Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy.
DNA methylation is an essential epigenetic mark, controlled by DNA methyltransferase (DNMT) proteins, which regulates chromatin structure and gene expression throughout the genome. In this study, we describe a family with adult-onset autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) caused by mutations in the maintenance methyltransferase DNMT1 and assess the DNA methylation profile of these individuals.



We report a family with six individuals affected with ADCA-DN; specifically, patients first developed hearing loss and ataxia, followed by narcolepsy, and cognitive decline. We identified a heterozygous DNMT1 variant, c.1709C>T [p.Ala570Val] by Sanger sequencing, which had been previously reported as pathogenic for ADCA-DN and segregated with disease in the family. DNA methylation analysis by high-resolution genome-wide DNA methylation array identified a decrease in CpGs with 0-10 % methylation and 80-95 % methylation and a concomitant increase in sites with 10-30 % methylation and >95 % methylation. This pattern suggests an increase in methylation of normally unmethylated regions, such as promoters and CpG islands, as well as further methylation of highly methylated gene bodies and intergenic regions. Furthermore, a regional analysis identified 82 hypermethylated loci with consistent robust differences across ≥5 consecutive probes compared to our large reference cohort.



This report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis.
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1 Canada.
Kristin D
KD
Kernohan
Department of Pathology and Lab Medicine, Western University, London, Ontario Canada.
Laila
L
Cigana Schenkel
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1 Canada.
Lijia
L
Huang
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1 Canada.
Amanda
A
Smith
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.|Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.
Guillaume
G
Pare
Department of Pathology and Lab Medicine, Western University, London, Ontario Canada.|Department of Biochemistry, Western University, London, ON Canada.|Children's Health Research Institute, London, ON Canada.
Peter
P
Ainsworth
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1 Canada.
Kym M
KM
Boycott
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1 Canada.|Division of Neurology, The Ottawa Hospital, Ottawa, Ontario Canada.|Ottawa Hospital Research Institute, Ottawa, Ontario Canada.
Jodi
J
Warman-Chardon
Department of Pathology and Lab Medicine, Western University, London, Ontario Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON Canada.|Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada.|Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Centre, 800 Commissioner's Road E, London, ON N6A 5W9 Canada.
Bekim
B
Sadikovic
D019943:Amino Acid Substitution; D002524:Cerebellar Ataxia / Q000235:genetics*; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D009290:Narcolepsy / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
Ataxia; CpG methylation array; DNA methylation; DNMT1; Dementia; Hearing loss; Narcolepsy