Astuti, DewiSabir, AtafFulton, PiersZatyka, MalgorzataWilliams, DeniseHardy, CarolMilan, GabriellaFavaretto, FrancescaYu-Wai-Man, PatrickRohayem, JuliaLópez de Heredia, MiguelHershey, TamaraTranebjaerg, LisbethChen, Jian-HuaChaussenot, AnnabelNunes, VirginiaMarshall, BessMcAfferty, SusanTillmann, ValloMaffei, PietroPaquis-Flucklinger, VeroniqueGeberhiwot, TarekignMlynarski, WojciechParkinson, KayPicard, VirginieBueno, Gema EstebanDias, RenukaArnold, AmyRichens, CaitlinPaisey, RichardUrano, FumihikoSemple, RobertSinnott, RichardBarrett, Timothy G2023-01-252023-01-252017-06-01http://hdl.handle.net/10668/11125We 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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Alström syndromeMonogenic diabetesThiamine-responsive megaloblastic anemia syndromeWolfram syndromegenotype-phenotype analysislocus-specific databaseAdolescentAdultAnemia, MegaloblasticChildChild, PreschoolDatabases, GeneticDiabetes MellitusExonsFamily HealthFemaleGenetic Association StudiesGenetic VariationGenotypeHearing Loss, SensorineuralHomozygoteHumansMalePhenotypePrognosisSensitivity and SpecificityThiamine DeficiencyWolfram SyndromeYoung Adultresearch article28432734open access10.1002/humu.232331098-1004PMC5535005https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/humu.23233https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535005/pdf