Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the likely disruption ofFOXA2

Abstract

AbstractPersistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene,FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent toFOXA2that encompasses multiple non-coding regulatory elements that are in conformational contact withFOXA2. Our data suggests that the deletions in these three patients may cause disease through the dysregulation ofFOXA2expression. These findings provide new insights into the regulation ofFOXA2in the beta-cell and confirm an aetiological role for chromosome 20p deletions in syndromic HI.