Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia

Dewi Astuti; Ataf Sabir; Piers Fulton; Malgorzata Zatyka; Denise Williams; Carol Hardy; Gabriella Milan; Francesca Favaretto; Patrick Yu-Wai-Man; Julia Rohayem; Miguel López de Heredia; Tamara Hershey; Lisbeth Tranebjaerg; Jian-Hua Chen; Annabel Chaussenot; Virginia Nunes; Bess Marshall; Susan McAfferty; Vallo Tillmann; Pietro Maffei; Veronique Paquis-Flucklinger; Tarekign Geberhiwot; Wojciech Mlynarski; Kay Parkinson; Virginie Picard; Gema Esteban Bueno; Renuka Dias; Amy Arnold; Caitlin Richens; Richard Paisey; Fumihiko Urano; Robert Semple; Richard Sinnott; Timothy G Barrett

doi:10.1002/humu.23233

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia

Dewi Astuti, Ataf Sabir, Piers Fulton, Malgorzata Zatyka, Denise Williams, Carol Hardy, Gabriella Milan, Francesca Favaretto, Patrick Yu-Wai-Man, Julia Rohayem, Miguel López de Heredia, Tamara Hershey, Lisbeth Tranebjaerg, Jian-Hua Chen, Annabel Chaussenot, Virginia Nunes, Bess Marshall, Susan McAfferty, Vallo Tillmann, Pietro MaffeiVeronique Paquis-Flucklinger, Tarekign Geberhiwot, Wojciech Mlynarski, Kay Parkinson, Virginie Picard, Gema Esteban Bueno, Renuka Dias, Amy Arnold, Caitlin Richens, Richard Paisey, Fumihiko Urano, Robert Semple, Richard Sinnott, Timothy G Barrett

Department of Clinical Medicine

24 Citations (Scopus)

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Abstract

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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.

Original language	English
Journal	Human Mutation
Volume	38
Issue number	7
Pages (from-to)	764-777
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.23233
Publication status	Published - Jul 2017

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Astuti, D., Sabir, A., Fulton, P., Zatyka, M., Williams, D., Hardy, C., Milan, G., Favaretto, F., Yu-Wai-Man, P., Rohayem, J., López de Heredia, M., Hershey, T., Tranebjaerg, L., Chen, J.-H., Chaussenot, A., Nunes, V., Marshall, B., McAfferty, S., Tillmann, V., ... Barrett, T. G. (2017). Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Human Mutation, 38(7), 764-777. https://doi.org/10.1002/humu.23233

Astuti, D, Sabir, A, Fulton, P, Zatyka, M, Williams, D, Hardy, C, Milan, G, Favaretto, F, Yu-Wai-Man, P, Rohayem, J, López de Heredia, M, Hershey, T, Tranebjaerg, L, Chen, J-H, Chaussenot, A, Nunes, V, Marshall, B, McAfferty, S, Tillmann, V, Maffei, P, Paquis-Flucklinger, V, Geberhiwot, T, Mlynarski, W, Parkinson, K, Picard, V, Bueno, GE, Dias, R, Arnold, A, Richens, C, Paisey, R, Urano, F, Semple, R, Sinnott, R & Barrett, TG 2017, 'Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia', Human Mutation, vol. 38, no. 7, pp. 764-777. https://doi.org/10.1002/humu.23233

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title = "Monogenic diabetes syndromes: Locus-specific databases for Alstr{\"o}m, Wolfram, and Thiamine-responsive megaloblastic anemia",

abstract = "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, Alstr{\"o}m, 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.",

author = "Dewi Astuti and Ataf Sabir and Piers Fulton and Malgorzata Zatyka and Denise Williams and Carol Hardy and Gabriella Milan and Francesca Favaretto and Patrick Yu-Wai-Man and Julia Rohayem and {L{\'o}pez de Heredia}, Miguel and Tamara Hershey and Lisbeth Tranebjaerg and Jian-Hua Chen and Annabel Chaussenot and Virginia Nunes and Bess Marshall and Susan McAfferty and Vallo Tillmann and Pietro Maffei and Veronique Paquis-Flucklinger and Tarekign Geberhiwot and Wojciech Mlynarski and Kay Parkinson and Virginie Picard and Bueno, {Gema Esteban} and Renuka Dias and Amy Arnold and Caitlin Richens and Richard Paisey and Fumihiko Urano and Robert Semple and Richard Sinnott and Barrett, {Timothy G}",

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year = "2017",

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doi = "10.1002/humu.23233",

language = "English",

volume = "38",

pages = "764--777",

journal = "Human Mutation",

issn = "1059-7794",

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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

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 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

SN - 1059-7794

VL - 38

SP - 764

EP - 777

JO - Human Mutation

JF - Human Mutation

IS - 7

ER -

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia

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