Comprehensive genetic rescreening improves diagnostic yield in congenital hyperinsulinism

Abstract

<p>Context</p><p>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.</p><p>Objective</p><p>To evaluate this hypothesis in a nationwide cohort of individuals with a historical diagnosis of HI of unknown genetic cause.</p><p>Methods</p><p>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 (<em>n</em> = 17) or inconclusive (<em>n</em> = 10) results.</p><p>Results</p><p>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 <em>ABCC8</em>, <em>HK1</em>, and <em>SLC16A1</em> genes, and a <em>GCK</em> mosaic variant (8% allele fraction). In 2 (7%) cases, rescreening revised genetic results but did not provide a definitive genetic diagnosis.</p><p>Conclusion</p><p>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.</p>