Non-syndromic Obesity Research Articles

Characterization of Circulating Protein Profiles in Individuals with Prader–Willi Syndrome and Individuals with Non-Syndromic Obesity

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder characterized by distinctive physical, cognitive, and behavioral manifestations, coupled with profound alterations in appetite regulation, leading to severe obesity and metabolic dysregulation. These clinical features arise from disruptions in neurodevelopment and neuroendocrine regulation, yet the molecular intricacies of PWS remain incompletely understood. Methods: This study aimed to comprehensively profile circulating neuromodulatory factors in the serum of 53 subjects with PWS and 34 patients with non-syndromic obesity, utilizing a proximity extension assay with the Olink Target 96 neuro-exploratory and neurology panels. The ANOVA p-values were adjusted for multiple testing using the Benjamani–Hochberg method. Protein–protein interaction networks were generated in STRING V.12. Corrplots were calculated with R4.2.2 by using the Hmisc, Performance Analytics, and Corrplot packages Results: Our investigation explored the potential genetic underpinnings of the circulating protein signature observed in PWS, revealing intricate connections between genes in the PWS critical region and the identified circulating proteins associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment involving, CD38, KYNU, NPM1, NMNAT1, WFIKKN1, and GDF-8/MSTN. The downregulation of CD38 in individuals with PWS (p < 0.01) indicates dysregulation of oxytocin release, implicating pathways associated with NAD metabolism in which KYNU and NMNAT1 are involved and significantly downregulated in PWS (p < 0.01 and p < 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p < 0.05) were also observed. Conclusions: This study highlights potential circulating protein biomarkers associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment in PWS individuals with potential clinical implications.

Liraglutide for Children 6 to

No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children. In this phase 3a trial, which consisted of a 56-week treatment period and a 26-week follow-up period,we randomly assigned children (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions. The primary end point was the percentage change in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters). The confirmatory secondary end points were the percentage change in body weight and a reduction in BMI of at least 5%. A total of 82 participants underwent randomization; 56 were assigned to the liraglutide group and 26 to the placebo group. At week 56, the mean percentage change from baseline in BMI was -5.8% with liraglutide and 1.6% with placebo, representing an estimated difference of -7.4 percentage points (95% confidence interval [CI], -11.6 to -3.2; P<0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, representing an estimated difference of -8.4 percentage points (95% CI, -13.4 to -3.3; P = 0.001), and a reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P = 0.02). Adverse events occurred in 89% and 88% of participants in the liraglutide and placebo groups, respectively. Gastrointestinal adverse events were more common in the liraglutide group (80% vs. 54%); serious adverse events were reported in 12% and 8% of participants in the liraglutide and placebo groups, respectively. Among children (6 to <12 years of age) with obesity, treatment with liraglutide for 56 weeks plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions. (Funded by Novo Nordisk; SCALE Kids ClinicalTrials.gov number, NCT04775082.).

Unleashing the power of retatrutide: A possible triumph over obesity and overweight: A correspondence.

Overweight and obesity have become global health challenges with increasing prevalence. Several drugs have received Food and Drug Administration approval for nonsyndromic obesity treatment, but most have limitations, including gastrointestinal side effects and limited weight loss efficacy. Retatrutide, a novel incretin mimetic agent, has shown promise in clinical trials for significant weight reduction. It has demonstrated dosage-dependent pharmacokinetics with favorable safety profiles. The primary focus of this paper is to explore retatrutide and critically assess its clinical trials to justify its use and feasibility while highlighting its shortcomings. This paper also delves into the subject of obesity and its health manifestations. It is expected that the use of retatrutide, a triple agonist, will result in significant weight loss among individuals who are obese or overweight.

Oligogenic inheritance in severe adult obesity.

The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance. Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service. We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance. Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.

