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- W1506086506 abstract "OBJECTIVE/ BACKGROUND: Progressive myoclonus epilepsy (PME) afflicts mainly teenagers. PME in young children and adults is mostly caused by neuronal ceroid lipofuscinosis (NCL). Using a whole-exome sequencing (WES) approach, we find that NCL is also a cause of teenage-onset PME. DESIGN/METHODS: A 24 year-old Pashtun Afghani man presented with myoclonus at age 15 years. Seizures and cognitive decline appeared later. Two cousins had the same disease and age of onset. Both died around age 30 with severe dementia. Investigations showed cortical myoclonus, multifocal epileptiform discharges, and generalized brain atrophy. Testing for known causes of teenage-onset PMEs were negative. Homozygosity mapping and WES, were performed to identify the disease gene. RESULTS: 600,000 SNPs were genotyped in the proband and one affected cousin. Homozygosity mapping revealed two shared regions of homozygosity. WES yielded 41,597 genetic variants of which only two were exonic, novel, nonsynonymous, and located within one of the shared homozygous regions. One variant was expressed in testis. The other variant was a homozygous sequence change in the CLN6 gene. This variant segregates with the disease in the pedigree. Sequencing for it in 268 control individuals, including 176 Pashtun, revealed it in one Pashtun, in heterozygote state. CONCLUSIONS: The patients in our study closely resemble Kufs disease generally, and the teenage-onset cases of Arsov et al. in particular. Combining this with our findings that the CLN6 sequence change we identified affects a highly conserved amino acid, is the only homozygous exomic alteration in a brain-expressed gene in a shared region of homozygosity, and is not present in homozygous state in vast control sequence datasets and 176 ethnic matches, confirms that CLN6 c.768C>G (D256E) is the mutation in our family. Combined WES and homozygosity mapping in two patients from one family without a priori hypothesis led directly to the causative defect. Disclosure: Dr. Andrade has nothing to disclose. Dr. Paton has nothing to disclose. Dr. Turnbull has nothing to disclose. Dr. Klein has received personal compensation for activities with Link Medicine, and Centogene. Dr. Marshall has nothing to disclose. Dr. Scherer has nothing to disclose. Dr. Minassian has nothing to disclose." @default.
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- W1506086506 date "2014-04-08" @default.
- W1506086506 modified "2023-09-23" @default.
- W1506086506 title "CLN6 Mutations Cause Teenage-Onset Progressive Myoclonus Epilepsy (P2.183)" @default.
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