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Linkage

Clinical Features

Linkage analysis (indirect DNA analysis) is often used when direct DNA analysis is not possible because, for example, 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, linkage analysis may be possible even when there is only one affected individual in the family.

• Direct mutation screening does not reveal a 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 performed 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 X-chromosome regions of family members whose genetic status is known (e.g., affected, unaffected), chromosome 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 when specifically using intragenic markers, this method is highly reliable.

Diagnostic