Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia
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Monogenic diabetes syndromes : Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. / Astuti, Dewi; Sabir, Ataf; Fulton, Piers; Zatyka, Malgorzata; Williams, Denise; Hardy, Carol; Milan, Gabriella; Favaretto, Francesca; Yu-Wai-Man, Patrick; Rohayem, Julia; López de Heredia, Miguel; Hershey, Tamara; Tranebjaerg, Lisbeth; Chen, Jian-Hua; Chaussenot, Annabel; Nunes, Virginia; Marshall, Bess; McAfferty, Susan; Tillmann, Vallo; Maffei, Pietro; Paquis-Flucklinger, Veronique; Geberhiwot, Tarekign; Mlynarski, Wojciech; Parkinson, Kay; Picard, Virginie; Bueno, Gema Esteban; Dias, Renuka; Arnold, Amy; Richens, Caitlin; Paisey, Richard; Urano, Fumihiko; Semple, Robert; Sinnott, Richard; Barrett, Timothy G.
I: Human Mutation, Bind 38, Nr. 7, 2017, s. 764-777.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Monogenic diabetes syndromes
T2 - Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia
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 - López de Heredia, Miguel
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, Fumihiko
AU - Semple, Robert
AU - Sinnott, Richard
AU - Barrett, Timothy G
N1 - © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.
PY - 2017
Y1 - 2017
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 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.
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.
U2 - 10.1002/humu.23233
DO - 10.1002/humu.23233
M3 - Journal article
C2 - 28432734
VL - 38
SP - 764
EP - 777
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 7
ER -
ID: 195042037