Whole-exome Sequencing Identifies Novel LEPR Mutations in Individuals with Severe Early Onset Obesity

Overview

Journal Obesity (Silver Spring)

Specialties Endocrinology
Nutritional Sciences
Physiology

Date 2013 Apr 26

PMID 23616257

Citations 21

Authors

Richard Gill

Yee Him Cheung

Yufeng Shen

Patricia Lanzano

Nazrat M Mirza

Svetlana Ten

Noel K Maclaren

Roja Motaghedi

Joan C Han

Jack A Yanovski

Rudolph L Leibel

Wendy K Chung

Affiliations

Soon will be listed here.

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.

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