%0 Journal Article
%A Astuti, Dewi
%A Sabir, Ataf
%A Fulton, Piers
%A Zatyka, Malgorzata
%A Williams, Denise
%A Hardy, Carol
%A Milan, Gabriella
%A Favaretto, Francesca
%A Yu-Wai-Man, Patrick
%A Rohayem, Julia
%A López de Heredia, Miguel
%A Hershey, Tamara
%A Tranebjaerg, Lisbeth
%A Chen, Jian-Hua
%A Chaussenot, Annabel
%A Nunes, Virginia
%A Marshall, Bess
%A McAfferty, Susan
%A Tillmann, Vallo
%A Maffei, Pietro
%A Paquis-Flucklinger, Veronique
%A Geberhiwot, Tarekign
%A Mlynarski, Wojciech
%A Parkinson, Kay
%A Picard, Virginie
%A Bueno, Gema Esteban
%A Dias, Renuka
%A Arnold, Amy
%A Richens, Caitlin
%A Paisey, Richard
%A Urano, Fumihiko
%A Semple, Robert
%A Sinnott, Richard
%A Barrett, Timothy G
%T Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.
%D 2017
%U http://hdl.handle.net/10668/11125
%X 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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
%K Alström syndrome
%K Monogenic diabetes
%K Thiamine-responsive megaloblastic anemia syndrome
%K Wolfram syndrome
%K genotype-phenotype analysis
%K locus-specific database
%~