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Vol. 80, No. 1, 2013
Issue release date: August 2013

Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q

Pinney S.E. · Ganapathy K. · Bradfield J. · Stokes D. · Sasson A. · Mackiewicz K. · Boodhansingh K. · Hughes N. · Becker S. · Givler S. · Macmullen C. · Monos D. · Ganguly A. · Hakonarson H. · Stanley C.A.
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Background/Aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.

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