrome, may reveal an abnormality other than the one
being tested for. If this possibility is known before testing, it
should be explained to the person being tested.
Chromosomal analysis
The correct chromosome complement in humans was
established in 1956, and the first chromosomal disorders
(Down, Turner, and Klinefelter syndromes) were defined in
1959. Since then, refinements in techniques of preparing and
examining samples have led to the description of hundreds of
disorders that are due to chromosomal abnormalities.
established in 1956, and the first chromosomal disorders
(Down, Turner, and Klinefelter syndromes) were defined in
1959. Since then, refinements in techniques of preparing and
examining samples have led to the description of hundreds of
disorders that are due to chromosomal abnormalities.
Cell Division
Most human somatic cells are diploid (2n46), contain two
copies of the genome and divide by mitosis. Germline oocytes
and spermatocytes divide by meiosis to produce haploid
gametes (n23). Some human somatic cells, for example giant
megakaryocytes, are polyploid and others, for example muscle
cells, contain multiple diploid nuclei as a result of cell fusion.
During cell division the DNA of the chromosomes becomes
highly condensed and they become visible under the light
microscope as structures containing two chromatids joined
together by a single centromere. This structure is essential for
segregation of the chromosomes during cell division and
chromosomes without centromeres are lost from the cell.
copies of the genome and divide by mitosis. Germline oocytes
and spermatocytes divide by meiosis to produce haploid
gametes (n23). Some human somatic cells, for example giant
megakaryocytes, are polyploid and others, for example muscle
cells, contain multiple diploid nuclei as a result of cell fusion.
During cell division the DNA of the chromosomes becomes
highly condensed and they become visible under the light
microscope as structures containing two chromatids joined
together by a single centromere. This structure is essential for
segregation of the chromosomes during cell division and
chromosomes without centromeres are lost from the cell.
Chromosomes
Chromosomes replicate themselves during the cell cycle
which consists of a short M phase during which mitosis occurs,
and a longer interphase. During interphase there is a G1 gap
phase, an S phase when DNA synthesis occurs and a G2 gap
phase. The stages of mitosis – prophase, prometaphase,
metaphase, anaphase and telophase – are followed by
cytokinesis when the cytoplasm divides to give two daughter
cells. The process of mitosis produces two identical diploid
daughter cells. Meiosis is also preceded by a single round of
DNA synthesis, but this is followed by two cell divisions to
produce the haploid gametes. The first division involves the
pairing and separation of maternal and paternal chromosome
homologs during which exchange of chromosomal material
takes place. This process of recombination separates groups of
genes that were originally located on the same chromosome
and gives rise to individual genetic variation. The second cell
division is the same as in mitosis, but there are only 23
chromosomes at the start of division. During spermatogenesis,
each spermatocyte produces four spermatozoa, but during
oogenesis there is unequal division of the cytoplasm, giving rise
to the first and second polar bodies with the production of only
one large mature egg cell.
which consists of a short M phase during which mitosis occurs,
and a longer interphase. During interphase there is a G1 gap
phase, an S phase when DNA synthesis occurs and a G2 gap
phase. The stages of mitosis – prophase, prometaphase,
metaphase, anaphase and telophase – are followed by
cytokinesis when the cytoplasm divides to give two daughter
cells. The process of mitosis produces two identical diploid
daughter cells. Meiosis is also preceded by a single round of
DNA synthesis, but this is followed by two cell divisions to
produce the haploid gametes. The first division involves the
pairing and separation of maternal and paternal chromosome
homologs during which exchange of chromosomal material
takes place. This process of recombination separates groups of
genes that were originally located on the same chromosome
and gives rise to individual genetic variation. The second cell
division is the same as in mitosis, but there are only 23
chromosomes at the start of division. During spermatogenesis,
each spermatocyte produces four spermatozoa, but during
oogenesis there is unequal division of the cytoplasm, giving rise
to the first and second polar bodies with the production of only
one large mature egg cell.
