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

Richard Gill, Yee Him Cheung, Yufeng Shen, Patricia Lanzano, Nazrat M. Mirza, Svetlana Ten, Noel K. MacLaren, Roja Motaghedi, Joan Han, Jack A. Yanovski, Rudolph L. Leibel, Wendy K. Chung

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)576-584
Number of pages9
JournalObesity
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2014

Fingerprint

Exome
Obesity
Mutation
Leptin Receptors
Frameshift Mutation
Genes
Organism Cloning
Public Health

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Nutrition and Dietetics

Cite this

Gill, R., Cheung, Y. H., Shen, Y., Lanzano, P., Mirza, N. M., Ten, S., ... Chung, W. K. (2014). Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity, 22(2), 576-584. https://doi.org/10.1002/oby.20492

Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. / Gill, Richard; Cheung, Yee Him; Shen, Yufeng; Lanzano, Patricia; Mirza, Nazrat M.; Ten, Svetlana; MacLaren, Noel K.; Motaghedi, Roja; Han, Joan; Yanovski, Jack A.; Leibel, Rudolph L.; Chung, Wendy K.

In: Obesity, Vol. 22, No. 2, 01.02.2014, p. 576-584.

Research output: Contribution to journalArticle

Gill, R, Cheung, YH, Shen, Y, Lanzano, P, Mirza, NM, Ten, S, MacLaren, NK, Motaghedi, R, Han, J, Yanovski, JA, Leibel, RL & Chung, WK 2014, 'Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity', Obesity, vol. 22, no. 2, pp. 576-584. https://doi.org/10.1002/oby.20492
Gill, Richard ; Cheung, Yee Him ; Shen, Yufeng ; Lanzano, Patricia ; Mirza, Nazrat M. ; Ten, Svetlana ; MacLaren, Noel K. ; Motaghedi, Roja ; Han, Joan ; Yanovski, Jack A. ; Leibel, Rudolph L. ; Chung, Wendy K. / Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. In: Obesity. 2014 ; Vol. 22, No. 2. pp. 576-584.
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