A1 Refereed original research article in a scientific journal
Comprehensive genetic rescreening improves diagnostic yield in congenital hyperinsulinism
Authors: Männistö, Jonna M. E.; Houghton, Jayne A. L.; Bennett, Jasmin J.; Keskinen, Päivi; Tuomi, Tiinamaija; Ruuskanen, Heli; Viikari, Liisa A.; Jokiniitty, Antti; Lähde, Jyrki; Raivo, Joose; Otonkoski, Timo; Huopio, Hanna; Flanagan, Sarah E.
Publication year: 2026
Journal: Journal of the Endocrine Society
Article number: bvag047
Volume: 10
Issue: 4
eISSN: 2472-1972
DOI: https://doi.org/10.1210/jendso/bvag047
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1210/jendso/bvag047
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/522936583
Self-archived copy's licence: CC BY
Self-archived copy's version: Publisher`s PDF
Context
Recent genetic discoveries in congenital hyperinsulinism (HI) and advances in sequencing technology suggest that the diagnostic yield may be improved by rescreening in people with genetically unsolved HI.
Objective
To evaluate this hypothesis in a nationwide cohort of individuals with a historical diagnosis of HI of unknown genetic cause.
Methods
Twenty-seven probands, representing 77% of the genetically unsolved HI cases in Finland, underwent rescreening which targeted the coding regions of 18 known HI genes, and 5 relevant non-coding regions. The median age of the cohort was 21 years (range, 4-44 years). Participants had previously undergone a median of 3 genetic tests (range, 1-4), all of which yielded negative (n = 17) or inconclusive (n = 10) results.
Results
Genetic rescreening was informative in 22% (6 of 27) of cases. Definitive genetic diagnoses were established in 4 (15%) participants. These included the detection of non-coding variants in the ABCC8, HK1, and SLC16A1 genes, and a GCK mosaic variant (8% allele fraction). In 2 (7%) cases, rescreening revised genetic results but did not provide a definitive genetic diagnosis.
Conclusion
In this Finnish cohort, rescreening with a comprehensive gene panel provided new or revised diagnoses in 22% of cases, informing on medical management and recurrence risk. These findings emphasize the importance of regularly updating genetic testing strategies and highlight the clinical value of re-evaluating the need for rescreening in genetically unexplained HI cases even following clinical remission.
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Funding information in the publication:
This research was funded in whole, or in part, by Wellcome [223187/Z/21/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author accepted Manuscript version arising from this submission. This research was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JMEM is the recipient of Fellowships by the European Society for Paediatric Endocrinology (ESPE) and the Finnish Foundation for Paediatric Research (Lastentautien tutkimussäätiö), and the State Research Funding for university-level health research, Kuopio University Hospital, Wellbeing services county of North Savo.
