ESPE Abstracts

Background and Aims: Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. The disease may occur in isolation or can present as part of a syndrome. Routine screening of the known etiological genes (n = >20) identifies a disease-causing mutation in 40-50% of all cases. An accurate and timely genetic diagnosis is clinically important for all individuals as understanding the underlying genetic cause of the HI can guide the clinician in both medical and surgical management.

Congenital Hyperinsulinism International (CHI) is a nonprofit organization dedicated to improving the lives of those living with HI. Since 2018, CHI has provided funding to the University of Exeter to cover the cost of genetic testing for individuals who would otherwise be unable to receive genetic screening. The objective of this study is to report on the results of the genetic testing conducted through this partnership and the benefits to patients worldwide.

Methods: Exeter recruited individuals with clinical diagnosis of HI who were unable to access genetic testing through their own healthcare provider. Exeter performed rapid Sanger sequencing of the KATP channel genes in all individuals. Targeted next-generation sequencing of the remaining known genes was performed in those without a KATP channel mutation if the HI persisted beyond 3 months or additional clinical features suggested syndromic disease.

Results: Between July 2018 and March 2021 CHI funded genetic testing for 526 individuals from 54 countries with medically diagnosed HI. Routine screening identified mutations in 251 out of 526 individuals (47.7%). These mutations were identified in 14 different genes. The most common genetic etiology was KATP channel HI, with ABCC8 and KCNJ11 mutations identified in 197 patients (78.4% of solved cases). Of these, 142 individuals had bi-allelic or a dominantly-acting mutation confirming diffuse pancreatic disease. In 55 individuals, a paternally-inherited mutation suggested focal disease which can be cured by lesionectomy.

Discussion: The partnership between CHI and Exeter has enabled 251 individuals with HI to receive an accurate genetic diagnosis. For all of these individuals understanding the underlying genetic cause of the HI has helped to guide medical management by informing on treatment decisions, prognosis and recurrence risk within families. By increasing access to genetic testing, this partnership is improving HI patient care around the world, providing novel insights into mechanisms of insulin secretion, and ensuring there are no barriers for children to receive testing regardless of where they are born.