Abstract Details

Title Whole Exome Sequencing as a Diagnostic Tool for Charcot-Marie-Tooth Disease

Topic Peripheral Nerve

Presentation(s) (-)

Poster/Presentation
Number 002

Objective

Background Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous disorder with variable inheritance modes. Particularly, CMT is a model disease to apply the exome sequencing, since more than 50 genes are involved its development with weak genotype-phenotype correlation.

Design/Methods For each patient, the whole exome was captured from the genomic DNA using the Human Whole exome SeqCap EZ, v2.0 (Roche-NimbleGen, Madison, WI), and next was performed using the Solexa GAIIx Genome Analyzer (Illumina, San Diego, CA).

Results We identified 69 causative heterozygous mutations of 71 families from total 162 unrelated families (43.8%). The detection rate seems rather high, since each sample was tested before the study for major genetic causes. Total yields of WES were 7.4 Gbp, and the mean coverage rate of targeted exon regions (?10X) was higher than 93.4%. The average number of observed variants per sample was 59,924 SNPs, and the mean number of nonsynonymous SNPs was 9,153. Among identified 69 causative mutations, the number of novel mutation was 42 (60.9%). When classifying these causative mutations, missense mutations were most frequent (84.1%). From 71 families causative mutations were detected, total 12 families were revealed to be de novo mutations (16.9%). Furthermore, through the exome sequencing, total 27 causative genes of each family were identified. Among this identified genes, 15 genes (55.6%) were first reported in Korean population.

Conclusions Whole exome analysis of the 248 CMT patients from 162 unrelated families revealed 69 causative mutations of 71 families (43.8%). This rate of detecting causative mutations seems rather high. We suggest that WES can be a highly exact, rapid and economic molecular diagnostic tool for CMT patients.

Authors/Disclosures
Sung-Hee Kim, MD PRESENTER	Dr. Kim has nothing to disclose.
	No disclosure on file
Jae Won Hyun, MD	No disclosure on file
Ye Ji Choi, MD	No disclosure on file
Hyeon Jin Kim, MD (Ewha Women's University, Neurology)	No disclosure on file
	No disclosure on file
Joshua Z. Willey, MD (Columbia University)	Dr. Willey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Edwards Scientific. Dr. Willey has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for RECARDIO. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbott. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BrainQ. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of the American College of Cardiology. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Uptodate. The institution of Dr. Willey has received research support from NIH. Dr. Willey has received personal compensation in the range of $500-$4,999 for serving as a Review chapter author, MKSAP 16-20 with American College of Physicians.
	No disclosure on file
Byung-Ok Choi, MD, PhD (Ewha Womans University)	No disclosure on file

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