Charcot-Marie-Tooth
disease (CMT) is a genetically and clinically heterogeneous disorder affecting the
motor and sensory neurons. X-linked CMT (CMTX) accounts for 15-20% of all cases
making it the second most commonly inherited CMT [
1-4]. There are 5 reported loci (CMTX1, CMTX2,
CMTX3, CMTX4 and CMTX5). Two genes,
connexin
32 and
PRPS1, are known to cause CMTX1
and CMTX5 respectively [
5,
6]. In this
study 2 families classified as CMTX were examined. The first family (US-PED2)
was one of the original families reporting the CMTX3 locus on Xq26.3-q27.3 [
7]. The second family (CMT346) was classified as
probable CMTX based on the absence of male to male inheritance. Both families
were small nuclear kinships not powerful enough to show independent significant
linkage to known CMTX loci. The aim of this study was to use exome sequencing
analysis in these families to identify candidate variants on both the X
chromosome as well as other regions of the genome. We have shown the exome data for US-PED2 and
CMT346 did not identify candidate variants at either the CMTX3 locus or other
regions of the X-chromosome. Examination of the other regions in the genome identified
variants on the autosomes for both families. A reported mutation (N885) was
identified in a distal hereditary motor neuron gene (
BSCL2) for US-PED2 [
8]. Analysis of CMT346 identified a candidate
variant in a gene expressed in peripheral nerve (
NAB1),
this variant
showed to segregate with the phenotype [
9]. This study demonstrates the power of exome
sequencing as a tool to identify gene mutations for small families in the
absence of statistically significant linkage data.