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

著者 Astuti D , Sabir A , Fulton P , Zatyka M , Williams D , Hardy C , Milan G , Favaretto F , Yu-Wai-Man P , Rohayem J , de Heredia ML , Hershey T , Tranebjaerg L , Chen JH , Chaussenot A , Nunes V , Marshall B , McAfferty S , Tillmann V , Maffei P , Paquis-F
Hum Mutat.2017 Apr 21 ; ():.
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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type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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 bi-allelic 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. This article is protected by copyright. All rights reserved.
PMID: 28432734 [PubMed - as supplied by publisher]
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