TY  - JOUR
AU  - Astuti, D
AU  - Sabir, A
AU  - Fulton, P
AU  - Zatyka, M
AU  - Williams, D
AU  - Hardy, C
AU  - Milan, G
AU  - Favaretto, F
AU  - Yu-Wai-Man, P
AU  - Rohayem, J
AU  - Lopez de Heredia, M
AU  - Hershey, T
AU  - Tranebjaerg, L
AU  - Chen, J-H
AU  - Chaussenot, A
AU  - Nunes, V
AU  - Marshall, B
AU  - McAfferty, S
AU  - Tillmann, V
AU  - Maffei, P
AU  - Paquis-Flucklinger, V
AU  - Geberhiwot, T
AU  - Mlynarski, W
AU  - Parkinson, K
AU  - Picard, V
AU  - Esteban Bueno, G
AU  - Dias, R
AU  - Arnold, A
AU  - Richens, C
AU  - Paisey, R
AU  - Urano, F
AU  - Semple, R
AU  - Sinnott, R
AU  - Barrett, TG
Y2  - 2021/02/04
Y1  - 2017/07/01
SN  - 1059-7794
UR  - http://hdl.handle.net/11343/259176
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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
LA  - English
PB  - WILEY
T1  - Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia
DO  - 10.1002/humu.23233
IS  - Human Mutation
VL  - 38
IS  - 7
SP  - 764-777
L1  - /bitstream/handle/11343/259176/PMC5535005.pdf?sequence=1&isAllowed=y
ER  -