Proteome profiling identifies circulating biomarkers associated with hepatic steatosis in subjects with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS. Circulating proteome profiling was conducted in 29 individuals with PWS (15 with steatosis, 14 without) using the Olink Target 96 metabolism and cardiometabolic panels. Correlation analysis was performed to identify the association between protein biomarkes and clinical variables, while the gene enrichment analysis was conducted to identify pathways linked to deregulated proteins. Receiver operating characteristic (ROC) curves assessed the discriminatory power of circulating protein while a logistic regression model evaluated the potential of a combination of protein biomarkers. CDH2, CTSO, QDPR, CANT1, ALDH1A1, TYMP, ADGRE, KYAT1, MCFD, SEMA3F, THOP1, TXND5, SSC4D, FBP1, and CES1 exhibited a significant differential expression in liver steatosis, with a progressive increase from grade 1 to grade 3. FBP1, CES1, and QDPR showed predominant liver expression. The logistic regression model, -34.19+0.85 * QDPR*QDPR + 0.75 * CANT1*TYMP - 0.46 * THOP1*ALDH1A, achieved an AUC of 0.93 (95% CI: 0.63-0.99), with a sensitivity of 93% and specificity of 80% for detecting steatosis in individuals with PWS. These biomarkers showed strong correlations among themselves and were involved in an interconnected network of 62 nodes, related to seven metabolic pathways. They were also significantly associated with cholesterol, LDL, triglycerides, transaminases, HbA1c, FLI, APRI, and HOMA, and showed a negative correlation with HDL levels. The biomarkers identified in this study offer the potential for improved patient stratification and personalized therapeutic protocols.

Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with p-value of 3.6e-12 in the UK biobank cohort. Additionally, we identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity and report the clinical histories of these individuals with non-syndromic obesity with no history of neurobehavioral or cognitive disability. The BMI association was replicated in the All of Us whole genome sequencing data. Heterozygous pLoF BSN variants constitute a new etiology for obesity.

Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity-The Case of BBS Obesity.

Obesity is a metabolic state generated by the expansion of adipose tissue. Adipose tissue expansion depends on the interplay between hyperplasia and hypertrophy, and is mainly regulated by a complex interaction between genetics and excess energy intake. However, the genetic regulation of adipose tissue expansion is yet to be fully understood. Obesity can be divided into common multifactorial/polygenic obesity and monogenic obesity, non-syndromic and syndromic. Several genes related to obesity were found through studies of monogenic non-syndromic obesity models. However, syndromic obesity, characterized by additional features other than obesity, suggesting a more global role of the mutant genes related to the syndrome and, thus, an additional peripheral influence on the development of obesity, were hardly studied to date in this regard. This review summarizes present knowledge regarding the hyperplasia and hypertrophy of adipocytes in common obesity. Additionally, we highlight the scarce research on syndromic obesity as a model for studying adipocyte hyperplasia and hypertrophy, focusing on Bardet-Biedl syndrome (BBS). BBS obesity involves central and peripheral mechanisms, with molecular and mechanistic alternation in adipocyte hyperplasia and hypertrophy. Thus, we argue that using syndromic obesity models, such as BBS, can further advance our knowledge regarding peripheral adipocyte regulation in obesity.

Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene’s candidacy in 6q16.1 deletions

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Genetic risk score for common obesity and anthropometry in Spanish schoolchildren

IntroductionCommon or non-syndromic obesity is a complex polygenic trait conditioned by biallelic or single-base polymorphisms called SNPs (Single-Nucleotide Polymorphisms) that present an additive effect and act synergistically. Most genotype-obese phenotype association studies include body mass index (BMI) or waist-to-height ratio (WtHR), and very few introduce a broad anthropometric profile.ObjectiveTo verify whether a genetic risk score (GRS) developed from 10 SNPs is associated with the obesity phenotype assessed from anthropometric measures indicative of excess weight, adiposity and fat distribution.Material and methodsA series of 438 Spanish schoolchildren (6–16 years old) were evaluated anthropometrically (weight, height, waist circumference, skinfold thickness, BMI, WtHR, body fat percentage [%BF]). Ten SNPs were genotyped from saliva samples, generating a GRS for obesity, establishing genotype-phenotype association.ResultsSchoolchildren categorised as obese by BMI, ICT and %BF had higher GRS than their non-obese peers. The prevalence of overweight and adiposity was higher in subjects with a GRS above the median. Similarly, between 11 and 16 years of age, all anthropometric variables presented higher averages.ConclusionsGRS estimated from the 10 SNPs can be a diagnostic tool for the potential risk of obesity in Spanish schoolchildren and could be useful from the preventive perspective.

