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 - X-linked diseases
This is not a direct test, but a comparative one, which is called linkage analysis.
The alleles (an allele is one member of the pair of genes at a given disease locus)
that have been transmitted by the parents to the affected child are compared in
order to establish which of the mother-s two X chromosomes the affected child has
inherited. If the mother is a carrier of an X-linked disease, she has a normal gene
on one of her X chromosomes and an abnormal gene on the other. Such a woman has
a 50% chance in every pregnancy of transmitting the abnormal gene to her offspring.
This means that 50% of her sons will be affected and 50% healthy, and 50% of her
daughters will be carriers and 50% will not.
In genetic linkage studies, alleles of each of the genes being tested 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
This is done by looking for the -shared allele- in the
DNA of the affected individuals in the family.
It is also possible to establish which women in the family are carriers. There are
- 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, two copies of the -shared allele- will be found in all
the patients, but in none of the healthy relatives. Among the healthy female relatives,
some will have one copy, in which case she is a carrier. In the other loci, complete
genotype-phenotype correlation will not be found.
So without identifying the mutation itself, the patient-s siblings can be tested,
and prenatal testing by amniocentesis or chorionic villus sampling can be carried
out, by looking for the -shared allele- in the DNA of the affected individual in
the family. It is also possible to establish which of the women in the family are
carriers. The problem is that if there is only one affected child, the mother is
not necessarily a carrier - this has to be established in genetic counseling. If there are a number of
patients, especially from different generations, it can be assumed with certainty
that there are a number of carriers, in which case the test for carrier status is
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.
- As there are a number of patients, it can be assumed with certainty that there are
a number of carriers, especially when the patients are from different generations.
Not every woman in the family who carries the allele that has been defined as -shared
by the patients- is necessarily a carrier, because in diseases with an X-linked inheritance pattern there is sometimes
a new mutation. It is therefore important to establish in genetic counseling which
women are potential carriers if the allele shared by the patients is found in them.
For some of these diseases, carrier status can be determined by a biochemical or
other test that may reveal mildly affected females. A female carrier can use this
indirect test for reliable prenatal diagnosis in each pregnancy.