title: Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.
abstract: 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.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Genomic Regulation of Pancreatic Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, 08036 Barcelona, Spain.
authors.forename: Ines
authors.initials: I
authors.lastname: Cebola
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Franco
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.affiliation: Genomic Regulation of Pancreatic Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, 08036 Barcelona, Spain.|Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE)-Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina.
authors.forename: Santiago A
authors.initials: SA
authors.lastname: Rodríguez-Seguí
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Shaw-Smith
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, West Forvie Site, Robinson Way, Cambridge, UK.
authors.forename: Candy H-H
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Hana Lango
authors.initials: HL
authors.lastname: Allen
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Jayne Al
authors.initials: JA
authors.lastname: Houghton
authors.affiliation: Seattle Children's Hospital Research Institute, Seattle, WA 98101, USA.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Roth
authors.affiliation: School of Biomedical Science, Waterloo Campus, King's College London, London, UK.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Chen
authors.affiliation: London Centre for Paediatric Endocrinology and Metabolism, in partnership with the Great Ormond Street Hospital for Children National Health Service Trust, London, UK.|Institute of Child Health, University College London, London, UK.
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.affiliation: Diabetes Research Group, Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Marsh
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, West Forvie Site, Robinson Way, Cambridge, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Genomic Regulation of Pancreatic Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Spain.|CIBER de Diabetes y Enfermedades Metabólicas, 08036 Barcelona, Spain.|Department of Medicine, Imperial College, London, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D002879:Chromosomes, Human, Pair 10; D053595:Embryonic Stem Cells / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D009154:Mutation; D010179:Pancreas / Q000002:abnormalities*; D010182:Pancreatic Diseases / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors; C062602:transcription factor PTF1