Oral Presentation 9th GeneMappers Conference 2012

Examining X-linked CMT Families With Exome Sequence Analysis (#27)

Rabia Chaudhry 1 , Aditi Kidambi 1 , Carolyn Ly 1 , Alexander Drew 1 , Megan Brewer 2 , Anthony Antonellis 2 , Katherine Mathews 3 , Garth Nicholson 1 , Marina Kennerson 1
  1. ANZAC Research Institute, Concord, NSW, Australia
  2. Department of Neurology, University of Michigan, Ann Arbor, MI, USA
  3. Development and Behaviour, University of Iowa Children's Hospital, Iowa city, IA, USA
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.