Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar.
Division of Endocrinology, Department of Pediatric Medicine, Sidra Medicine, Doha P.O. Box 26999, Qatar.
Genes (Basel). 2024 Jul 23;15(8):966. doi: 10.3390/genes15080966.
The kinase suppressor of Ras 2 () gene is associated with monogenic obesity, and loss-of-function variants in have been identified in individuals with severe early-onset obesity. This study investigated variants in 9 pediatric patients with severe early-onset obesity in Qatar using whole genome sequencing among a cohort of 240 individuals. We focused on variants with a minor allele frequency (MAF) below 1% and a Combined Annotation Dependent Depletion (CADD) score above 13 to identify potential causative variants. Our analysis identified four variants: one intronic (c.1765-8G>A) and three missense variants (c.1057G>A, c.1673G>A, and c.923T>C) in nine patients. The intronic variant c.1765-8G>A was the most frequent (seen in six individuals) and had a CADD score of 21.10, suggesting possible pathogenicity. This variant showed a significantly higher allele frequency in the Qatari population compared to the Genome Aggregation Database (gnomAD), indicating a possible founder effect. Molecular modeling of the missense variants revealed structural changes in the protein structure. The study concludes that these four variants are associated with monogenic obesity, with an autosomal dominant inheritance pattern. The c.1765-8G>A variant's prevalence in Qatar underscores its importance in genetic screening for severe obesity. This research advances the understanding of genetic factors in severe early-onset obesity and may inform better management strategies.
Ras 抑制因子 2 () 基因与单基因肥胖有关，在严重早发性肥胖个体中已发现 基因的功能丧失变异。本研究通过对卡塔尔 240 名个体的全基因组测序，在 9 名患有严重早发性肥胖的儿科患者中研究了 基因的变异。我们重点关注 MAF 低于 1%且 CADD 评分高于 13 的变异，以鉴定潜在的致病变异。我们的分析在 9 名患者中鉴定出 4 种 基因变异：一种内含子变异（c.1765-8G>A）和三种错义变异（c.1057G>A、c.1673G>A 和 c.923T>C）。内含子变异 c.1765-8G>A 最为常见（在 6 名个体中可见），CADD 评分为 21.10，提示可能具有致病性。该变异在卡塔尔人群中的等位基因频率明显高于基因组聚集数据库（gnomAD），提示可能存在一个创始者效应。对这些错义变异的分子建模揭示了蛋白质结构的结构变化。本研究得出结论，这四种 基因变异与单基因肥胖有关，呈常染色体显性遗传模式。c.1765-8G>A 变异在卡塔尔的流行强调了其在严重肥胖症遗传筛查中的重要性。本研究加深了对严重早发性肥胖遗传因素的理解，可能为更好的管理策略提供信息。
