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

Astuti, D. et al. (2017) Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Human Mutation, 38(7), pp. 764-777. (doi: 10.1002/humu.23233) (PMID:28432734)

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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.

• Item Type: Articles
• Keywords: Genetics(clinical), Genetics
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McCafferty, Ms Susan
• Authors: 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., McCafferty, S., Tillmann, V., Maffei, P., Paquis-Flucklinger, V., Geberhiwot, T., Mlynarski, W., Parkinson, K., Picard, V., Bueno, G. E., Dias, R., Arnold, A., Richens, C., Paisey, R., Urano, F., Semple, R., Sinnott, R., and Barrett, T. G.
• College/School: University Services > IT Services > Computing Service
• Journal Name: Human Mutation
• Publisher: Wiley-Blackwell
• ISSN: 1059-7794
• Published Online: 01 June 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Human Mutation 38(7):764-777
• Publisher Policy: Reproduced under a Creative Commons License