Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements

This is the final version. Available on open access from Springer Nature via the DOI in this recordData availability: All non-clinical data analyzed during this study are included in this article (and its Supplementary Information). The 20p11.2 variants reported in this study were uploaded to ClinVar (SUB14235415). Clinical and genotype data can be used to identify individuals and are therefore available only through collaboration to experienced teams working on approved studies examining the mechanisms, cause, diagnosis and treatment of diabetes and other beta cell disorders. Requests for collaboration will be considered by a steering committee following an application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current-research/genetic-beta-cell-research-bank/). Contact by email should be directed to S. Flanagan ([email protected]). All requests for access to data will be responded to within 14 d. Accession codes and DOI numbers for all ChIP-seq, ATAC-seq, RNA-seq and scRNA-seq datasets are provided in Supplementary Table 2. We used the Genome Reference Consortium Human Build 37 (GRCh37) to annotate genetic data (accession number GCF_000001405.13). Details of this assembly are provided at https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.13/.Persistent 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 (>1 Mb) 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 to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.Wellcome Trus