Abstract Details

Title Exome Sequencing Reveals PMM2-CDG Gene Mutations in French-Canadian Siblings with Recessive Cerebellar Ataxia, Hand Tremor and Cognitive Impairment

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 041

Objective

Background BACKGROUND: A French-Canadian family of two affected and one unaffected siblings was evaluated in our neurogenetics clinic. The oldest brother had intentional and postural hand tremor while his youngest sister had mild ataxia, a similar hand tremor and global developmental delay. Their brain MRIs showed significant cerebellar atrophy.

Design/Methods DESIGN/METHODS: We followed standard manufacturer protocols to perform target capture with the Agilent SureSelect All Exon 50 MB (V3) exome enrichment kit and sequencing of 100 bp paired end reads on Illumina HiSeq 2000.For each sample, single nucleotide variants (SNVs) and short insertions and deletions (indels) were called using samtools mpileup with the extended base alignment quality (BAQ) adjustment (-E), and were then quality filtered to require at least 20% of reads supporting the variant call. Variants were annotated using both Annovar and custom scripts to identify whether they affected protein coding sequence, and whether they had previously been seen in dbSNP132, the 1000 genomes dataset (Nov. 2011), or in approximately 400 exomes previously sequenced at our center. All interesting variant were confirmed by traditional Sanger Sequencing in the five family members.

Results RESULTS: We identified two mutations known to cause a rare disorder called Jaeken syndrome. This syndrome is caused by mutations in the PMM2-CDG gene, leading to a deficiency of the phosphomannomutase (PMM) enzyme resulting in defective synthesis of N-linked oligosaccharides. In our family, the two affected siblings harbor compound heterozygote mutations: c.422G>A (p.R141H) and c.722G>C (p.C241S).

Conclusions CONCLUSIONS: Many patients with the phenotype of mild tremor associated with cerebellar atrophy might benefit from testing to search for PMM2-CDG mutations, while undiagnosed patients in neurogentic clinics may benefit from the availability of new technologies such as exome sequencing.

Authors/Disclosures
Philippe Beauchemin, MD PRESENTER	Dr. Beauchemin has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Dr. Beauchemin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche Canada. Dr. Beauchemin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Beauchemin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Canada. Dr. Beauchemin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pendopharm. Dr. Beauchemin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Beauchemin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche.
	No disclosure on file
Jeffrey A. Cohen, MD (Cleveland Clinic)	Dr. Cohen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Convelo. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astoria. Dr. Cohen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viatris. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PSI. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celltrion.
	No disclosure on file
Guy A. Rouleau, MD, PhD, FAAN (Montreal Neurological Institute and Hospital)	Dr. Rouleau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NovoNordisk. Dr. Rouleau has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for AL-S Pharma.
Nicolas Dupre, MD, FAAN (CHU de Quebec - U Laval)	Dr. Dupre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Akcea Therapeutics Canada. The institution of Dr. Dupre has received research support from ARSACS Foundation. The institution of Dr. Dupre has received research support from CHUdeQuebec Foundation.

��ɫ��

��ɫ��