Monogenic forms of childhood obesity: a review

Childhood obesity has become a notable health concern in the world. According to American Medical Association, obesity is defined as having a body mass index greater than 30 kg/m2. Childhood obesity is classified into three main categories, polygenic obesity, which is the most common form; followed by monogenic obesity, which is rare; and non-syndromic obesity. The management of childhood obesity is complex and requires a multidisciplinary approach. For monogenic obesity, several treatment options have been investigated. Long-term body weight maintenance is challenging. This review aimed to provide an overview of monogenic obesity, its mechanisms, evaluation, and treatment options. Monogenic forms of childhood obesity are rare. However, early diagnosis using whole-exome sequencing is needed to identify the causes of obesity and its associated anomalies for subsequent treatment. In addition, the early initiation of a multidisciplinary management approach is essential to prevent long-term morbidity and mortality. Several new treatment options have recently emerged, which could, in combination with lifestyle modifications, provide a favorable outcome for patients with non-syndromic forms of obesity.

Puntuación de riesgo genético para la obesidad común y antropometría en escolares españoles

IntroductionCommon or non-syndromic obesity is a complex polygenic trait conditioned by biallelic or single-base polymorphisms called SNPs (Single-Nucleotide Polymorphisms) that present an additive effect and act synergistically. Most genotype-obese phenotype association studies include body mass index (BMI) or waist-to-height ratio (WtHR), and very few introduce a broad anthropometric profile. ObjectiveTo verify whether a genetic risk score (GRS) developed from 10SNPs is associated with the obesity phenotype assessed from anthropometric measures indicative of excess weight, adiposity and fat distribution. Material and methodsA series of 438 Spanish schoolchildren (6 to 16years old) were evaluated anthropometrically (weight, height, waist circumference, skinfold thickness, BMI, WtHR, body fat percentage [%BF]). Ten SNPs were genotyped from saliva samples, generating a GRS for obesity, establishing genotype-phenotype association. ResultsSchoolchildren categorised as obese by BMI, ICT and %BF had higher GRS than their non-obese peers. The prevalence of overweight and adiposity was higher in subjects with a GRS above the median. Similarly, between 11 and 16years of age, all anthropometric variables presented higher averages. ConclusionsGRS estimated from the 10SNPs can be a diagnostic tool for the potential risk of obesity in Spanish schoolchildren and could be useful from the preventive perspective.

RF02 | PSAT110 Resting Energy Expenditure and Body Composition in Children and Adolescents with Genetic, Hypothalamic, Medication-Induced or Multifactorial Severe Obesity

Abstract Background Pediatric obesity is a multifactorial disease characterized by a prolonged imbalance between energy intake and expenditure. In rare cases, it is caused by underlying medical disorders arising from disruptions in the leptin-melanocortin pathway which regulates satiety and energy expenditure. Aim To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with and without underlying medical causes. Methods This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic center in which endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity were evaluated. Patients in whom no underlying medical cause was identified were classified as multifactorial obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio measured REE (mREE) vs predicted REE (Schofield equations) was expressed as REE%, with decreased mREE defined as REE% ≤90% and elevated mREE as ≥110%. Additionally, the ratio mREE vs fat-free-mass (FFM) was calculated. Results We included 292 patients, of which 218 (75%) patients had multifactorial obesity and 74 (25%) had an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p&amp;lt;0.01). Measured REE was decreased in 60 (21%) patients (corresponding to an average overprediction of daily caloric needs of 341 kcal/day) and elevated in 69 (24%) patients. Only in hypothalamic obesity, a larger proportion of patients showed a decreased REE compared to multifactorial obesity (6/10 vs 41/218, p&amp;lt;0.01). FFM was higher in children with non-syndromic obesity compared to multifactorial obesity (+7.5kg, p&amp;lt;0.001), but lower in syndromic obesity (-5.2kg, p=0.03), hypothalamic obesity (-12.6kg, p&amp;lt;0.001), and similar in medication-induced obesity (+1.5kg FFM, p=0.80). Mean mREE/FFM was 46.5 ± 10.6 kcal/day/kg FFM and did not differ between patients with underlying medical causes compared to multifactorial obesity (all p&amp;gt;0.05). Conclusion In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Almost half of patients had decreased or elevated mREE. When relating mREE to FFM, no differences were found between children with underlying medical causes versus multifactorial obesity. Thus, our study underlines the importance of measuring REE and relating mREE to FFM in children with early-onset severe obesity with or without underlying medical causes. This knowledge is important for patient-tailored treatment, e.g. personalized dietary or physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m.

