Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis
- Weedon, M. N.
- Cebola, I.
- Patch, A. M.
- Flanagan, S.
- De Franco, E.
- Caswell, R.
- Rodríguez Seguí, Santiago Andrés
- Shaw Smith, C.
- Cho, C.
- Allen, H. L.
- Houghton, J.
- Roth, C. L.
- Chen, R.
- Hussain, K.
- Marsh, P.
- Vallier, L.
- Murray, A.
- International Pancreatic Agenesis Consortium
- Ellard, S.
- Ferrer, J.
- Hattersley, A. T.
DOIAbstract
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 ...
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