How to assess the pathogenicity of mutations in CMT and other diseases

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J Appl Genet. 2006;47(3):255-60.

How to assess the pathogenicity of mutations in Charcot-Marie-Tooth

disease and other diseases?

Kochanski A.

Neuromuscular Unit, Mossakowski Medical Research Center, Pawinskiego

5, 02-106 Warszawa, Poland.

Knowledge whether a certain DNA variant is a pathogenic mutation or a

harmless polymorphism is a critical issue in medical genetics, in

which results of a molecular analysis may serve as a basis for

diagnosis and genetic counseling. Due to its genetic heterogeneity

expressed at the levels of loci, genes and mutations, Charcot-Marie-

Tooth (CMT) disease can serve as a model group of clinically

homogenous diseases for studying the pathogenicity of mutations.

Close to a 17p11.2-p12 duplication occurring in 70% of patients with

the demyelinating form of CMT disease, numerous mutations have been

identified in poorly characterized genes coding for proteins of an

unknown function. Functional analyses, segregation analyses of large

pedigrees, and inclusion of large control groups are required to

assess the potential pathogenicity of CMT mutations. Hence, the

pathogenicity of numerous CMT mutations remains unclear.

Some variants detected in the CMT genes and originally described as

pathogenic mutations have been shown to have a polymorphic character.

In contrast, polymorphisms initially considered harmless were later

reclassified as pathogenic mutations. However, the process of

assessing the pathogenicity of mutations, as presented in this study

for CMT disorders, is a more general issue concerning all disorders

with a genetic background.

Since the number of DNA variants is still growing, in the near future

geneticists will increasingly have to cope with the problem of

pathogenicity of identified genetic variants.