Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620501
Title:
Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.
Authors:
Patel, K. A.; Kettunen, J.; Laakso, M.; Stančáková, A.; Laver, T. W.; Colclough, Kevin; Johnson, M. B.; Abramowicz, M.; Groop, L.; Miettinen, P. J.; Shepherd, Maggie ( 0000-0003-2660-0955 ) ; Flanagan, S. E.; Ellard, Sian ( 0000-0002-7620-5526 ) ; Inagaki, N.; Hattersley, Andrew T.; Tuomi, T.; Cnop, M.; Weedon, M. N.
Abstract:
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10(-4)). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10(-5)) and Finnish (n = 80, odds ratio = 22, P = 1 × 10(-6)) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
Citation:
Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. 2017, 8 (1):888 Nat Commun
Publisher:
Nature
Journal:
Nature Communications
Issue Date:
12-Oct-2017
URI:
http://hdl.handle.net/11287/620501
DOI:
10.1038/s41467-017-00895-9
PubMed ID:
29026101
Additional Links:
http://dx.doi.org/10.1038/s41467-017-00895-9
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
2041-1723
Appears in Collections:
Diabetes/Endocrine Services; Molecular Genetics; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorPatel, K. A.en
dc.contributor.authorKettunen, J.en
dc.contributor.authorLaakso, M.en
dc.contributor.authorStančáková, A.en
dc.contributor.authorLaver, T. W.en
dc.contributor.authorColclough, Kevinen
dc.contributor.authorJohnson, M. B.en
dc.contributor.authorAbramowicz, M.en
dc.contributor.authorGroop, L.en
dc.contributor.authorMiettinen, P. J.en
dc.contributor.authorShepherd, Maggieen
dc.contributor.authorFlanagan, S. E.en
dc.contributor.authorEllard, Sianen
dc.contributor.authorInagaki, N.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorTuomi, T.en
dc.contributor.authorCnop, M.en
dc.contributor.authorWeedon, M. N.en
dc.date.accessioned2017-11-10T14:38:53Z-
dc.date.available2017-11-10T14:38:53Z-
dc.date.issued2017-10-12-
dc.identifier.citationHeterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. 2017, 8 (1):888 Nat Communen
dc.identifier.issn2041-1723-
dc.identifier.pmid29026101-
dc.identifier.doi10.1038/s41467-017-00895-9-
dc.identifier.urihttp://hdl.handle.net/11287/620501-
dc.description.abstractFinding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10(-4)). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10(-5)) and Finnish (n = 80, odds ratio = 22, P = 1 × 10(-6)) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/s41467-017-00895-9en
dc.rightsArchived with thanks to Nature Communications. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subjectWessex Classification Subject Headings::Endocrinology::Diabetesen
dc.titleHeterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.en
dc.typeJournal Articleen
dc.identifier.journalNature Communicationsen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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