DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered a DNMT1 mutation (Y495C) underlying central and peripheral neurodegeneration in hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). The mutant DNMT1 protein showed premature degradation and reduced DNA methyltransferase activity. Methylation analysis of gene promoters (27K CpG sites) indicated global hypomethylation and localized hypermethylation. However, the impact of mutant DNMT1 on the genome-wide scale, especially on intergenic regions and gene bodies, has not been explored. We investigated genome-wide DNA methylation at single-base resolution using whole-genome bisulfite sequencing in lymphocytes from 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample, in which 12 million were at >10X coverage in all 6 samples. Of these, 564,218 (4.76%) contained differentially methylated CpGs (DMCs; p<0.05), with 300,134 and 264,084 mapping to intergenic and coding regions, respectively. In HSAN1E patients, DMCs in genic and intergenic regions including promoters and exons, as well as L1, L2, Alu, satellite and simple repeat sequences were generally hypomethylated. In contrast, CpG islands appeared to be hypermethylated. We also found more DMCs in DNMT3B and 201 imprinted genes compared to other genes. These DMCs were hypomethylated and located mainly within gene bodies. Chromosomes 18 and X showed the most decrease in overall methylation. Differentially methylated region (DMR) analysis revealed 7,521 significantly altered DMRs associated with 1,693 genes. Of these, 1,872 were hypermethylated and 5,649 hypomethylated. No significant difference was found in ~2.2 million SNVs detected. These results will be critical in deciphering the pathogenesis of neurodegeneration by the DNMT1 defect.