When a genetic test is requested to confirm a clinical diagnosis
in a child or adult, specialist genetic counselling may not be
requested until after the test result. It is therefore the
responsibility of the clinician offering the test to inform the
patient (or the parents, if a child is being tested) before the test
is undertaken, that the results may have genetic as well as
clinical implications. Confirming the diagnosis of a genetic
disorder in a child, for example, may indicate that younger
siblings are also at risk of developing the disorder. For late
onset conditions such as Huntington disease, it is crucial that
samples sent for diagnostic testing are from patients already
symptomatic, as there are stringent counselling protocols for
presymptomatic testing
Saturday, April 11, 2009
Presymptomatic testing
Genetic testing in some late onset autosomal dominant
disorders can be used to predict the future health of a well
individual, sometimes many decades in advance of onset of
symptoms. For some conditions, such as Huntington disease,
having this knowledge does not currently alter medical
management or prognosis, whereas for others, such as familial
breast cancer, there are preventative options available. For adult
onset disorders, testing is usually offered to individuals above
the age of 18. For conditions where symptoms or preventative
options occur in late childhood, such as familial adenomatous
polyposis, children are involved in the testing decision.
Presymptomatic testing is most commonly done for individuals
at 50% risk of an autosomal dominant condition. Testing
someone at 25% is avoided wherever possible, as this could
disclose the status of the parent at 50% risk who may not want
to have this information. There are clear guidelines for
provision of genetic counselling for presymptomatic testing,
which include full discussion of the potential drawbacks of
testing (psychological, impact on the family and financial), with
ample opportunity for an individual to withdraw from testing
right up until disclosure of results, and a clear plan for follow up.
disorders can be used to predict the future health of a well
individual, sometimes many decades in advance of onset of
symptoms. For some conditions, such as Huntington disease,
having this knowledge does not currently alter medical
management or prognosis, whereas for others, such as familial
breast cancer, there are preventative options available. For adult
onset disorders, testing is usually offered to individuals above
the age of 18. For conditions where symptoms or preventative
options occur in late childhood, such as familial adenomatous
polyposis, children are involved in the testing decision.
Presymptomatic testing is most commonly done for individuals
at 50% risk of an autosomal dominant condition. Testing
someone at 25% is avoided wherever possible, as this could
disclose the status of the parent at 50% risk who may not want
to have this information. There are clear guidelines for
provision of genetic counselling for presymptomatic testing,
which include full discussion of the potential drawbacks of
testing (psychological, impact on the family and financial), with
ample opportunity for an individual to withdraw from testing
right up until disclosure of results, and a clear plan for follow up.
Carrier testing
Testing an individual to establish his or her carrier state for an
autosomal or X linked recessive condition or chromosomal
rearrangement, will usually be for future reproductive, rather
than health, implications. Confirmation of carrier state may
indicate a substantial risk of reproductive loss or of having an
affected child. Genetic counselling before testing ensures that
the individual is informed of the potential consequences of
carrier testing including the option of prenatal diagnosis. In
the presence of a family history, carrier testing is usually
offered in the mid-teens when young people can decide
whether they want to know their carrier status. For autosomal
recessive conditions such as cystic fibrosis, some people may
wish to wait until they have a partner so that testing can be
done together, as there will be reproductive consequences only
if both are found to be carriers.
autosomal or X linked recessive condition or chromosomal
rearrangement, will usually be for future reproductive, rather
than health, implications. Confirmation of carrier state may
indicate a substantial risk of reproductive loss or of having an
affected child. Genetic counselling before testing ensures that
the individual is informed of the potential consequences of
carrier testing including the option of prenatal diagnosis. In
the presence of a family history, carrier testing is usually
offered in the mid-teens when young people can decide
whether they want to know their carrier status. For autosomal
recessive conditions such as cystic fibrosis, some people may
wish to wait until they have a partner so that testing can be
done together, as there will be reproductive consequences only
if both are found to be carriers.
Prenatal testing
The availability of prenatal genetic testing has enabled many
couples at high genetic risk to embark upon pregnancies that
they would otherwise have not undertaken. However, prenatal
testing, and the associated option of termination of pregnancy,
can have important psychological sequelae for pregnant women
and their partners. In the presence of a known family history,
genetic counselling is ideally offered in advance of pregnancy
so that couples have time to make a considered choice. This
also enables the laboratory to complete any family testing
necessary before a prenatal test can be undertaken.
Counselling should be provided within the antenatal setting
when prenatal genetic tests are offered to couples without a
previous family history, such as amniocentesis testing after a
raised Down syndrome biochemical screening result. To help
couples make an informed choice, information should be
presented about the condition, the chance of it occurring, the
test procedure and associated risks, the accuracy of the test,
and the potential outcomes of testing including the option of
termination of pregnancy. Couples at high genetic risk often
require ongoing counselling and support during pregnancy.
Psychologically, many couples cope with the uncertainty by
remaining tentative about the pregnancy until receiving the test
result. If the outcome of testing leads to termination of a
wanted pregnancy, follow-up support should be offered. Even if
favourable results are given, couples may still have some anxiety
until the baby is born and clinical examination in the newborn
period gives reassurance about normality. Occasionally,
confirmatory investigations may be indicated.
couples at high genetic risk to embark upon pregnancies that
they would otherwise have not undertaken. However, prenatal
testing, and the associated option of termination of pregnancy,
can have important psychological sequelae for pregnant women
and their partners. In the presence of a known family history,
genetic counselling is ideally offered in advance of pregnancy
so that couples have time to make a considered choice. This
also enables the laboratory to complete any family testing
necessary before a prenatal test can be undertaken.
