Künzel Robert, Faust Helene, Bundalian Linnaeus, Blüher Matthias, Jasaszwili Mariami, Kirstein Anna, Kobelt Albrecht, Körner Antje, Popp Denny, Wenzel Eric, Jamra Rami Abou, Lemke Johannes R, Schöneberg Torsten, Stein Robert, Garten Antje, Le Duc Diana
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
Int J Obes (Lond). 2025 Jun 16. doi: 10.1038/s41366-025-01819-0.
BACKGROUND/OBJECTIVES: Obesity poses a major public health concern. Although BMI heritability is estimated at 40-80%, genetic diagnostics remain challenging. This study aims to (i) assess the diagnostic yield of monogenic obesity in a large patient sample using exome-wide data, (ii) identify predictors to improve genetic testing criteria, and (iii) evaluate whether the identified genes are included in public obesity gene panels.
SUBJECTS/METHODS: We reviewed the genetic test results of 521 patients with obesity. 84.7% underwent whole-exome analysis, 15.3% were analyzed using a multi-thousand-gene panel.
Monogenic obesity was diagnosed in 5.8% of patients, while 7.1% carried a potentially obesogenic variant. Diagnostic yield was higher in children (6.3%) and patients with syndromic obesity (7.0%). Surprisingly, diagnostic yield was lower in severe obesity cases. 40% of patients with monogenic obesity carried variants in genes not included in current obesity panels.
Overall, 12.9% of patients had monogenic obesity or a potentially obesogenic variant. These findings suggest that genetic testing should not be limited to patients with extreme obesity. Current obesity panels miss crucial syndromic genes, demonstrating a need for more comprehensive panels and the superiority of whole-exome sequencing in obesity.
背景/目的：肥胖是一个重大的公共卫生问题。尽管体重指数（BMI）的遗传度估计在40%-80%，但基因诊断仍然具有挑战性。本研究旨在（i）使用全外显子组数据评估大量患者样本中单基因肥胖的诊断率，（ii）确定改善基因检测标准的预测因素，以及（iii）评估已鉴定的基因是否包含在公共肥胖基因检测板中。
对象/方法：我们回顾了521例肥胖患者的基因检测结果。84.7%的患者接受了全外显子组分析，15.3%的患者使用了包含数千个基因的检测板进行分析。
5.8%的患者被诊断为单基因肥胖，7.1%的患者携带潜在致肥胖变体。儿童（6.3%）和综合征性肥胖患者（7.0%）的诊断率较高。令人惊讶的是，重度肥胖病例的诊断率较低。40%的单基因肥胖患者携带的变体存在于当前肥胖检测板未包含的基因中。
总体而言，12.9%的患者患有单基因肥胖或携带潜在致肥胖变体。这些发现表明，基因检测不应局限于极度肥胖的患者。当前的肥胖检测板遗漏了关键的综合征基因，这表明需要更全面的检测板以及全外显子组测序在肥胖检测中的优越性。
