Genome-wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion

Clin Epigenetics. 2018 Jul 18;10(1):97. doi: 10.1186/s13148-018-0530-z.


Heterozygous mutation of the transcription factor HNF1B is the most common cause of monogenetic developmental renal disease. Disease-associated mutations fall into two categories: HNF1B intragenic mutations and a 1.3 Mb deletion at chromosome 17q12. An increase in neurodevelopmental disorders has been observed in individuals harbouring the 17q12 deletion but not in patients with HNF1B coding mutations.Previous investigations have concentrated on identifying a genetic cause for the increase in behavioural problems seen in 17q12 deletion carriers. We have taken the alternative approach of investigating the DNA methylation profile of these two HNF1B genotype groups along with controls matched for age, gender and diabetes status using the Illumina 450K DNA methylation array (total sample n = 60).We identified a number of differentially methylated probes (DMPs) that were associated with HNF1B-associated disease and passed our stringent experiment-wide significance threshold. These associations were largely driven by the deletion patients and the majority of the significant probes mapped to the 17q12 deletion locus. The observed changes in DNA methylation at this locus were not randomly dispersed and occurred in clusters, suggesting a regulatory mechanism reacting to haploinsufficiency across the entire deleted region.Along with these deletion-specific changes in DNA methylation, we also identified a shared DNA methylation signature in both mutation and deletion patient groups indicating that haploinsufficiency of HNF1B impacts on the methylome of a number of genes, giving further insight to the role of HNF1B.

Keywords: 17q12 deletion; Autism; CNV; DNA methylation; Epigenetics; HNF1B; Renal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 17 / genetics*
  • DNA Methylation*
  • Female
  • Haploinsufficiency
  • Hepatocyte Nuclear Factor 1-beta / genetics*
  • Humans
  • Kidney Diseases / genetics*
  • Male
  • Mutation*
  • Sequence Deletion*
  • Whole Genome Sequencing / methods*
  • Young Adult


  • HNF1B protein, human
  • Hepatocyte Nuclear Factor 1-beta