Genome Medicine (Mar 2025)

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

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

DOI
https://doi.org/10.1186/s13073-025-01440-w
Journal volume & issue
Vol. 17, no. 1
pp. 1 – 11

Abstract

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Abstract 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.

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