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Obesity (Silver Spring). 2014 Feb;22(2):576-84. doi: 10.1002/oby.20492. Epub 2013 Oct 15.

Whole-exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity.

Author information

1
Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, New York, USA.

Abstract

OBJECTIVE:

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.

RESULTS:

Two novel frameshift mutations in the leptin receptor in two of the families were identified.

CONCLUSIONS:

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.

PMID:
23616257
PMCID:
PMC3791145
DOI:
10.1002/oby.20492
[Indexed for MEDLINE]
Free PMC Article

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