title: Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism.
abstract: Genetic sequencing has become a critical part of the diagnosis of certain forms of pancreatic beta cell dysfunction. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenicity of variants remains a challenge, and requires sharing of sequence and phenotypic data between laboratories. We reviewed all diabetes and hyperinsulinism-associated molecular testing done at the Seattle Children's Molecular Genetics Laboratory from 2009 to 2013. 331 probands were referred to us for molecular genetic sequencing for Neonatal Diabetes (NDM), Maturity-Onset Diabetes of the Young (MODY), or Congenital Hyperinsulinism (CHI) during this period. Reportable variants were identified in 115 (35%) patients with 91 variants in one of 6 genes: HNF1A, GCK, HNF4A, ABCC8, KCNJ11, or INS. In addition to identifying 23 novel variants, we identified unusual mechanisms of inheritance, including mosaic and digenic MODY presentations. Re-analysis of all reported variants using more recently available databases led to a change in variant interpretation from the original report in 30% of cases. These results represent a resource for molecular testing of monogenic forms of diabetes and hyperinsulinism, providing a mutation spectrum for these disorders in a large North American cohort. In addition, they highlight the importance of periodic review of molecular testing results.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Bennett
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Vasta
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Narayanan
authors.affiliation: Department of Pediatric Endocrinology, Beaumont Children's Hospital, Royal Oak, MI 48073, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Gerrits
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: sihahn@uw.edu.
authors.forename: Si Houn
authors.initials: SH
authors.lastname: Hahn
mesh_terms: D002648:Child; D003920:Diabetes Mellitus / Q000175:diagnosis* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013997:Time Factors
keywords: Hyperinsulinism; MODY; Mosaicism; Mutation spectrum; Neonatal diabetes; Variant classification