Open Access Highly Accessed Research article

Segregation analysis in families with Charcot-Marie-Tooth disease allows reclassification of putative disease causing mutations

Rune Østern12*, Toril Fagerheim1, Helene Hjellnes1, Bjørn Nygård1, Svein Ivar Mellgren23 and Øivind Nilssen12

Author Affiliations

1 Department of Medical Genetics, University Hospital of North-Norway, NO9038 Tromsø, Norway

2 Department of Clinical Medicine, Neuromuscular Research Group, University of Tromsø, NO9037 Tromsø, Norway

3 Department of Neurology, University Hospital of North-Norway, NO9038 Tromsø, Norway

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BMC Medical Genetics 2014, 15:12  doi:10.1186/1471-2350-15-12

Published: 21 January 2014



The identification of disease causing, or putative disease causing, mutations in index patients with Charcot-Marie-Tooth disease (CMT) allows for genetic testing of family members. Relevant variants identified in index patients are of either definite, likely or uncertain pathogenicity. The main objective of this study was to make an evaluation of the family investigations performed as part of the assessment of genetic variants of unknown clinical significance (VUS).


Between 2004 and 2010 molecular genetic family investigations were requested for 87 family members from 41 families harbouring PMP22dup or genetic variants in GJB1, MPZ, MFN2 and NEFL. Relatives were tested for the family mutation and data from the requisitions were evaluated by means of statistical tools.


The results within each indication category are presented and discussed in detail. Twenty-two relatives (9 affected) from eight families were included in the segregation analyses, which invoked reclassification of three MFN2 mutations, two of which were de novo substitutions (c.2146_2148dup, c.692C > T). One MFN2 substitution was downgraded due to non-segregation (c.1709 A > G), and a MPZ substitution (c.103 G > A) upgraded due to segregation with the phenotype in the family.


The results allow for the evaluation of the patient phenotypes ascertained in families, as opposed to the phenotypic descriptions of index patients. They indicate that de novo MFN2 mutations are regularly found in patients with a classical CMT2 phenotype. They also demonstrate the importance of a precise clinical and neurophysiologic diagnosis of affected family members. This particularly applies for the examination of variants of uncertain clinical significance. Finally, the fact that 14,6% of affected relatives tested for (probable or certain) pathogenic mutations were mutation negative, demonstrates that clinical evaluation alone is not always sufficient in order to determine their diagnosis. We believe that the results will aid in the estimation and planning of resources required for the various aspects of family evaluations in CMT.

Charcot-Marie-Tooth; Genetic and inherited disorders; Neuromuscular diseases; Mutation analysis; Family investigations