Journal Article

Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity

Männistö, Jonna M. E., Mohnike, Klaus, Bennett, Jasmin J., Locke, Jonathan M., Demirbilek, Hüseyin, Owens, Nick D. L., Bellanné-Chantelot, Christine, Zenker, Martin, Flanagan, Sarah E., Mitchell, John, Johnson, Matthew B., Saint-Martin, Cécile, Laver, Thomas W., Neumann, Bianca, Empting, Susann, Spurrier, Benjamin, Dastamani, Antonia, Arnoux, Jean-Baptiste, Houghton, Jayne A. L., Wakeling, Matthew N., Banerjee, Indraneel, Stange, Markus

2025

Overview

Background 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. Methods 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. Results 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. Conclusions 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Adult / Beta cells / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Child / Child, Preschool / Congenital diseases / Congenital hyperinsulinism / Congenital Hyperinsulinism - diagnosis / Congenital Hyperinsulinism - genetics / Congenital Hyperinsulinism - pathology / Drug dosages / Enzymes / Ethics / Families & family life / Female / Genetic disorders / Genetic testing / Genetic Variation / Genomes / Genomics / Glucose / Health aspects / Hexokinase / Hexokinase - genetics / Hexokinase 1 / Human Genetics / Humans / Hypoglycemia / Infant / Infant, Newborn / Insulin / Insulin secretion / Male / Medicine/Public Health / Metabolomics / Monogenic disease / Neonates / Non-coding / Pancreas / Pancreatic beta cells / Phenotype / Phenotypes / Remission / Severity of Illness Index / Software / Systems Biology / Variable penetrance / Young Adult