title: Dominant form of congenital hyperinsulinism maps to HK1 region on 10q.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pa. 19104, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Pinney
authors.forename: Karthik
authors.initials: K
authors.lastname: Ganapathy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bradfield
authors.forename: David
authors.initials: D
authors.lastname: Stokes
authors.forename: Ariella
authors.initials: A
authors.lastname: Sasson
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mackiewicz
authors.forename: Kara
authors.initials: K
authors.lastname: Boodhansingh
authors.forename: Nkecha
authors.initials: N
authors.lastname: Hughes
authors.forename: Susan
authors.initials: S
authors.lastname: Becker
authors.forename: Stephanie
authors.initials: S
authors.lastname: Givler
authors.forename: Courtney
authors.initials: C
authors.lastname: Macmullen
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Monos
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000235:genetics*; D003981:Diazoxide / Q000627:therapeutic use; D005215:Fasting; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006593:Hexokinase / Q000235:genetics*; D006801:Humans; D007223:Infant; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D001786:Blood Glucose; D007328:Insulin; C472074:HK1 protein, human; D006593:Hexokinase; D003981:Diazoxide