ArticleEBioMedicine2026
Low-level mosaic variants causing the pancreatic disease congenital hyperinsulinism can be detected from blood DNA.
Article in EBioMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundA substantial proportion of individuals with a well-defined monogenic disorder remain without a genetic diagnosis. Low-level mosaic pathogenic variants are recognised as an underappreciated cause of monogenic disease but are technically challenging to detect, particularly in organ-specific conditions when affected tissue is inaccessible.
methodsWe systematically investigated low-level mosaic variants in individuals with congenital hyperinsulinism (CHI: n = 1252) or neonatal diabetes (NDM: n = 312), two opposing pancreatic disorders of insulin secretion. We screened for established pathogenic variants with variant allele fraction (VAF) < 8% in dominant CHI (ABCC8, GCK, GLUD1, HK1) or dominant NDM (ABCC8, KCNJ11, INS) genes in targeted next-generation sequencing (tNGS) data using Mutect2.
findingsThis called 40 variants across the four genes in 39 individuals with CHI. No candidate variants were found in the NDM cohort. Orthogonal validation of 35 variants using TaqMan-based droplet digital PCR (ddPCR) confirmed 26/35 variants. The median VAF for confirmed variants was 3.6% (1.0-7.8%), while false positives (9/35) predominantly had a VAF <1% with some overlap in VAF with true positives.
interpretationThis study shows that disease-causing low-level mosaic variants in dominant CHI genes can be detected in blood using tNGS but require orthogonal validation. These results provide a framework to improve diagnostic yield in organ-specific conditions where mosaic variants may represent an important missed cause of disease.
fundingThis work was supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with the Team CHIbra and Congenital Hyperinsulinism International [MDBR-23-020-CHI] and the Wellcome Trust [223187/Z/21/Z].
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