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

Authors

  • Richard Gill,

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

    1. Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
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  • Yufeng Shen,

    1. Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
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  • Patricia Lanzano,

    1. Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
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  • Nazrat M. Mirza,

    1. Section on Growth and Obesity Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA
    2. Children's National Medical Center, Washington, District of Columbia, USA
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  • Svetlana Ten,

    1. Division of Pediatric Endocrinology at Maimonides Infants and Children's Hospital of Brooklyn and SUNY, Downstate Medical Center, Brooklyn, New York, USA
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  • Noel K. Maclaren,

    1. Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA
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  • Roja Motaghedi,

    1. Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
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  • Joan C. Han,

    1. Section on Growth and Obesity Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA
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  • Jack A. Yanovski,

    1. Section on Growth and Obesity Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA
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  • Rudolph L. Leibel,

    1. Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
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  • Wendy K. Chung

    Corresponding author
    1. Division of Molecular Genetics Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
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  • 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.

  • 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.

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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