Genetics of Obesity in Humans: A Clinical Review.

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11–13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.

Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans.

Growing evidence supports syndromic and nonsyndromic causes of obesity, including genome-wide association studies, candidate gene analysis, advanced genetic technology using next-generation sequencing (NGS), and identification of copy number variants. Identification of susceptibility genes impacts mechanistic understanding and informs precision medicine. The cause of obesity is heterogeneous with complex biological processes playing a role by controlling peptides involved in regulating appetite and food intake, cellular energy, and metabolism. Evidence for heritability shows genetic components contributing to 40%-70% of obesity. Monogenic causes and obesity-related syndromes are discussed and illustrated as well as biological pathways, gene interactions, and factors contributing to the obesity phenotype. Over 550obesity-related single genes have been identified and summarized in tabular form with approximately 20% of these genes have been added to obesity gene panels for testing by commercially available laboratories. Early studies show that about 10% of patients with severe obesity using NGS testing have a pathogenic gene variant. Discussion to help characterize gene-gene interactions and disease mechanisms for early diagnosis, treatment, and risk factors contributing to disease is incorporated in this review.

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program.

BackgroundGenetic screening for youth with obesity in the absence of syndromic findings has not been part of obesity management. For children with early onset obesity, genetic screening is recommended for those having clinical features of genetic obesity syndromes (including hyperphagia).ObjectivesThe overarching goal of this work is to report the findings and experiences from one pediatric weight management program that implemented targeted sequencing analysis for genes known to cause rare genetic disorders of obesity.Subjects/MethodsThis exploratory study evaluated youth tested over an 18-month period using a panel of 40-genes in the melanocortin 4 receptor pathway. Medical records were reviewed for demographic and visit information, including body mass index (BMI) percent of 95th percentile (%BMIp95) and two eating behaviors.ResultsOf 117 subjects: 51.3% were male; 53.8% Hispanic; mean age 10.2 years (SD 3.8); mean %BMIp95 157% (SD 29%). Most subjects were self- or caregiver-reported to have overeating to excess or binge eating (80.3%) and sneaking food or eating in secret (59.0%). Among analyzed genes, 72 subjects (61.5%) had at least one variant reported; 50 (42.7%) had a single variant reported; 22 (18.8%) had 2–4 variants reported; most variants were rare (<0.05% minor allele frequency [MAF]), and of uncertain significance; all variants were heterozygous. Nine subjects (7.7%) had a variant reported as PSCK1 “risk” or MC4R “likely pathogenic”; 39 (33.3%) had a Bardet-Biedl Syndrome (BBS) gene variant (4 with “pathogenic” or “likely pathogenic” variants). Therefore, 9 youth (7.7%) had gene variants previously identified as increasing risk for obesity and 4 youth (3.4%) had BBS carrier status.ConclusionsPanel testing identified rare variants of uncertain significance in most youth tested, and infrequently identified variants previously reported to increase the risk for obesity. Further research in larger cohorts is needed to understand how genetic variants influence the expression of non-syndromic obesity.

Familial early-onset obesity in Turkish children: variants and polymorphisms in the melanocortin-4 receptor (MC4R) gene.

Genetic factors have a key role in childhood obesity with higher rates in children than adults. Among the monogenic types of non-syndromic obesity, melanocortin-4 receptor (MC4R) deficiency is the most frequent cause. Beside pathogenic variants, single-nucleotide polymorphisms in MC4R gene are also associated with lower energy expenditure. The aim of this study was to estimate the frequency of MC4R variants and polymorphisms in a cohort of Turkish children and adolescents with severe early-onset obesity, and to understand the clinical features of patients. Patients, 1-17 years of age, with the onset of obesity before 10 years of age and a body mass index (BMI) standard deviation score (SDS) of >2.3, and who had a family history of early-onset obesity in at least one of their first-degree relatives were included in the study. Beside routine blood tests genetic analyses for MC4R gene were performed. Analyses of MC4R revealed previously known variations in three (3.5%) patients, and pathogenic polymorphisms related with obesity in four (4.7%) patients. BMI SDS values were between 2.8 and 5.5 SDS in the pathogenic variant carrier group, and 2.8-4.9 SDS in the polymorphism group. Mean BMI SDS in variant-negative group was 3.4±0.82. Investigation of the MC4R in individuals with early-onset obesity and presence of obesity first-degree relatives is important. Hypertension is a rare comorbidity compared to other causes. Contrary to studies reporting that insulin resistance was absent or very rare, we found it as a frequent finding in both pathogenic variants and polymorphisms of MC4R.

