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

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Congenital hyperinsulinism (HI) can be caused by non-coding variants in the hexokinase 1 (HK1) gene's cis-regulatory element.
• These variants disrupt HK1 repression in pancreatic beta-cells, leading to inappropriate insulin secretion during hypoglycemia.

Purpose of the Study:

• To determine the prevalence, genetic basis, and clinical characteristics of HK1-related hyperinsulinism.
• Screening a large international cohort of patients with hyperinsulinism of unknown origin.

Main Methods:

• Screening of the HK1 cis-regulatory region in 1761 probands with hyperinsulinism.
• Genetic analysis and clinical phenotyping of affected individuals and their families.

Main Results:

• Identified HK1 variants in 5% (89/1761) of probands, confirming HK1 as a significant cause of HI (2.8% of genetic diagnoses in the Exeter cohort).
• Disease onset ranged from birth to 26 years, with variable treatment responses (80% medical management, 20% surgery).
• Observed a spectrum of glycemic outcomes and identified variable penetrance in inherited cases.

Conclusions:

• Non-coding HK1 variants are a major cause of hyperinsulinism, presenting with variable severity and penetrance.
• This highlights the critical role of the non-coding genome in monogenic diseases like hyperinsulinism.