Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism

This is the final version. Available on open access from Wiley via the DOI in this recordCongenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life-threatening hypoglycaemia if not effectively managed. CHI can be sub-classifiedinto three distinct groups:diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised,the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic-CHI we studied the islet tissuehistopathologyderived from limited surgical resection from the tail of the pancreasin a patientwithCHI. The underlying genetic aetiologywas investigated using a combination of high depth next-generation sequencing, microsatellite analysis and p57kip2immunostaining.Histopathology of thepancreatic tissue confirmed the presence of a defined areaassociated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localisedto a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novomosaic ABCC8mutation and mosaic paternal uniparental disomy which werenot present in leukocyte DNA or the surrounding unaffected pancreatic tissue. Thisstudyprovidesthe first description of two independent disease-causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findingsincrease knowledge ofthe genetic causes of isletdiseaseand provide further insights into the underlying developmental changes associated with β-cell expansion in CHI.Wellcome Trus