Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis

Nat Genet. 2014 Jan;46(1):61-64. doi: 10.1038/ng.2826. Epub 2013 Nov 10.


The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomes, Human, Pair 10
  • Embryonic Stem Cells / physiology
  • Enhancer Elements, Genetic / genetics*
  • Epigenomics / methods
  • Female
  • Genes, Recessive
  • Humans
  • Male
  • Mutation*
  • Pancreas / abnormalities*
  • Pancreatic Diseases / congenital*
  • Pancreatic Diseases / genetics
  • Pedigree
  • Transcription Factors / genetics*


  • Transcription Factors
  • transcription factor PTF1

Supplementary concepts

  • Pancreatic Agenesis, Congenital