Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia

Hum Mutat. 2017 Jul;38(7):764-777. doi: 10.1002/humu.23233. Epub 2017 Jun 1.


We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at

Keywords: Alström syndrome; Monogenic diabetes; Thiamine-responsive megaloblastic anemia syndrome; Wolfram syndrome; genotype-phenotype analysis; locus-specific database.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anemia, Megaloblastic / genetics*
  • Child
  • Child, Preschool
  • Databases, Genetic*
  • Diabetes Mellitus / genetics*
  • Exons
  • Family Health
  • Female
  • Genetic Association Studies
  • Genetic Variation
  • Genotype
  • Hearing Loss, Sensorineural / genetics*
  • Homozygote
  • Humans
  • Male
  • Phenotype
  • Prognosis
  • Sensitivity and Specificity
  • Thiamine Deficiency / congenital*
  • Thiamine Deficiency / genetics
  • Wolfram Syndrome / genetics*
  • Young Adult

Supplementary concepts

  • Thiamine responsive megaloblastic anemia syndrome