Monogenic causes of autoimmunity give key insights to the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in 5 individuals with a spectrum of early-onset autoimmune disease including type 1 diabetes. These findings emphasise the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in Hyper IgE syndrome.

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole genome sequencing can identify all non-coding variants, yet discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in hESC-derived embryonic pancreatic progenitor cells to guide the interpretation of whole genome sequences from patients with isolated pancreatic agenesis. This uncovered six different recessive mutations in a previously uncharacterized ~400bp sequence located 25kb downstream of PTF1A (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 uncover novel non-coding elements underlying human development and disease.

Aims/hypothesisCurrent genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene for analysis according to the patient’s phenotype. Next-generation sequencing enables the simultaneous analysis of multiple genes in a single test. Our aim was to develop a targeted next-generation sequencing assay to detect mutations in all known MODY and neonatal diabetes genes.MethodsWe selected 29 genes in which mutations have been reported to cause neonatal diabetes, MODY, maternally inherited diabetes and deafness (MIDD) or familial partial lipodystrophy (FPLD). An exon-capture assay was designed to include coding regions and splice sites. A total of 114 patient samples were tested—32 with known mutations and 82 previously tested for MODY (n = 33) or neonatal diabetes (n = 49) but in whom a mutation had not been found. Sequence data were analysed for the presence of base substitutions, small insertions or deletions (indels) and exonic deletions or duplications.ResultsIn the 32 positive controls we detected all previously identified variants (34 mutations and 36 polymorphisms), including 55 base substitutions, ten small insertions or deletions and five partial/whole gene deletions/duplications. Previously unidentified mutations were found in five patients with MODY (15%) and nine with neonatal diabetes (18%). Most of these patients (12/14) had mutations in genes that had not previously been tested.Conclusions/interpretationOur novel targeted next-generation sequencing assay provides a highly sensitive method for simultaneous analysis of all monogenic diabetes genes. This single test can detect mutations previously identified by Sanger sequencing or multiplex ligation-dependent probe amplification dosage analysis. The increased number of genes tested led to a higher mutation detection rate.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-2962-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.The genetic basis for most instances of pancreatic agenesis is unknown; mutations in PDX1 (MIM#260 370) and PTF1A (MIM#609 069) have been reported in only five families 1-3 . We studied a cohort of 27 individuals with pancreatic agenesis, defined as neonatal diabetes requiring insulin treatment and exocrine pancreatic insufficiency requiring enzyme replacement therapy, born to non diabetic parents. In all subjects for whom pancreatic imaging was performed (n=21), there was a complete absence (n=16) or marked hypoplasia of the pancreas. We found one affected subject to have a homozygous PTF1A splice site mutation, but we identified no mutations in PDX1 in this cohort. A common recessive