Curating the Clinical Genome 2024 ePoster Gallery-Estimating the Genetic Prevalence of Congenital Hyperinsulinism Workflow and Challenges in ABCC8

Estimating the Genetic Prevalence of Congenital Hyperinsulinism Workflow and Challenges in ABCC8

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This document discusses the challenges and workflow involved in estimating the genetic prevalence of Congenital Hyperinsulinism (CHI) due to ABCC8 gene variations. CHI is a condition where pancreatic β-cells produce excess insulin, leading to low blood sugar levels and potential severe consequences. The study highlights that ABCC8 gene variations contribute to 40%-45% of CHI cases. The workflow involved annotating and curating variants to estimate prevalence using tools like GeniE. It was noted that pathogenic variants need further investigation and incorrect inclusion can lead to overestimation. Factors like population representation, unidentified variants, and consanguinity rates affecting autosomal recessive conditions were considered limitations. The study estimated a global carrier frequency of 1/318 and a genetic prevalence of 1/404,541 for AR CHI. The prevalence was highest among Ashkenazi Jews due to specific founder variants. The analysis excluded variants associated solely with diabetes and emphasized distinguishing between CHI and related conditions like diabetes and pulmonary arterial hypertension. The study identified 132 pathogenic variants for prevalence calculations after filtering. The workflow also differentiated between focal and diffuse CHI as well as between dominant and recessive inheritance patterns. Variability in disease presentation due to the same genetic variant was highlighted. The study was a collaborative effort with patient advocacy groups and was funded by the Chan Zuckerberg Initiative.

Keywords

Congenital Hyperinsulinism

ABCC8 gene variations

Genetic prevalence

Pancreatic β-cells

GeniE tool

Pathogenic variants

Autosomal recessive conditions

Carrier frequency

Founder variants

Chan Zuckerberg Initiative