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

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.

背景与目的：在由McQuarrie于1950年代首次报道的先天性高胰岛素血症（congenital hyperinsulinism, HI）家系中，我们针对一种新型显性遗传型HI的遗传位点与临床表型展开研究。方法：我们纳入25名受累个体，其中7人接受了胰岛素代谢异常相关检测（24小时禁食试验、口服葡萄糖耐量试验与蛋白质耐量试验）。为明确疾病位点及潜在的疾病相关突变，我们开展了连锁分析、全转录组测序、全基因组测序、基因捕获及下一代测序技术。结果：绝大多数受累个体于1岁前被确诊为HI，其中40%以癫痫为首发症状。所有受累个体对二氮嗪（diazoxide）治疗均应答良好。受累个体在口服葡萄糖耐量试验或长时间禁食后，胰岛素分泌未能得到有效抑制；无一例患者出现蛋白质敏感性低血糖。连锁分析将HI位点定位于10号染色体q21-22区域，该区域共包含48个基因。我们在己糖激酶1（hexokinase 1, HK1）中发现3个全新的非编码变异，同时在DNA2的编码区发现1个错义变异。结论：本家系中的显性遗传、二氮嗪应答型HI定位于10号染色体q21-22上的全新位点。己糖激酶1（HK1）是更具潜力的疾病候选基因，因为干扰β细胞中HK1正常表达抑制的突变，可合理解释该家系的低血糖表型。