RT Journal Article
T1 Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.
A1 Astuti, Dewi
A1 Sabir, Ataf
A1 Fulton, Piers
A1 Zatyka, Malgorzata
A1 Williams, Denise
A1 Hardy, Carol
A1 Milan, Gabriella
A1 Favaretto, Francesca
A1 Yu-Wai-Man, Patrick
A1 Rohayem, Julia
A1 López de Heredia, Miguel
A1 Hershey, Tamara
A1 Tranebjaerg, Lisbeth
A1 Chen, Jian-Hua
A1 Chaussenot, Annabel
A1 Nunes, Virginia
A1 Marshall, Bess
A1 McAfferty, Susan
A1 Tillmann, Vallo
A1 Maffei, Pietro
A1 Paquis-Flucklinger, Veronique
A1 Geberhiwot, Tarekign
A1 Mlynarski, Wojciech
A1 Parkinson, Kay
A1 Picard, Virginie
A1 Bueno, Gema Esteban
A1 Dias, Renuka
A1 Arnold, Amy
A1 Richens, Caitlin
A1 Paisey, Richard
A1 Urano, Fumihiko
A1 Semple, Robert
A1 Sinnott, Richard
A1 Barrett, Timothy G
K1 Alström syndrome
K1 Monogenic diabetes
K1 Thiamine-responsive megaloblastic anemia syndrome
K1 Wolfram syndrome
K1 genotype-phenotype analysis
K1 locus-specific database
AB 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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
YR 2017
FD 2017-06-01
LK http://hdl.handle.net/10668/11125
UL http://hdl.handle.net/10668/11125
LA en
DS RISalud
RD Apr 7, 2025