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Lookup NU author(s): Dr Patrick Yu Wai Man
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2017 Wiley Periodicals, Inc. 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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
Author(s): Astuti 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, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2017
Volume: 38
Issue: 7
Pages: 764-777
Print publication date: 01/07/2017
Online publication date: 21/04/2017
Acceptance date: 13/04/2017
Date deposited: 20/06/2017
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/humu.23233
DOI: 10.1002/humu.23233
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