PDF(Pubmed)
Abstract：
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.
摘要：
持续性先天性高胰岛素血症（HI）是一种罕见的遗传异质性疾病，其特征是胰岛素分泌失调，导致危及生命的低血糖。对于高达50%的受影响个体,已知的HI基因的筛选不能鉴定致病变异。以前已经使用大的缺失来鉴定引起HI的新的调节区。这里,我们使用基因组测序在180名有未知原因HI的先证者中搜索新的大缺失(>1Mb),并使用来自靶向基因组的脱靶拷贝数变异调用,在883名有HI的遗传未解决个体的大队列中复制了我们的发现.我们在跨越染色体20p11.2的五个个体（范围3-8Mb）中发现了重叠的杂合缺失。胰腺β细胞转录因子基因,FOXA2，HI的已知原因在五个人中的两个被删除。剩下的三个,我们发现与FOXA2相邻的2.4Mb的最小缺失区包含多个与FOXA2构象接触的非编码调控元件.我们的数据表明，这三个孩子的缺失可能通过FOXA2表达失调而导致疾病。这些发现为β细胞中FOXA2的调节提供了新的见解，并证实了综合征HI中染色体20p11.2缺失的病因作用。