Chromosomal analysis
Chromosomal analysis is usually performed on white blood cell
cultures. Other samples analysed on a routine basis include
cultures of fibroblasts from skin biopsy samples, chorionic villi
and amniocytes for prenatal diagnosis, and actively dividing
bone marrow cells. The cell cultures are treated to arrest
growth during metaphase or prometaphase when the
chromosomes are visible. Until the 1970s, chromosomes could
only be analysed on the basis of size and number. A variety of
banding techniques are now possible and allow more precise
identification of chromosomal rearrangements. The most
commonly used is G-banding, in which the chromosomes are
subjected to controlled trypsin digestion and stained with
Giemsa to produce a specific pattern of light and dark bands
for each chromosome.
cultures. Other samples analysed on a routine basis include
cultures of fibroblasts from skin biopsy samples, chorionic villi
and amniocytes for prenatal diagnosis, and actively dividing
bone marrow cells. The cell cultures are treated to arrest
growth during metaphase or prometaphase when the
chromosomes are visible. Until the 1970s, chromosomes could
only be analysed on the basis of size and number. A variety of
banding techniques are now possible and allow more precise
identification of chromosomal rearrangements. The most
commonly used is G-banding, in which the chromosomes are
subjected to controlled trypsin digestion and stained with
Giemsa to produce a specific pattern of light and dark bands
for each chromosome.
chromosome constitution of a cell
The chromosome constitution of a cell is referred to as its
karyotype and there is an International System for Human
Cytogenetic Nomenclature (ISCN) for describing
abnormalities. The Paris convention in 1971 defined the
terminology used in reporting karyotypes. The centromere is
designated “cen” and the telomere (terminal structure of the
chromosome) as “ter”. The short arm of each chromosome is
designated “p” (petit) and the long arm “q” (queue). Each arm
is subdivided into a number of bands and sub-bands depending
on the resolution of the banding pattern achieved. High
resolution cytogenetic techniques have permitted identification
of small interstitial chromosome deletions in recognised
disorders of previously unknown origin, such as Prader–Willi
and Angelman syndromes. Deletions too small to be detected
by microscopy may be amenable to diagnosis by molecular
in situ hybridisation techniques.
karyotype and there is an International System for Human
Cytogenetic Nomenclature (ISCN) for describing
abnormalities. The Paris convention in 1971 defined the
terminology used in reporting karyotypes. The centromere is
designated “cen” and the telomere (terminal structure of the
chromosome) as “ter”. The short arm of each chromosome is
designated “p” (petit) and the long arm “q” (queue). Each arm
is subdivided into a number of bands and sub-bands depending
on the resolution of the banding pattern achieved. High
resolution cytogenetic techniques have permitted identification
of small interstitial chromosome deletions in recognised
disorders of previously unknown origin, such as Prader–Willi
and Angelman syndromes. Deletions too small to be detected
by microscopy may be amenable to diagnosis by molecular
in situ hybridisation techniques.
Karyotype
Karyotypes are reported in a standard format giving the
total number of chromosomes first, followed by the sex
chromosome constitution. All cell lines are described in mosaic
abnormalities, indicating the frequency of each. Additional or
missing chromosomes are indicated by or for whole
chromosomes, with an indication of the type of abnormality if
there is a ring or marker chromosome. Structural
rearrangements are described by in dicating the p or q arm and
the band position of the break points.
total number of chromosomes first, followed by the sex
chromosome constitution. All cell lines are described in mosaic
abnormalities, indicating the frequency of each. Additional or
missing chromosomes are indicated by or for whole
chromosomes, with an indication of the type of abnormality if
there is a ring or marker chromosome. Structural
rearrangements are described by in dicating the p or q arm and
the band position of the break points.
