Bennett Jasmin J, Saint-Martin Cécile, Neumann Bianca, Männistö Jonna M E, Houghton Jayne A L, Empting Susann, Johnson Matthew B, Laver Thomas W, Locke Jonathan M, Spurrier Benjamin, Wakeling Matthew N, Banerjee Indraneel, Dastamani Antonia, Demirbilek Hüseyin, Mitchell John, Stange Markus, Mohnike Klaus, Arnoux Jean-Baptiste, Owens Nick D L, Zenker Martin, Bellanné-Chantelot Christine, Flanagan Sarah E
Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, EX2 5DW, UK.
Department of Medical Genetics, AP-HP Sorbonne University, Pitié-Salpêtrière Hospital, 75013, Paris, France.
Genome Med. 2025 Mar 3;17(1):17. doi: 10.1186/s13073-025-01440-w.
We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition.
We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories.
We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp.
Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.
我们最近报道，β细胞不允许基因己糖激酶1（HK1）的顺式调控元件中的非编码变异是先天性高胰岛素血症的一个新病因。这些变异导致胰腺β细胞中HK1的抑制作用丧失，在低血糖期间引起胰岛素分泌。在本研究中，我们旨在通过筛查一大群患有该疾病的国际患者队列，来确定HK1相关性高胰岛素血症的患病率、遗传学特征和表型。
我们对1761名病因不明的高胰岛素血症先证者的HK1顺式调控区域进行了筛查，这些先证者已被转诊至三个大型欧洲基因组学实验室之一。
我们在89名/1761名先证者（5%）和63名家庭成员中鉴定出HK1变异。在埃克塞特高胰岛素血症队列中，这些变异占所有阳性基因诊断的2.8%（n = 54/1913），确立了其作为高胰岛素血症的一个重要病因。患有致病变异的个体在出生至26岁之间被诊断为高胰岛素血症（中位数：7天），对治疗的反应各异；80%接受药物治疗，20%因对药物治疗反应不佳而接受胰腺手术。血糖结果从自发缓解到持续至成年期的低血糖不等。8名先证者从未报告患有高胰岛素血症的父母那里遗传了该变异（当前年龄中位数：39岁），证实了可变外显率。23个新的HK1变异中的两个使我们能够将最小顺式调控区域从42 bp扩展到46 bp。
HK1顺式调控区域内的非编码变异可导致严重程度各异的高胰岛素血症，范围从新生儿期发病、难治性疾病到成年期无症状。在89个家庭中发现变异证实了HK1是高胰岛素血症的主要病因，并突出了非编码基因组在人类单基因疾病中的重要作用。
