Oral Presentation 9th GeneMappers Conference 2012

Exome Sequencing: Diagnosis and Gene Discovery in a Cohort of Charcot-Marie-Tooth Neuropathy Families (#6)

Marina L Kennerson 1 , Carolyn Ly 1 , Aditi Kidambi 1 , Alexander P Drew 1 , Rabia Chaudhry 1 , Danqing Zhu 2 , Garth A Nicholson 1
  1. ANZAC Research Institute, Concord, NSW, Australia
  2. Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia

Inherited peripheral neuropathies represent one of the most common groups of neuromuscular disorders. Charcot-Marie-Tooth (CMT) neuropathy involves both the motor and sensory neurons and affects 1 in 2500 of the population.1  CMT is a clinically and genetically heterogeneous disorder in which all Mendelian types of inheritance have been reported. Clinically, patients present with distal muscle wasting and weakness with pes cavus or foot drop.  Sensory symptoms may include numbness, pins and needles, loss of balance and insensitivity to temperature and pain. Traditionally, the clinical distinction between demyelinating (CMT1), axonal (CMT2) and intermediate (int-CMT) types has been possible through electrophysiology criteria. However, with the involvement of more than 40 genes known to cause CMT, the selection of genes for mutation analysis is challenging. In addition, whilst many genes have been identified, there are still approximately 10% of CMT1 and 70% of CMT2 genes to be discovered. In this study we have performed exome sequence analysis on a single affected patient from 114 unrelated dominant CMT families. This approach is feasible for CMT as in 85% of Mendelian disorders mutations reside in exons.2 3   Exome sequencing has provided an affordable tool to simultaneously screen for mutations in known CMT genes as well as identifying novel genes in families too small for traditional positional cloning approaches. We have identified variants in known genes for 26 families. Eight are reported mutations and the remainder are being validated. We have subsequently selected families negative for known genes for exome analysis of additional family members to identify new CMT genes. Using this approach we have identified variants in two highly likely candidate genes. With over 800 index peripheral neuropathy families in our database this strategy is proving to be a fruitful approach for both the diagnostic setting and gene discovery.

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  2. Ng SB et al. Targeted capture and massively parallel sequencing of 12 human exomes Nature 2009 461: 272-276
  3. Ku CS, Naidoo N and Pawitan Y. Revisiting mendelian disorders through exome sequencing. Hum Genet 2011 129: 351-370