TY - JOUR
T1 - Monogenic diabetes syndromes
T2 - Locus-specific databases for Alström, Wolfram and Thiamine-responsive megaloblastic anaemia
AU - Astuti, Dewi
AU - Sabir, Ataf
AU - Fulton, Piers
AU - Zatyka, Malgorzata
AU - Williams, Denise
AU - Hardy, Carol
AU - Milan, Gabriella
AU - Favaretto, Francesca
AU - Yu-Wai-Man, Patrick
AU - Rohayem, Julia
AU - de Heredia, Miguel López
AU - Hershey, Tamara
AU - Tranebjaerg, Lisbeth
AU - Chen, Jian-Hua
AU - Chaussenot, Annabel
AU - Nunes, Virginia
AU - Marshall, Bess
AU - McAfferty, Susan
AU - Tillmann, Vallo
AU - Maffei, Pietro
AU - Paquis-Flucklinger, Veronique
AU - Geberhiwot, Tarekign
AU - Mlynarski, Wojciech
AU - Parkinson, Kay
AU - Picard, Virginie
AU - Bueno, Gema Esteban
AU - Dias, Renuka
AU - Arnold, Amy
AU - Richens, Caitlin
AU - Paisey, Richard
AU - Urano, Fumi
AU - Semple, Robert
AU - Sinnott, Richard
AU - Barrett, Timothy G
N1 - This article is protected by copyright. All rights reserved.
PY - 2017/7
Y1 - 2017/7
N2 - 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type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.
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 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.
KW - Genotype-phenotype analysis
KW - Wolfram syndrome
KW - Alström syndrome
KW - Thiamine responsive megaloblastic anaemia syndrome
KW - Monogenic diabetes
KW - Locus-specific database
U2 - 10.1002/humu.23233
DO - 10.1002/humu.23233
M3 - Article
C2 - 28432734
SN - 1059-7794
VL - 38
SP - 764
EP - 777
JO - Human Mutation
JF - Human Mutation
IS - 7
ER -