Funding agencies: This work was supported by NIH DK52431-19, DK26687-31, UL1 RR024156, the Russell Berrie Foundation, and the Intramural Research Program of NICHD, NIH, Z1A-HD-00641. RG is supported by funding from CIHR DFSA-113549.
Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity
Article first published online: 15 OCT 2013
Copyright © 2013 The Obesity Society
Volume 22, Issue 2, pages 576–584, February 2014
How to Cite
Gill, R., Cheung, Y. H., Shen, Y., Lanzano, P., Mirza, N. M., Ten, S., Maclaren, N. K., Motaghedi, R., Han, J. C., Yanovski, J. A., Leibel, R. L. and Chung, W. K. (2014), Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity, 22: 576–584. doi: 10.1002/oby.20492
Disclosure: The authors report no conflicts of interest.
Author contribution: RG and WKC conceived the experiments. RG carried out the experiments and analyzed the data. YHC and YS processed the data. RLL, WKC, PL, NMM, ST, JCH, JAY, NKM, and RM oversaw data collection. WKC and RLL designed the study. RG, RLL, and WKC wrote the paper. All authors had final approval of the submitted version of the paper.
- Issue published online: 3 FEB 2014
- Article first published online: 15 OCT 2013
- Accepted manuscript online: 24 APR 2013 03:22PM EST
- Manuscript Accepted: 2 APR 2013
- Manuscript Received: 4 FEB 2013
Obesity is a major public health problem that increases the risk for a broad spectrum of co-morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance.
Design and Methods
Deploying a strategy combining analysis of exome sequencing data in extremely obese members of four consanguineous families with segregation analysis, we screened for causal genetic variants. Filter-based analysis and homozygosity mapping were used to identify and prioritize putative functional variants.
Two novel frameshift mutations in the leptin receptor in two of the families were identified.
These results provide proof-of-principle that whole-exome sequencing of families segregating for extreme obesity can identify causal pathogenic mutations. The methods described here can be extended to additional families segregating for extreme obesity and should enable the identification of mutations in novel genes that predispose to obesity.