Counselling should be provided within the antenatal setting
when prenatal genetic tests are offered to couples without a
previous family history, such as amniocentesis testing after a
raised Down syndrome biochemical screening result. To help
couples make an informed choice, information should be
presented about the condition, the chance of it occurring, the
test procedure and associated risks, the accuracy of the test,
and the potential outcomes of testing including the option of
termination of pregnancy. Couples at high genetic risk often
require ongoing counselling and support during pregnancy.
Psychologically, many couples cope with the uncertainty by
remaining tentative about the pregnancy until receiving the test
result. If the outcome of testing leads to termination of a
wanted pregnancy, follow-up support should be offered. Even if
favourable results are given, couples may still have some anxiety
until the baby is born and clinical examination in the newborn
period gives reassurance about normality. Occasionally,
confirmatory investigations may be indicated.
Common chromosomal disorders
Abnormalities of the autosomal chromosomes generally cause
multiple congenital malformations and mental retardation.
Children with more than one physical abnormality and
developmental delay or learning disability should therefore
undergo chromosomal analysis as part of their investigation.
Chromosomal disorders are incurable but most can be reliably
detected by prenatal diagnostic techniques. Amniocentesis or
chorionic villus sampling should be offered to women whose
pregnancies are at increased risk – namely, couples in whom
one partner carries a balanced translocation, women identified
by biochemical screening for Down syndrome and couples who
already have an affected child. Unfortunately, when there is no
history of previous abnormality the risk in many affected
pregnancies cannot be predicted before the child is born.
multiple congenital malformations and mental retardation.
Children with more than one physical abnormality and
developmental delay or learning disability should therefore
undergo chromosomal analysis as part of their investigation.
Chromosomal disorders are incurable but most can be reliably
detected by prenatal diagnostic techniques. Amniocentesis or
chorionic villus sampling should be offered to women whose
pregnancies are at increased risk – namely, couples in whom
one partner carries a balanced translocation, women identified
by biochemical screening for Down syndrome and couples who
already have an affected child. Unfortunately, when there is no
history of previous abnormality the risk in many affected
pregnancies cannot be predicted before the child is born.
Translocation Down syndrome
About 5% of cases of Down syndrome are due to translocation,
in which chromosome 21 is translocated onto chromosome 14
or, occasionally, chromosome 22. In less than half of these cases
one of the parents has a balanced version of the same
translocation. A healthy adult with a balanced translocation
has 45 chromosomes, and the affected child has 46
chromosomes, the extra chromosome 21 being present
in the translocation form. The risk of Down syndrome in
offspring is about 10% when the balanced translocation is
carried by the mother and 2.5% when carried by the father. If
neither parent has a balanced translocation, the chromosomal
abnormality in an affected child represents a spontaneous,
newly arising event, and the risk of recurrence is low (1%).
Recurrence due to parental gonadal mosaicism cannot be
completely excluded.
in which chromosome 21 is translocated onto chromosome 14
or, occasionally, chromosome 22. In less than half of these cases
one of the parents has a balanced version of the same
translocation. A healthy adult with a balanced translocation
has 45 chromosomes, and the affected child has 46
chromosomes, the extra chromosome 21 being present
in the translocation form. The risk of Down syndrome in
offspring is about 10% when the balanced translocation is
carried by the mother and 2.5% when carried by the father. If
neither parent has a balanced translocation, the chromosomal
abnormality in an affected child represents a spontaneous,
newly arising event, and the risk of recurrence is low (1%).
Recurrence due to parental gonadal mosaicism cannot be
completely excluded.
Other autosomal trisomies
Trisomy 18 (Edwards syndrome)
Trisomy 18 has an overall incidence of around 1 in 6000 live
births. As with Down syndrome most cases are due to
nondisjunction and the incidence increases with maternal age.
The majority of trisomy 18 conceptions are lost spontaneously
with only about 2.5% surviving to term. Many cases are now
detectable by prenatal ultasound scanning because of a
combination of intrauterine growth retardation,
oligohydramnios or polyhydramnios and major malformations
that indicate the need for amniocentesis. About one third of
cases detected during the second trimester might survive to
term. The main features of trisomy 18 include growth
deficiency, characteristic facial appearance, clenched hands
with overlapping digits, rocker bottom feet, cardiac defects,
renal abnormalities, exomphalos, myelomeningocele,
oesophageal atresia and radial defects. Ninety percent of
affected infants die before the age of 6 months but 5% survive
beyond the first year of life. All survivors have severe mental
and physical disability. The risk of recurrence for any trisomy is
probably about 1% above the population age-related risk.
Recurrence risk is higher in cases due to a translocation where
one of the parents is a carrier.
Trisomy 18 has an overall incidence of around 1 in 6000 live
births. As with Down syndrome most cases are due to
nondisjunction and the incidence increases with maternal age.
The majority of trisomy 18 conceptions are lost spontaneously
with only about 2.5% surviving to term. Many cases are now
detectable by prenatal ultasound scanning because of a
combination of intrauterine growth retardation,
oligohydramnios or polyhydramnios and major malformations
that indicate the need for amniocentesis. About one third of
cases detected during the second trimester might survive to
term. The main features of trisomy 18 include growth
deficiency, characteristic facial appearance, clenched hands
with overlapping digits, rocker bottom feet, cardiac defects,
renal abnormalities, exomphalos, myelomeningocele,
oesophageal atresia and radial defects. Ninety percent of
affected infants die before the age of 6 months but 5% survive
beyond the first year of life. All survivors have severe mental
and physical disability. The risk of recurrence for any trisomy is
probably about 1% above the population age-related risk.
Recurrence risk is higher in cases due to a translocation where
one of the parents is a carrier.
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