title: Linkage analysis and exome sequencing identify a novel mutation in KCTD7 in patients with progressive myoclonus epilepsy with ataxia.
abstract: Epilepsy affects approximately 1% of the world's population. Genetic factors and acquired etiologies, as well as a range of environmental triggers, together contribute to epileptogenesis. We have identified a family with three daughters affected with progressive myoclonus epilepsy with ataxia. Clinical details of the onset and progression of the neurologic presentation, epileptic seizures, and the natural history of progression over a 10-year period are described. Using autozygosity genetic mapping, we identified a high likelihood homozygous region on chromosome 7p12.1-7q11.22. We subsequently applied whole-exome sequencing and employed a rare variant prioritization analysis within the homozygous region. We identified p.Tyr276Cys in the potassium channel tetramerization domain-containing seven gene, KCTD7, which is expressed predominantly in the brain. Mutations in this gene have been implicated previously in epileptic phenotypes due to disturbances in potassium channel conductance. Pathogenicity of the mutation was supported by bioinformatic predictive analyses and variant cosegregation within the family. Further biologic validation is necessary to fully characterize the pathogenic mechanisms that explain the phenotypic causes of epilepsy with ataxia in these patients.
authors: Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors: Sali M K
authors: SM
authors: Farhan
authors: Lisa M
authors: LM
authors: Murphy
authors: John F
authors: JF
authors: Robinson
authors: Jian
authors: J
authors: Wang
authors: Victoria M
authors: VM
authors: Siu
authors: C Anthony
authors: CA
authors: Rupar
authors: Asuri N
authors: AN
authors: Prasad
authors: Robert A
authors: RA
authors: Hegele
mesh_terms: D000293:Adolescent; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D002675:Child, Preschool; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D004569:Electroencephalography; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D020191:Myoclonic Epilepsies, Progressive / Q000150:complications / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics
chemical_list: C522280:KCTD7 protein, human; D015221:Potassium Channels; D014443:Tyrosine; D003545:Cysteine
keywords: Epilepsy; KCTD7; Whole-exome sequencing