back to the list

Linkage

Clinical Features

Linkage analysis (indirect DNA analysis) is often used when direct DNA analysis is not possible because the gene of interest is unknown or a mutation within that gene cannot be detected in a specific family. Some clinical applications:

1. Clinical diagnosis and localization of the respective gene are evident. Depending on the mode of inheritance and pedigree situation, linkage analysis may even be possible if there is only one affected individual in the family.

• Direct mutation screening did not reveal the disease-causing mutation in the index patient. Example: Parents have a child with DMD. Direct mutation analysis revealed no mutation. In a future pregnancy, prenatal testing is possible by linkage analysis.
• The gene of interest has not yet been cloned or mutation analysis is too costly. Example: following the birth of a child with autosomal recessive inherited polycystic kidney disease prenatal diagnostics in the next pregnancy may be carried out by linkage analysis.

2. Gene and chromosomal localization are unknown, but several family members are affected by the identical disease. Example: Families with several members affected by X-linked mental retardation. By comparing the X-chromosomal regions of family members whose genetic status is known (e.g., affected, unaffected), chromosomal regions shared by all affected individuals may be identified. Subsequent direct analysis of a gene located within the shared region may reveal the underlying disease-causing mutation.

In contrast to direct molecular genetic diagnostics, linkage analysis will always only yield a probability statement due to possible meiotic crossing over. Depending on the available markers and in particular when using intragenic markers this method is highly reliable.

Diagnostic