ESPE2024 Free Communications Fetal and Neonatal Endocrinology (6 abstracts)
A novel 94bp deletion in the SLC16A1 promoter causes fasting and exercise-induced hyperinsulinaemic hypoglycaemia
Jasmin Hopkins 1 , Jonna Mannisto 1,2 , Jessica Hopkinson 1 , Matthew Wakeling 1 , Colm Costigan 3 , Rachel Crowley 4 , James Gibney 5 , Muhammad Faiz Muhamad 5 , Orla Neylon 6 , Donal O'Shea 4 , Julie Okiro 5 , Elizabeth Palmer 7 , Niall Swann 4 , Jayne Houghton 8 , Timo Otonkoski 9 & Sarah Flanagan 1
1University of Exeter, Exeter, United Kingdom. 2University of Eastern Finland, Kuopio, Finland. 3Our Lady's Children's Hospital, Dublin, Ireland. 4St Vincent's University Hospital, Dublin, Ireland. 5Tallaght University Hospital, Dublin, Ireland. 6University of Limerick, Limerick, Ireland. 7University of New South Wales, Sydney, Australia. 8Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom. 9University of Helsinki, Helsinki, Finland
Background: In 2007, non-coding variants in the promoter of SLC16A1, a beta-cell disallowed gene, were reported as a novel genetic cause of exercise-induced hyperinsulinism (HI). In this study, three different promoter variants were identified in 13 affected individuals from three families. It was proposed that these variants caused MCT1, which is encoded by SLC16A1, to be inappropriately expressed in the pancreatic beta cells resulting in insulin secretion in response to pyruvate. Since the initial discovery, no further disease-causing SLC16A1 promoter variants have been reported. The aim of this study was to screen the SLC16A1 promoter region in individuals with genetically-unsolved congenital HI to identify further disease-causing variants.
Methods: Using targeted next generation sequencing we screened 478bp of the SLC16A1 promoter in an internationally referred cohort of 1,065 individuals with HI of unknown genetic cause. Cascade testing was performed in affected family members when a likely pathogenic variant was identified, with haplotype analysis undertaken using a SNP array. Clinical features of all affected individuals were assessed. Immunohistochemical analyses to investigate MCT1 expression in beta-cells was performed when resected pancreatic tissue was available.
Results: We identified a novel heterozygous 94bp deletion in the SLC16A1 promoter in 20 individuals with HI from nine families. Eight families were referred from Ireland and one from Australia. Haplotype analysis identified a common allele shared between the Irish families only, in keeping with a founder variant in this population. Affected individuals had a wide range in age at diagnosis (1.8 years to 65 years). Of the 20 cases, five (25%) were clinically diagnosed with HI in childhood or adolescence. HI was diagnosed by a formal exercise stress test in 2/20 cases (median glucose 1.6 mmol/L, insulin 102 pmol/L) and by a fasting test in 10/20 cases (median glucose 2.4 mmol/L, insulin 100 pmol/L). Physical exercise-related symptoms were reported in nine individuals. Five individuals had undergone pancreatic resection, following surgery two of these individuals continued to have hypoglycaemia. Of the remaining 14, four were treated with diazoxide, six were not receiving treatment at referral, and for five treatment was unknown. Immunohistochemical staining of resected pancreatic tissue from three individuals confirmed the aberrant expression of MCT1 in the pancreatic beta cells.
Conclusion: Our results expand knowledge of the genetics and clinical features of SLC16A1 -HI. Importantly, they demonstrate that hypoglycaemia may occur in the absence of exercise, suggesting alternative triggers for insulin release from the beta-cell.
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