dc.contributor.author | Laver, TW | |
dc.contributor.author | Patel, KA | |
dc.contributor.author | Colclough, K | |
dc.contributor.author | Curran, J | |
dc.contributor.author | Dale, J | |
dc.contributor.author | Davis, N | |
dc.contributor.author | Savage, DB | |
dc.contributor.author | Flanagan, SE | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Weedon, MN | |
dc.date.accessioned | 2018-08-01T15:11:48Z | |
dc.date.issued | 2018-07-17 | |
dc.description.abstract | Context: Monogenic partial lipodystrophy is a genetically heterogenous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance. Objective: We investigated if null variants in PLIN1 cause lipodystrophy. Methods: As part of a targeted sequencing panel test we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal. Results: We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632 - 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Conclusions: Our study suggests that heterozygous variants which are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy. | en_GB |
dc.description.sponsorship | KAP has a postdoctoral fellowship funded by the Wellcome Trust (110082/Z/15/Z). DBS is supported by the Wellcome Trust (WT107064), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). ATH and SE are Wellcome Trust Senior Investigators (WT098395/Z/12/Z). ATH is also supported by a National Institute for Health Research Senior Investigator award. MNW is supported by Medical Research Council grant MR/M005070/1. The authors thank Garan Jones, Andrew Parrish, Anna Bussell and Jessica Settle (Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK) and Matthew Johnson (University of Exeter) for their technical assistance. | en_GB |
dc.identifier.citation | Vol. 103 (9), pp. 3225–3230 | en_GB |
dc.identifier.doi | 10.1210/jc.2017-02662 | |
dc.identifier.uri | http://hdl.handle.net/10871/33637 | |
dc.language.iso | en | en_GB |
dc.publisher | Oxford University Press (OUP) | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/30020498 | en_GB |
dc.rights | Open access. This article has been published under the terms of the Creative Commons Attribution
License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author
and source are credited. Copyright for this article is retained by the author(s). | en_GB |
dc.subject | Human Genetics | en_GB |
dc.subject | Lipodystrophy | en_GB |
dc.subject | Genetic Screening | en_GB |
dc.subject | Familial Partial Lipodystrophy | en_GB |
dc.subject | Monogenics | en_GB |
dc.title | PLIN1 haploinsufficiency is not associated with lipodystrophy | en_GB |
dc.type | Article | en_GB |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version of the article. Available from OUP via the DOI in this record. | en_GB |
dc.identifier.journal | Journal of Clinical Endocrinology and Metabolism | en_GB |