Comprehensive genetic rescreening improves diagnostic yield in congenital hyperinsulinism

Area of Science:

• Genetics
• Pediatrics
• Medical Diagnostics

Background:

• Congenital hyperinsulinism (HI) is a rare genetic disorder of insulin regulation.
• Advances in genetic sequencing necessitate re-evaluation of diagnostic strategies for unsolved cases.
• Previous genetic testing in this cohort was negative or inconclusive.

Purpose of the Study:

• To assess the diagnostic utility of genetic rescreening in individuals with a history of genetically unsolved HI.
• To evaluate the impact of comprehensive gene panel testing on diagnosis and management.

Main Methods:

• A nationwide cohort of 27 Finnish individuals with genetically unexplained HI underwent targeted gene panel rescreening.
• The panel included coding regions of 18 known HI genes and 5 relevant non-coding regions.
• Participants had a median age of 21 years and had undergone prior genetic testing.

Main Results:

• Genetic rescreening provided new or revised diagnoses in 22% (6/27) of cases.
• Definitive diagnoses were established in 15% (4/27), including novel non-coding variants and a mosaic variant.
• Rescreening revised results in an additional 7% (2/27) without providing a definitive diagnosis.

Conclusions:

• Genetic rescreening with a comprehensive panel is valuable for diagnosing previously unsolved congenital hyperinsulinism.
• Updated genetic testing strategies can identify new diagnoses, impacting medical management and recurrence risk.
• Re-evaluation of rescreening is crucial for genetically unexplained HI, even after remission.