The Journal of clinical endocrinology and metabolism · 2025
Low-Level Mosaic GCK Mutations in Children With Diazoxide-Unresponsive Congenital Hyperinsulinism.
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Boodhansingh Kara E, Lord Katherine, Adzick N Scott, Bhatti Tricia, Ganguly Arupa, Stanley Charles A, De Leon Diva D
Аннотация
CONTEXT: Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral-blood DNA.
OBJECTIVE: This work aimed to examine whether somatic postzygotic 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% to 10.1% in pancreatic DNA from 5 of these 10 children. The GCK mutations were not detectable in peripheral-blood DNA by NGS in 3 cases from which peripheral-blood DNA was available for testing. All 4 GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse HI in 4 of the 5 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 although molecular analysis for 11pUPD was negative in pancreas.
CONCLUSION: These results indicate that postzygotic somatic GCK mutations are responsible for some cases of nonfocal diazoxide-unresponsive HI.
OBJECTIVE: This work aimed to examine whether somatic postzygotic 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% to 10.1% in pancreatic DNA from 5 of these 10 children. The GCK mutations were not detectable in peripheral-blood DNA by NGS in 3 cases from which peripheral-blood DNA was available for testing. All 4 GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse HI in 4 of the 5 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 although molecular analysis for 11pUPD was negative in pancreas.
CONCLUSION: These results indicate that postzygotic somatic GCK mutations are responsible for some cases of nonfocal diazoxide-unresponsive HI.