Table_1_Identification of a Rare and Potential Pathogenic MC4R Variant in a Brazilian Patient With Adulthood-Onset Severe Obesity.DOCX

BackgroundThe melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor (MC4R) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity.MethodsThis study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m2, stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0–11 years), 19 patients in the adolescence/youth-onset group (12–21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject’s DNA was assessed using automated Sanger sequencing.ResultsSignificant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity.ConclusionThis study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity.

背景：黑素皮质素能通路调控能量稳态，该系统功能障碍常导致体重增加。已描述的黑素皮质素4受体（MC4R）基因的罕见变异，导致部分或完全功能丧失，具有常染色体共显性遗传特征。这些突变是非综合征性单基因肥胖的最常见原因。在此背景下，本研究旨在对巴西严重肥胖成人队列中的MC4R基因进行测序。方法：本研究纳入了163名无关的先证者，其体重指数（BMI）≥ 35 kg/m2，根据肥胖发病时期分为三组。在总样本中，25名患者被纳入儿童发病组（0–11岁），19名患者被纳入青少年/青年发病组（12–21岁），119名患者被纳入成人发病组（>21岁）。收集血压、人体测量学和生化特征，并使用自动Sanger测序技术评估每位受试者的MC4R编码区。结果：观察到各组之间存在显著的体格测量学差异。与成人发病组相比，儿童发病或青少年/青年发病组的患者体重和BMI中位数更高。共鉴定出5种突变，包括4种错义变异：p.Ser36Thr、p.Val103Ile、p.Ala175Thr和p.Ile251Leu。此外，我们还观察到1种同义变异（p.Ile198=）。p.Ala175Thr变异在一例严重肥胖和成人发病的女性病例中被鉴定出来。该变异先前被描述为部分功能丧失突变，其中次等位基因具有显性负效应，可能引起cAMP活性降低。结论：本研究表明，在巴西严重肥胖成人队列中，常见和罕见变异的患病率较高，且为减重手术候选人。我们在一位严重肥胖和成人发病的巴西患者中鉴定出一种罕见的潜在致病性MC4R变异。