Whole‐Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity

R Gill, YH Cheung, Y Shen, P Lanzano, NM Mirza… - …, 2014 - Wiley Online Library
R Gill, YH Cheung, Y Shen, P Lanzano, NM Mirza, S Ten, NK Maclaren, R Motaghedi…
Obesity, 2014Wiley Online Library
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 …
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.
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