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Background <p>We recently reported non-coding variants in a <i>cis</i>-regulatory element of the beta-cell disallowed gene hexokinase 1 (<i>HK1</i>) 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 <i>HK1</i>-hyperinsulinism by screening a large international cohort of patients living with the condition.</p> Methods <p>We screened the <i>HK1 cis</i>-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories.</p> Results <p>We identified a <i>HK1</i> 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 (<i>n</i> = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26&#xa0;years (median: 7&#xa0;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&#xa0;years), confirming variable penetrance. Two of the 23 novel <i>HK1</i> variants allowed us to extend the minimal <i>cis</i>-regulatory region from 42 to 46&#xa0;bp.</p> Conclusions <p>Non-coding variants within the <i>HK1 cis</i>-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 <i>HK1</i> as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.</p>

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

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  • 发表日期：

    2025年3月3日

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  • 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,
  • Marie-Thérèse Abi Warde,
  • Mehta Amrita,
  • Romy Aravena,
  • Alina Arion,
  • Navoda Atapattu,
  • Ivo Barić,
  • Jérôme Bertherat,
  • Esra Bilici,
  • Juliette Bouchereau,
  • Karine Braun,
  • Marie-Neige Campas-Lebecque,
  • Mireille Castanet,
  • Catie Cessans,
  • Louise S. Conwell,
  • Preeti Dabadghao,
  • Archana Dayal Arya,
  • Pascale de Lonlay,
  • Liat de Vries,
  • Céline Droumaguet,
  • Noémie Faure-Galon,
  • Olivier Gilly,
  • Alice Goldenberg,
  • Anne-Sophie Guemann,
  • Anne-Marie Guerrot,
  • Julie Harvengt,
  • Samar S. Hassan,
  • Saw Shi Hui,
  • Khadija Nuzhat Humayun,
  • M. Ibrahim,
  • Vandana Jain,
  • Dhivyalakshmi Jeevarathnam,
  • Kah Yin Loke,
  • Vaman Khadilkar,
  • I. P. S. Kochar,
  • Abhishek Kulkarni,
  • Aniket Kumbhojkar,
  • Delphine Lamireau,
  • Floris Levy-Khademi,
  • Catarina Limbert,
  • Martin Lindner,
  • Catherine Lombard,
  • François Maillot,
  • Karine Mention,
  • Verónica Mericq,
  • Zainaba Mohamed,
  • Coline Mornet,
  • Philip Murray,
  • Alexandre Naccache,
  • Lusine V. Navasardyan,
  • Kristen Neville,
  • Ramona Nicolescu,
  • Marc Nicolino,
  • Elisa Nishimura-Meguro,
  • Nattakarn Numsriskulrat,
  • Sinead O’sullivan,
  • Yasmine Ouarezki,
  • Armelle Pambou,
  • Florence Petit,
  • V. P. Praveen,
  • Mélanie Priou-Guesdon,
  • Stoeva Radka,
  • Birgit Rami-Merhar,
  • Sudha Rao,
  • Yves Reznik,
  • Laurence Rulquin,
  • Maria Salomon Estebanez,
  • Isabelle Souto,
  • Antoine Tabarin,
  • Ana Tangari,
  • Sara Van Aken,
  • Charles Verge,
  • Hélène Vinolas,
  • Christel Voinot,
  • Robert Wagner,
  • Jan Walker,
  • Esko Wiltshire,
  • Klaus Mohnike,
  • Jean-Baptiste Arnoux,
  • Nick D. L. Owens,
  • Martin Zenker,
  • Christine Bellanné-Chantelot,
  • Sarah E. Flanagan

摘要

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.