Monogenic diabetes syndromes: Locus-specific databases for Alström, 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type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1.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.

• Authors: 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
• Journal: Human mutation (Hum Mutat) Vol. 38 Issue 7 Pg. 764-777 (07 2017) ISSN: 1098-1004 [Electronic] United States
• PMID: 28432734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Topics

• Adolescent
• Adult
• Anemia, Megaloblastic (genetics)
• Child
• Child, Preschool
• Databases, Genetic
• Diabetes Mellitus (genetics)
• Exons
• Family Health
• Female
• Genetic Association Studies
• Genetic Variation
• Genotype
• Hearing Loss, Sensorineural (genetics)
• Homozygote
• Humans
• Male
• Phenotype
• Prognosis
• Sensitivity and Specificity
• Thiamine Deficiency (congenital, genetics)
• Wolfram Syndrome (genetics)
• Young Adult