Supplementary Material for: Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q

<b><i>Background/Aims:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 <i>(HK1)</i> and one missense variant in the coding region of <i>DNA2</i>. <b><i>Conclusion:</i></b> Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. <i>HK1</i> 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.