EP252: A multidisciplinary endocrine-genetic obesity clinic for children: Diagnostic utility and insights

Obesity is a widespread disease globally, with an estimated 7% of cases representing childhood-onset disease associated with multiple comorbidities. Several genes have been implicated in the increased predisposition to syndromic and non-syndromic obesity. However, due to the genetic heterogeneity of early-onset obesity, the identification of pediatric patients with obesity that warrant a genetic evaluation poses a clinical challenge. Consequently, we have established an Endocrine-Genetics clinic with a multidisciplinary approach to evaluate pediatric patients with early-onset, severe obesity.

EP126: Frequency of MC4R pathway variants in a large US cohort of pediatric and adult patients with severe obesity

The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of energy balance. Variants in a number of genes within this pathway have well-established associations with severe obesity. However, the overall frequency of rare variants in these genes has not been assessed systematically in a clinically relevant population, and it is unknown whether variant frequency differs depending on the age of ascertainment. Genetic testing can improve diagnosis of rare genetic diseases of obesity and identify patients who may benefit from targeted therapeutic intervention. We sequenced exons and intron-exon boundaries for 40 obesity-related genes in individuals with severe obesity (defined as ≥97th percentile of body mass index [BMI] for age in those <18 years old, or BMI ≥40 kg/m2 in those ≥18 years old) who participated in the US-based Uncovering Rare Obesity diagnostic genetic testing program. This next-generation sequencing panel included 11 genes associated with nonsyndromic obesity that encode proteins functioning in the MC4R pathway (POMC, PCSK1, LEPR, SRC1 [NCOA1], SH2B1, MC4R, MC3R, CPE, LEP, KSR2, and SIM1). Variants were classified as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS) according to American College of Medical Genetics and Genomics criteria. We additionally included 1 nonrare variant, PCSK1 p.N221D, for which published functional and population studies suggests a potential contribution to obesity. Individuals with variants in 5 of these genes (POMC, PCSK1, LEPR, SRC1, and SH2B1) have previously been assessed in a trial using the MC4R agonist setmelanotide and demonstrated meaningful weight loss. Variants were classified according to their classical mode of inheritance (autosomal dominant: SRC1, SH2B1, MC4R, MC3R, KRS2, and SIM1; autosomal recessive: POMC, PCSK1, CPE, and LEP). Among 7,826 individuals, 16%, 33%, 30%, and 21% were aged <6, 6–12, 12–18, and >18 years, respectively. Among these individuals, 19% carried ≥1 rare variant in ≥1 of the 11 studied genes, including 3.6% carrying a P/LP variant and 15.4% carrying a VUS variant. Additionally, 11.9% of individuals had variants in line with mode of inheritance, including 2.1% of individuals with all P/LP variants. Restricting to the 5 genes with prior demonstrated responsiveness to setmelanotide (POMC, PCSK1, LEPR, SRC1, and SH2B1), the variant frequency was 11% for P/LP or VUS variants. An additional 6.4% of individuals carried the PCSK1 p.N221D variant. No differences in frequency were observed by age group. In our large US-based cohort of individuals with early-onset, severe obesity, 25.4% of individuals carried a potentially clinically relevant variant in ≥1 of 11 MC4R pathway–related genes, including 11.9% of individuals with variants in line with classical mode of inheritance. Genetic testing of patients with severe obesity may therefore be an important component of understanding the etiology of these patients’ phenotypes. No differences in variant frequency were observed across age groups, indicating that genetic testing for obesity-related genes is appropriate in both pediatric and adult patients with severe obesity.

The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Introduction: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Methods: Whole genome sequencing data of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2, and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. Results: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. Conclusion: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.