Molecular cytogenetics
Fluorescence in situ hybridisation (FISH) is a recently
developed molecular cytogenetic technique, involving
hybridisation of a DNA probe to a metaphase chromosome
spread. Single stranded probe DNA is fluorescently labelled
using biotin and avidin and hybridised to the denatured DNA
of intact chromosomes on a microscope slide. The resultant
DNA binding can be seen directly using a fluorescence
microscope.
developed molecular cytogenetic technique, involving
hybridisation of a DNA probe to a metaphase chromosome
spread. Single stranded probe DNA is fluorescently labelled
using biotin and avidin and hybridised to the denatured DNA
of intact chromosomes on a microscope slide. The resultant
DNA binding can be seen directly using a fluorescence
microscope.
single DNA probe
Alternatively, a single DNA probe corresponding to a
specific locus can be used. Hybridisation reveals fluorescent
spots on each chromatid of the relative chromosome.
This method is used to detect the presence or absence of
specific DNA sequences and is useful in the diagnosis of
syndromes caused by sub-microscopic deletions, such as
William syndrome, or in identifying carriers of single gene
defects due to large deletions, such as Duchenne muscular
dystrophy.
specific locus can be used. Hybridisation reveals fluorescent
spots on each chromatid of the relative chromosome.
This method is used to detect the presence or absence of
specific DNA sequences and is useful in the diagnosis of
syndromes caused by sub-microscopic deletions, such as
William syndrome, or in identifying carriers of single gene
defects due to large deletions, such as Duchenne muscular
dystrophy.
Chromosomal abnormalities
Chromosomal abnormalities are particularly common in
spontaneous abortions. At least 20% of all conceptions are
estimated to be lost spontaneously, and about half of these are
associated with a chromosomal abnormality, mainly autosomal
trisomy. Cytogenetic studies of gametes have shown that 10% of
spermatozoa and 25% of mature oocytes are chromosomally
abnormal. Between 1 and 3% of all recognised conceptions are
triploid. The extra haploid set is usually due to fertilisation of a
single egg by two separate sperm. Very few triploid pregnancies
continue to term and postnatal survival is not possible unless
there is mosaicism with a normal cell line present as well. All
autosomal monosomies and most autosomal trisomies are also
lethal in early embryonic life. Trisomy 16, for example, is
frequently detected in spontaneous first trimester abortuses,
but never found in liveborn infants.
spontaneous abortions. At least 20% of all conceptions are
estimated to be lost spontaneously, and about half of these are
associated with a chromosomal abnormality, mainly autosomal
trisomy. Cytogenetic studies of gametes have shown that 10% of
spermatozoa and 25% of mature oocytes are chromosomally
abnormal. Between 1 and 3% of all recognised conceptions are
triploid. The extra haploid set is usually due to fertilisation of a
single egg by two separate sperm. Very few triploid pregnancies
continue to term and postnatal survival is not possible unless
there is mosaicism with a normal cell line present as well. All
autosomal monosomies and most autosomal trisomies are also
lethal in early embryonic life. Trisomy 16, for example, is
frequently detected in spontaneous first trimester abortuses,
but never found in liveborn infants.
chromosomal abnormalities
In liveborn infants chromosomal abnormalities occur in
about 9 per 1000 births. The incidence of unbalanced
abnormalities affecting autosomes and sex chromosomes is
about the same. The effect on the child depends on the type of
abnormality. Balanced rearrangements usually have no
phenotypic effect. Aneuploidy affecting the sex chromosomes is
fairly frequent and the effect much less severe than in
autosomal abnormalities. Unbalanced autosomal abnormalities
cause disorders with multiple congenital malformations, almost
invariably associated with mental retardation.
about 9 per 1000 births. The incidence of unbalanced
abnormalities affecting autosomes and sex chromosomes is
about the same. The effect on the child depends on the type of
abnormality. Balanced rearrangements usually have no
phenotypic effect. Aneuploidy affecting the sex chromosomes is
fairly frequent and the effect much less severe than in
autosomal abnormalities. Unbalanced autosomal abnormalities
cause disorders with multiple congenital malformations, almost
invariably associated with mental retardation.
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