Current Research

By combining lab-based studies with patient-focused research, we seek to uncover the underlying biology of congenital hyperinsulinism, identify new drug targets, and bring discoveries from the bench to the bedside. Our research goes beyond genetics as we explore other key aspects of the condition, including neurological outcomes, pregnancy-related impacts, and broader clinical consequences.

Co-producing Research Questions with Families and the Public

All of our research is designed and shaped with meaningful Patient and Public Involvement (PPI) at its core. People with lived experience of congenital hyperinsulinism, along with their families and carers, are involved throughout the research process, from shaping research questions and study design to advising on participant materials and the dissemination of findings.

How to get involved?

If you are a family living with congenital hyperinsulinism, or a clinician caring for patients with this condition and interested in taking part in research, we would be very pleased to hear from you. Please contact the team by email.

Current Research Areas

Studying the role of the pancreatic beta-cell disallowed gene, SLC16A1, in adult-onset hyperinsulinism

The Exeter team has recently identified a 94 bp deletion in the promoter region of the pancreatic β-cell disallowed gene, SLC16A1, in over 13 families with congenital hyperinsulinism. We have performed immunofluorescence studies on patient-derived pancreatic tissue and generated an induced pluripotent stem cell (iPSC) model, providing mechanistic insight into its impact on β-cell function. Our ongoing research aims to clinically characterise this condition by identifying triggers of hypoglycaemia and evaluating potential treatment strategies for affected families.

Detection of low-level mosaic variants in the regulatory region of HK1 from FFPE pancreatic tissue using laser-capture microdissection

Dr Jessica Hopkinson is leading this NIHR BRC–funded project, which uses laser-capture microdissection to isolate islets that aberrantly express HK1 from formalin-fixed, paraffin-embedded pancreatic tissue. DNA extracted from these islets will be sequenced to identify disease-causing changes. This work will underpin a broader programme aimed at using laser-capture microdissection to detect extremely low-level mosaic variants in children with congenital hyperinsulinism and other rare diseases. Here is a video showing the technology in action.

Gene Discovery Studies

We are using high-resolution sequencing to uncover new genetic causes of congenital hyperinsulinism. Families can enrol in the study when routine genetic testing has not identified the cause of disease. The results of these studies are fed back to families through their clinicians once a disease-causing variant has been identified. This work aims to improve biological understanding of the condition, deliver clearer diagnoses for families, and identify pathways that may become targets for drug development.

Understanding Monogenic Forms of Adult-Onset Hyperinsulinism

Dr Jayne Houghton is leading a study to investigate whether specific genes known to cause congenital hyperinsulinism can also lead to hyperinsulinism that first presents in adulthood. This work aims to clarify the genetic mechanisms underlying adult-onset disease, improve diagnostic pathways by informing gene panel analysis, and support more targeted management for affected individuals.

Reducing Diagnostic Uncertainty

We are using state-of-the-art genomic technologies to reduce the number of variants of uncertain significance (VUS) reported to families, helping to ease anxiety and shorten diagnostic journeys and also studying the burden of VUS in congenital hyperinsulinism to better understand their role. Our approaches include epigenomic analysis in methylation disorders such as Kabuki syndrome to assess epigenomic signatures,  phasing variants in ABCC8 and MAGEL2 to determine their parental origin, and minigene assays to assess the impact of variants on splicing. Together, these methods help us more accurately identify disease-causing changes and provide clearer diagnoses.

Feasibility Study for Non-Invasive Prenatal Testing (NIPT) of HNF4A

Dr Alice Hughes and Dr Jayne Houghton are leading a study to evaluate the feasibility of non-invasive prenatal testing (NIPT) for HNF4A-related congenital hyperinsulinism. The study will examine how knowledge of the fetal genotype influences pregnancy management, delivery planning, immediate postnatal care and long-term outcomes. Insights gained will inform the broader development and implementation of CHI-focused NIPT. Further information about this service can be found here.

Assessing the role of copy number variants in Congenital Hyperinsulinism

Dr Thomas Laver is leading this Academy of Medical Sciences funded project to investigate copy number variants (CNVs) as a cause of congenital hyperinsulinism and diabetes. CNVs are where large sections of DNA have been gained (duplicated) or lost (deleted). CNVs are a known cause of rare disease but are not always detected by standard genetic tests. Dr Matthew Wakeling has developed a tool, SavvyCNV, which makes it possible to detect CNVs beyond the targeted genes. We have already used this to help identify a novel cause of hyperinsulinism and establish that cumulatively large CNVs are an important cause of the disease. Further research to identify novel CNVs causing hyperinsulinism is ongoing.

Studying the impact of fetal insulin secretion and risk of pre-eclampsia in CHI-pregnancies

Research led by the Prof Rachel Freathy of the Pregnancy and Fetal Growth Genomics research team aims to investigate a possible link between fetal hyperinsulinism and maternal preeclampsia. Several children with congenital hyperinsulinism are born to mothers who developed preeclampsia, raising the hypothesis that increased fetal insulin secretion in utero may contribute to the condition. The project aims to explore whether fetal insulin levels play a causative or contributory role in preeclampsia.

Epigenetic Signatures in Rare Genetic Disorders of Insulin Secretion: Developing Diagnostic Classifiers

Working with Dr Emma Dempster from the University of Exeter Epigenomics group, the HIGenes team are employing innovative bioinformatic techniques to investigate how epigenetic processes contribute to rare genetic disorders that affect insulin secretion. The team are aiming use disease-specific epigenetic patterns to develop classifiers termed “episignatures” to assist with the interpretation of novel genetic variants and as a diagnosis tool. This means that people with these rare genetic disorders can receive the right genetic diagnosis and treatment. This work also involves collaboration with Illumina on a collaborative project using the new Illumina 5-base solution.

In this BRC-NIHR funded project, Dr Pamela Bowman is investigating how genetic and environmental factors impact intellectual disability in people with KATP-channel-related conditions. This project aims to study how the effects of the following on nature and severity of ID and other problems: 1. Genetics: the impact of different changes in KATP-channel genes 2. Interventions: the impact of different treatments 3. Environment: the impact of very low blood sugar.

Data Quality Control and Genetic Analyses Software Development

Alongside detecting variants in DNA sequenced in the lab, Dr. Matthew Wakeling is developing software to perform quality control of the data and extract extra information. We can now detect low-level contamination in the DNA samples and determine how the samples were contaminated, which helps prevent incorrect conclusions. We are also able to search for more unusual kinds of event in the analysed DNA, such as copy number variants, mosaic or full UPD, runs of homozygosity, and relatedness (sometimes quite distant) between samples.