Abstract Details

Title A Combination of Linkage Analysis and Exome Sequencing Identifies a New Gene for X-linked Charcot-Marie-Tooth Neuropathy

Topic Peripheral Nerve

Presentation(s) S26 - (-)

Poster/Presentation
Number 007

Objective

Background X-linked Charcot-Marie-Tooth disease (CMTX) accounts for 10-15% of all CMT. Five genetic subtypes of CMTX have been identified to date. Two genes have been identified including GJB1/Cx32 (CMTX1) and PRPS1 (CMTX5).

Design/Methods Detailed clinical and neurophysiologic information was collected on family members. Mutations in the Cx32 gene were excluded for pathogenic mutations (coding, UTR and promoter). Traditional linkage analysis was combined with whole exome sequencing of family members.

Results Five affected males and eight carrier females were clinically characterized. Affected males were more severely affected than females, and presented in the first 13 years of life with foot deformity and gait abnormalities. Distal upper and lower limb wasting and weakness, foot deformity and absent ankle jerks were present. Carrier females were either mildly affected, or asymptomatic with subtle clinical and/or neurophysiologic findings. Neurophysiologic findings indicated an axonal motor and sensory neuropathy. Linkage analysis established a new locus for X-linked CMT to a 1.4-Mb interval on Xp22.11. Whole exome sequencing and bioinformatic analysis identified a non-synonymous exonic variant that maps within the established linkage region. The variant fully segregates with the affected phenotype and has been excluded in 1200 ethnically matched control chromosomes. The variant occurs in a highly conserved amino acid residue of the protein and is predicted to be pathogenic. Genetic validation and functional studies supporting pathogenicity of the variant will be presented.

Conclusions A novel locus and exonic variant has been identified in a large X-linked axonal CMT pedigree and the combination of linkage analysis and exome sequencing has expedited this process.

Authors/Disclosures
Marina Kennerson (ANZAC Research Institute) PRESENTER	Marina Kennerson has nothing to disclose.
Eppie Yiu, MD (Royal Children'S Hospital Melbourne)	The institution of Dr. Yiu has received research support from Biogen. The institution of Dr. Yiu has received research support from Roche . The institution of Dr. Yiu has received research support from PTC. The institution of Dr. Yiu has received research support from Pfizer .
	No disclosure on file
	No disclosure on file
Wengui Yu, MD, PhD (UC Irvine, Neurology Dept)	Dr. Yu has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
Monique M. Ryan, MD (Childrens Hospital)	Dr. Ryan has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen . Dr. Ryan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CSL Behring . Dr. Ryan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Ryan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen . The institution of Dr. Ryan has received research support from Save our Sons Muscular Dystrophy . The institution of Dr. Ryan has received research support from Muscular Dystrophy Australia. Dr. Ryan has received publishing royalties from a publication relating to health care.
Garth Nicholson, PhD (Concord Hospital 2139)	No disclosure on file

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