# Neurological Phenotyping in Hyperinsulinism – Administrative Supplement to Islet dysregulation in Infants with Congenital Hyperinsulinism

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $203,709

## Abstract

PROJECT SUMMARY
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children.
In the last 20+ years a total of 9 genetic loci have been associated with HI, however, in approximately 40-50%
of cases a genetic cause is not identified. The elucidation of the molecular mechanisms responsible for HI is of
great importance to guide the development of novel therapies and eventually, a cure. Building on the success
of the previous cycles of this award, we propose a comprehensive approach to examine the mechanisms of
disease for two novel forms of HI that we have previously mapped to specific genomic loci by linkage analysis
and whole exome sequencing. In addition, we propose a broad discovery effort for novel mechanisms of
disease by performing deep genotyping and phenotyping of both individuals and isolated islets in cases with
negative genetic testing on constitutional DNA. Our overall hypothesis is that genetic testing negative HI
cases can be explained by novel genetic loci encompassing factors important for ß-cell function and
by somatic mutations of known HI genes. To test this hypothesis, we propose two aims: to examine the
mechanisms responsible for dysregulated insulin secretion by novel genetic loci identified in families with
dominantly-inherited HI: Hexokinase 1 and PASK; to identify the role of post-zigotic mutations in HI; and to
continue our discovery efforts through a comprehensive approach to examine genomics and functionomics of
HI by deep genotyping and functional evaluations of affected individuals and their pancreatic islets. This study
will expand our understanding of the molecular genetics and pathophysiology of HI and will facilitate the
identification of new genetic causes and potential new therapeutic targets for this devastating disease. The
discovery of novel HI loci may lead to a better understanding of the mechanisms regulating insulin secretion
and may benefit the development of new therapies not only for HI, but also for diabetes.

## Key facts

- **NIH application ID:** 10339264
- **Project number:** 3R01DK056268-22S1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Diva D. De Leon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $203,709
- **Award type:** 3
- **Project period:** 1999-08-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339264

## Citation

> US National Institutes of Health, RePORTER application 10339264, Neurological Phenotyping in Hyperinsulinism – Administrative Supplement to Islet dysregulation in Infants with Congenital Hyperinsulinism (3R01DK056268-22S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10339264. Licensed CC0.

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