Clinical and molecular characterisation of children with monogenic obesity: a case series.

INTRODUCTION: To study the clinical profile and molecular diagnosis of children with severe early-onset non-syndromic monogenic obesity. METHODS: The clinical and molecular data (performed using whole exome sequencing) of 7 children with early-onset (< 5 years) non-syndromic monogenic obesity were extracted from the Obesity Clinic files and analysed retrospectively. RESULTS: The median (IQR) age at presentation was 18 (10.5-27) months. Of the 7 patients, 5 were boys, 3 had a history of parental consanguinity, and 4 had a family history of severe early-onset obesity. All patients exhibited hyperphagia and showed signs of insulin resistance. Dyslipidaemia and fatty liver were observed in 4. The variants identified in 6 patients included 2 in leptin receptor, and one each in melanocortin 4 receptor, pro-opiomelanocortin, leptin, and neurotrophic tyrosine kinase receptor type 2 genes. Notably, 4 of these variants were novel. CONCLUSIONS: This case series provides valuable insights into the spectrum of genetic mutations associated with non-syndromic monogenic obesity in North Indian children. The findings underscore the significance of next-generation sequencing in identifying the aetiology of severe early-onset obesity.

Medical semiology of patients with monogenic obesity: A systematic review.

Patients with monogenic obesity display numerous medical features on top of hyperphagic obesity, but no study to date has provided an exhaustive description of their semiology. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to January 2022 to identify studies that described symptoms of patients carrying pathogenic mutations in at least one of eight monogenic obesity genes (ADCY3, LEP, LEPR, MC3R, MC4R, MRAP2, PCSK1, and POMC). Of 5207 identified references, 269 were deemed eligible after title and abstract screening, full-text reading, and risk of bias and quality assessment. Data extraction included mutation spectrum and mode of inheritance, clinical presentation (e.g., anthropometry, energy intake and eating behaviors, digestive function, puberty and fertility, cognitive features, infectious diseases, morphological characteristics, chronic respiratory disease, and cardiovascular disease), biological characteristics (metabolic profile, endocrinology, hematology), radiological features, and treatments. The review provides an exhaustive description of mandatory, non-mandatory, and unique symptoms in heterozygous and homozygous carriers of mutation in eight monogenic obesity genes. This information is critical to help clinicians to orient genetic testing in subsets of patients with suspected monogenic obesity and provide actionable treatments (e.g., recombinant leptin and MC4R agonist).

Case report: Nerve fiber regeneration in children with melanocortin 4 receptor gene mutation related obesity treated with semaglutide.

Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].

Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity.

PURPOSE OF REVIEW: The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care. RECENT FINDINGS: Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% -new variants in known genes as well as identification of novel genes- causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity. While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.

Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management.

Background: Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies. Methods: In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity. Results: Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists. Conclusion: Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.

Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C>T p.Arg57* Variant in CEP19 Gene.

Introduction: Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The "centrosomal protein 19 (CEP19)" gene encodes for a centrosomal and ciliary protein. Homozygous variants in the CEP19 gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features. Methods: Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family. Results: The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m2), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C>T, p. Arg57*) pathogenic variant was detected in exon 3 of the CEP19 gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein. Discussion/Conclusion: Our study expands the phenotypical manifestations and variation database of CEP19 variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.

Whole-exome sequencing combined with postoperative data identify c.1614dup (CAMKK2) as a novel candidate monogenic obesity variant.

Early-onset obesity is a rising health concern influenced by heredity. However, many monogenic obesity variants (MOVs) remain to be discovered due to differences in ethnicity and culture. Additionally, patients with known MOVs have shown limited weight loss after bariatric surgery, suggesting it can be used as a screening tool for new candidates. In this study, we performed whole-exome sequencing (WES) combined with postoperative data to detect candidate MOVs in a cohort of 62 early-onset obesity and 9 late-onset obesity patients. Our findings demonstrated that patients with early-onset obesity preferred a higher BMI and waist circumference (WC). We confirmed the efficacy of the method by identifying a mutation in known monogenic obesity gene, PCSK1, which resulted in less weight loss after surgery. 5 genes were selected for further verification, and a frameshift variant in CAMKK2 gene: NM_001270486.1, c.1614dup, (p. Gly539Argfs*3) was identified as a novel candidate MOV. This mutation influenced the improvement of metabolism after bariatric surgery. In conclusion, our data confirm the efficacy of WES combined with postoperative data in detecting novel candidate MOVs and c.1614dup (CAMKK2) might be a promising MOV, which needs further confirmation. This study enriches the human monogenic obesity mutation database and provides a scientific basis for clinically accurate diagnosis and treatment.

Classification of Congenital Leptin Deficiency.

PURPOSE: Bi-allelic pathogenic leptin gene variants cause severe early onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties. METHODS: We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype. RESULTS: A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into three different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients) and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n=1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th BMI percentile (%BMIp95) compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin. MAIN CONCLUSIONS: Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency.

Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment.

Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms "obesity", "genetics", "monogenic", "syndromic", "drugs", "autosomal dominant", "autosomal recessive", "leptin-melanocortin pathway", and "children" in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background.

Rare genetic forms of obesity in childhood and adolescence: A narrative review of the main treatment options with a focus on innovative pharmacological therapies.

