ESPE2023 Rapid Free Communications Fat, metabolism and obesity 2 (6 abstracts)
Understanding the genetics of early onset obesity in a cohort of children from Qatar
Idris Mohammed 1,2 , Basma Haris 2 , Tara Al-Barazenji 3 , Dhanya Vasudeva 2 , Sara Tomei 2 , Iman Al Azwani 2 , Hajar Dauleh 2 , Saira Shehzad 2 , Shiga Chirayath 2 , Ghassan Mohamadsalih 2 , Goran Petrovski 2 , Amel Khalifa 2 , Donald love 2 , Mashael Al-Shafai 3 & Khalid Hussain 2
1Hamad Bin Khalifa University, DOHA, Qatar. 2Sidra Medicine, Doha, Qatar. 3Qatar University, Doha, Qatar
Context: Monogenic obesity (MO) 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 MC4R and Leptin genes are the commonest causes of MO. Determining the genetic causes has important clinical benefits as novel therapeutic interventions were developed for some forms of MO.
Objective: This study aimed to unravel and understand the epidemiology and genetic causes of early onset childhood obesity in the population of Qatar.
Methods: 324 patients with early-onset obesity below 10 years with a BMI percentile above the 95th percentile were enrolled. All the coding regions and exon-intron boundaries of 52 genes associated with obesity were sequenced using a targeted gene panel. To analyze, classify and interpret the pathogenicity of the variants identified, several in silico prediction tools were used.
Results: Thirty-one potentially disease-causing variants were identified in 36 probands (14.8%) in 15 candidate genes (LEP, LEPR, POMC, MC3R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, PPARG, ADCY3 and RAI1, and BBS2). Twenty-four of the variants were novel, and the rest, seven variants, were previously reported in literature. Variants in the MC4R gene were the most common in our cohort, and the variant c.485C>T p.T162I in this gene was the most frequent variant seen in five unrelated Qatari probands. Moreover, the majority of the probands carried either variants of uncertain clinical significance (56.4%) or no variants (28.8%) in the 52 genes included in the gene panel.
Conclusion: This study represents the largest MO cohort in this understudied Middle Eastern population which identified variants that seem to explain the phenotype in 14.8% of the cohort. Variants in the MC4R gene seem to be the commonest cause of MO in this population. Early diagnosis potentially improves obesity management and early interventions and helps to identify patients who may benefit from the emerging personalized therapeutic interventions for MO.
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