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Understanding the Genetics of Early-Onset Obesity in a Cohort of Children From Qatar

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submitted on 2024-02-22, 11:29 and posted on 2024-02-22, 11:30 authored by Idris Mohammed, Basma Haris, Tara Al-Barazenji, Dhanya Vasudeva, Sara Tomei, Iman Al Azwani, Hajar Dauleh, Saira Shehzad, Shiga Chirayath, Ghassan Mohamadsalih, Goran Petrovski, Amel Khalifa, Donald R Love, Mashael Al-Shafai, Khalid Hussain

Context

Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin–melanocortin signaling pathway and accounts for around 5% of severe early-onset obesity. Mutations in the genes encoding the MC4R, leptin, and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity.

Objective

To unravel the genetic causes of early-onset obesity in the population of Qatar.

Methods

In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes.

Results

Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, 7 variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C>T p.T162I variant was the most frequent MC4R variant seen in 5 patients.

Conclusion

We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East and revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.

Other Information

Published in: The Journal of Clinical Endocrinology & Metabolism
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1210/clinem/dgad366

Funding

Open Access funding provided by the Qatar National Library.

History

Language

  • English

Publisher

Endocrine Society

Publication Year

  • 2023

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Sidra Medicine
  • Weill Cornell Medicine - Qatar
  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Qatar University
  • Biomedical Research Center - QU
  • Qatar University Health - QU
  • College of Health Sciences - QU HEALTH

Methodology

In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes.

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