Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia
AuthorAstuti, D; Sabir, A; Fulton, P; Zatyka, M; Williams, D; Hardy, C; Milan, G; Favaretto, F; Yu-Wai-Man, P; Rohayem, J; ...
Source TitleHuman Mutation
University of Melbourne Author/sSinnott, Richard
AffiliationComputing and Information Systems
Document TypeJournal Article
CitationsAstuti, D., Sabir, A., Fulton, P., Zatyka, M., Williams, D., Hardy, C., Milan, G., Favaretto, F., Yu-Wai-Man, P., Rohayem, J., Lopez 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 Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia. HUMAN MUTATION, 38 (7), pp.764-777. https://doi.org/10.1002/humu.23233.
Access StatusOpen Access
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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
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