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 - not all genes
having been located / identified / mapped - autosomal recessive 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. The
parents are both carriers (i.e. each parent carries one normal and one abnormal
gene), and there is a 25% risk in every subsequent pregnancy that both will transmit
the abnormal allele to their offspring, in which case the fetus will be affected
because he has received two copies of the abnormal gene.
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
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.
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.
Because not all of the genes have been identified, the test cannot be completed
- it takes a long time and will not be completely reliable.
However, in very large families with a large number of affected individuals (at
least 7), an attempt can be made.
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 relatives, some will have one copy, in
which case he or she is a carrier. In the other loci, complete genotype-phenotype
correlation will not be found.
The test requires comparison of a number of affected and healthy members of the
same family. The 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. 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. Sometimes
the test is pure research. The more candidate genes there are, the more complex
and difficult it is to perform the test. If none of the known genes is responsible
for the disease in the family being investigated, a different gene must be sought.
If the gene responsible for the disease in the family is found, it will also be
possible to determine the carrier status of family members, including of distant
family members, provided that all people related to the patient give blood samples.
However, this method cannot establish the carrier status of their partners.