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 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.
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
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, where there is a minimum of 5 family members, not including parents,
of which 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. 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
Carrier status of family members can also be determined, including of distant family
members, provided that all the people related to the patient give blood samples.
However, this method cannot establish the carrier status of their partners.