AI Article Synopsis
- - The study investigates children with congenital hyperinsulinism (HI) who do not respond to diazoxide and lack detectable mutations in their blood, focusing on potential hidden genetic changes in pancreatic tissue.
- - Through next-generation sequencing on pancreatic specimens from 10 children, four unique GCK mutations were found at low levels, indicating that these mutations may be responsible for their HI, despite not being detectable in their blood samples.
- - The findings suggest that post-zygotic somatic mutations in the GCK gene contribute to certain cases of non-focal diazoxide-unresponsive hyperinsulinism, shedding light on the complexity of genetic causes in this condition.
Article Abstract
Context: Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral blood DNA.
Objective: To examine whether somatic post-zygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or Localized Islet Nuclear Enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA.
Methods: Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI.
Results: Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4-10.1% in pancreatic DNA from five of these 10 children. The GCK mutations were not detectable in peripheral blood DNA by NGS in three cases from which peripheral blood DNA was available for testing. All four GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse-HI in four of the five cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith Wiedemann Spectrum (BWSp) although molecular analysis for 11pUPD was negative in pancreas.
Conclusion: These results indicate that post-zygotic somatic GCK mutations are responsible for some cases of non-focal diazoxide-unresponsive hyperinsulinism.
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| http://dx.doi.org/10.1210/clinem/dgae713 | DOI Listing |
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