Exome Sequencing Identifies a New Locus for DI-CMT (P05.143)

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Objective: To utilize exome sequencing to identify the genetic cause of CMT in a family with no mutation in previously identified CMT genes. Background Family WSU-75549 has nine living family members with an unidentified form of CMT with intermediate nerve conduction velocities (NCV). There are multiple cases of male-to-male transmission. Previous genetic testing for multiple genes including those known to cause Dominant Intermediate CMT (DI-CMT) have been negative as has been chromosome analysis. Whole exome sequencing is capable of re-sequencing the near complete set of coding exons of an individual. Design/Methods: DNA from all nine affected individuals and one unaffected sibling control was collected. Affected members were evaluated clinically and by electrophysiology. Exome sequencing was performed on three samples. Other family members were then tested for identified mutations. Results: The family phenotype was variable with CMTNS ranging from 8 (mild) in one patient aged 28 years to 32 (severe) in a 50 year old. Progression appears to quicken in this family during the fourth and fifth decades. Median NCV in upper extremities ranged between 29.2 m/s and 39.8 m/s. Exome sequencing did not identify mutations for any known CMT gene. However, utilizing rare variants identified by exome sequencing a novel locus was found for the family at 1p12. The two-point LOD score was 3.27 at a SNV marker in the gene WARS2. Genome-wide comparative genomic hybridization analysis did not reveal any copy number variations in the vicinity of 1p12. Further studies are ongoing to determine the nature of the familial CMT mutation. Conclusions: This is a large family with a previously unidentified form of DI-CMT. Data derived from exome sequencing enabled us to identify a novel chromosomal CMT locus at 1p12. A detailed genetic follow-up studies are under way to identify the causative mutation. Supported by: NINDS, ORD, MDA. Disclosure: Dr. Siskind has nothing to disclose. Dr. Speziani has nothing to disclose. Dr. Gonzalez has nothing to disclose. Dr. Blanton has nothing to disclose. Dr. Shy has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics.