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Indirect testing for genetic markers in a family that has a number of patients -
when there are a number of genes that can each cause the disease - all genes having
been located / identified / mapped - autosomal dominant diseases
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This is not a direct test, but a comparative one, which is called linkage analysis.
In genetic linkage studies, alleles of each of the genes being tested (an allele
is one member of the pair of genes at a given disease locus) are compared between
the patients and the healthy family members. The allele that is present only in
the patients but in none of the healthy family members - i.e. the -shared allele-
of these patients - is the one in which the mutation responsible for the disease
is located. If the -shared allele- is found, it will be possible to test other family
members without identifying the mutation itself, and prenatal testing by amniocentesis
or chorionic
villus sampling can be carried out. This is done by looking for the -shared
allele- in the DNA of the affected individuals
in the family.
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The problem here is that there is genetic heterogeneity, and the gene responsible
for the disease in the family being investigated must be identified out of the several
genes that can cause the disease.
This can be done by performing a separate comparative test for the locus of each
of the possible genes.
Only in the locus containing the gene responsible for the disease will there be
complete correlation between the genotype and the phenotype - in other words, the
-shared allele- will be found in all the patients, but in none of the healthy relatives.
In the other loci, complete genotype-phenotype correlation will not be found.
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The test requires comparison of a number of affected and healthy members of the
same family, where there is a minimum of 6 family members, not including partners,
of whom at least half, preferably more, are affected. This test is only reliable
if DNA from several affected individuals in the family is already available, or
if it can be obtained from a blood (or other) sample. In these cases it is possible
to carry out the test if there is DNA from at least two affected individuals. The
cooperation of the family members is required - they must be examined by a physician
in order to ascertain whether they have signs of the disease, and must agree to
give a blood sample. The more candidate genes there are, the more complex and difficult
it is to perform the test. Its reliability increases the larger the family is and
the more affected individuals there are, but this indirect method always has a risk
for errors of about 1% depending on the genetic counseling given.
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