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

Dewi Astuti, Ataf Sabir, Piers Fulton, Malgorzata Zatyka, Denise Williams, Carol Hardy, Gabriella Milan, Francesca Favaretto, Patrick Yu-Wai-Man, Julia Rohayem, Miguel López de Heredia, Tamara Hershey, Lisbeth Tranebjaerg, Jian Hua Chen, Annabel Chaussenot, Virginia Nunes, Bess Marshall, Susan McAfferty, Vallo Tillmann, Pietro MaffeiVeronique Paquis-Flucklinger, Tarekign Geberhiwot, Wojciech Mlynarski, Kay Parkinson, Virginie Picard, Gema Esteban Bueno, Renuka Dias, Amy Arnold, Caitlin Richens, Richard Paisey, Fumihiko Urano, Robert Semple, Richard Sinnott, Timothy G. Barrett

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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 https://lovd.euro-wabb.org.

Original languageEnglish
Pages (from-to)764-777
Number of pages14
JournalHuman mutation
Volume38
Issue number7
DOIs
StatePublished - Jul 2017

Keywords

  • Alström syndrome
  • Monogenic diabetes
  • Thiamine-responsive megaloblastic anemia syndrome
  • Wolfram syndrome
  • genotype–phenotype analysis
  • locus-specific database

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    Astuti, D., Sabir, A., Fulton, P., Zatyka, M., Williams, D., Hardy, C., Milan, G., Favaretto, F., Yu-Wai-Man, P., Rohayem, J., López de Heredia, M., Hershey, T., Tranebjaerg, L., Chen, J. H., Chaussenot, A., Nunes, V., Marshall, B., McAfferty, S., Tillmann, V., ... Barrett, T. G. (2017). Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Human mutation, 38(7), 764-777. https://doi.org/10.1002/humu.23233