Identification of a methylation profile for DNMT1-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy

• Published in: Clinical epigenetics Vol. 8; no. 1; p. 91
• Main Authors: Kernohan, Kristin D., Cigana Schenkel, Laila, Huang, Lijia, Smith, Amanda, Pare, Guillaume, Ainsworth, Peter, Boycott, Kym M., Warman-Chardon, Jodi, Sadikovic, Bekim
• Format: Journal Article
• Language: English
• Published: London BioMed Central 05.09.2016; BioMed Central Ltd
• Subjects: All other subjects; Amino Acid Substitution; Analysis; Biomedical and Life Sciences; Biomedicine; Cerebellar ataxia; Cerebellar Ataxia - genetics; CpG Islands; Deafness; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; Epigenesis, Genetic; Female; Gene expression; Gene Function; Genes; Genetic aspects; Genetic Loci; Genome-Wide Association Study; Genomics; Hearing Loss, Sensorineural - genetics; Human Genetics; Humans; Male; Mutation; Narcolepsy; Narcolepsy - genetics; Pedigree; Risk factors; Sequence Analysis, DNA - methods; Short Report; United States; DNMT1; DNA methylation; CpG methylation array; Ataxia; Narcolepsy; Dementia; Hearing loss
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-016-0254-x

Background 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. Results 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. Conclusions This report identifies robust changes in the DNA methylation patterns in ADCA-DN patients, which is an important step towards elucidating disease pathogenesis.