The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists throughout life. Both polygenic and monogenic obesity are influenced by a combination of genetic predisposition and environmental factors. Rare genetic obesity forms are caused by specific pathogenic variants in single genes that have a significant impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. Genetic testing is recommended for patients who exhibit rapid weight gain in infancy and show additional clinical features suggestive of monogenic obesity as an early identification allows for appropriate treatment, preventing the development of obesity-related complications, avoiding the failure of traditional treatment approaches. In the past, the primary recommendations for managing obesity in children and teenagers have been focused on making multiple lifestyle changes that address diet, physical activity, and behaviour, with the goal of maintaining these changes long-term. However, achieving substantial and lasting weight loss and improvements in body mass index (BMI) through lifestyle interventions alone is rare. Recently the progress made in genetic analysis has paved the way for innovative pharmacological treatments for different forms of genetic obesity. By understanding the molecular pathways that contribute to the development of obesity, it is now feasible to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms.  Conclusion: However, additional preclinical research and studies in the paediatric population are required, both to develop more personalised prevention and therapeutic programs, particularly for the early implementation of innovative and beneficial management options, and to enable the translation of these novel therapy approaches into clinical practice. What is Known: • The prevalence of obesity in the paediatric population is increasing, and it is considered as a multifaceted condition that often begins in early childhood and persists in the adult life. Particularly, rare genetic forms of obesity are influenced by a combination of genetic predisposition and environmental factors and are caused by specific pathogenic variants in single genes showing a remarkable impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. • Patients who present with rapid weight gain in infancy and show additional clinical characteristics indicative of monogenic obesity should undergo genetic testing, which, by enabling a correct diagnosis, can prevent the development of obesity-related consequences through the identification for appropriate treatment. What is New: • In recent years, advances made in genetic analysis has made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. In fact, it is now achievable to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms by understanding the molecular pathways involved in the development of obesity. • As demonstrated over the last years, two drugs, setmelanotide and metreleptin, have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function mutations in genes involved in the leptin-melanocortin pathway. Recent advancements have led to the development of novel treatments, including liraglutide, semaglutide and retatrutide, that have the potential to prevent the progression of metabolic abnormalities and improve the prognosis of individuals with these rare and severe forms of obesity. However, extensive preclinical research and, specifically, additional studies in the paediatric population are necessary to facilitate the translation of these innovative treatment techniques into clinical practice.

Beneficial Effects of Setmelanotide in a 5-Year-Old Boy With POMC Deficiency and on His Caregivers.

The melanocortin-4 receptor agonist setmelanotide is now recommended for the treatment of genetic obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency in patients aged 6 years and older. Here, we describe the clinical benefit of setmelanotide administration in a 5-year-old child with severe hyperphagia and obesity due to POMC deficiency. Daily administration of 0.5 mg setmelanotide for 12 months resulted in significant weight loss of -30 kg from baseline (-36% of weight loss) and improvements in hyperphagia and metabolic status. No major side effects were observed, except for hyperpigmentation and transient spontaneous erections. Interestingly, the clinical improvement of the child was associated with a remarkable improvement in the quality of life of the parents, along with a decrease in their emotional scores. This observation supports the early use of setmelanotide in young children with melanocortin pathway variants, in order to limit the adverse consequences of early and extreme weight gain, and to improve the quality of life of patients and of their relatives.

Management of Monogenic and Syndromic Obesity.

Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. Additional therapies, including metreleptin and setmelanotide, that target defects within the leptin signaling pathway can effectively synergize with lifestyle efforts to treat monogenic disorders of leptin, leptin receptor, proopiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1) and syndromic conditions, such as the ciliopathies Bardet-Biedl and Alström syndromes, whose pathophysiological mechanisms also converge on the leptin pathway. Investigational treatments for Prader-Willi syndrome target specific defects caused by reduced expression of paternally derived genes within the chromosome 15q region.

Functional Characterization of Novel MC4R Variants Identified in Two Unrelated Patients with Morbid Obesity in Qatar.

The leptin-melanocortin pathway is pivotal in appetite and energy homeostasis. Pathogenic variants in genes involved in this pathway lead to severe early-onset monogenic obesity (MO). The MC4R gene plays a central role in leptin-melanocortin signaling, and heterozygous variants in this gene are the most common cause of MO. A targeted gene panel consisting of 52 obesity-related genes was used to screen for variants associated with obesity. Variants were analyzed and filtered to identify potential disease-causing activity and validated using Sanger sequencing. We identified two novel heterozygous variants, c.253A>G p.Ser85Gly and c.802T>C p.Tyr268His, in the MC4R gene in two unrelated patients with morbid obesity and evaluated the functional impact of these variants. The impact of the variants on the MC4R gene was assessed using in silico prediction tools and molecular dynamics simulation. To further study the pathogenicity of the identified variants, GT1-7 cells were transfected with plasmid DNA encoding either wild-type or mutant MC4R variants. The effects of allelic variations in the MC4R gene on cAMP synthesis, MC4R protein level, and activation of PKA, ERB, and CREB signaling pathways in both stimulated and unstimulated ɑ-MSH paradigms were determined for their functional implications. In silico analysis suggested that the variants destabilized the MC4R structure and affected the overall dynamics of the MC4R protein, possibly leading to intracellular receptor retention. In vitro analysis of the functional impact of these variants showed a significant reduction in cell surface receptor expression and impaired extracellular ligand binding activity, leading to reduced cAMP production. Our analysis shows that the variants do not affect total protein expression; however, they are predicted to affect the post-translational localization of the MC4R protein to the cell surface and impair downstream signaling cascades such as PKA, ERK, and CREB signaling pathways. This finding might help our patients to benefit from the novel therapeutic advances for monogenic forms of obesity.

A Rare Case of Monogenic Obesity due to a Novel Variant in the ADCY3 Gene: Challenges in Follow-up and Treatment.

Adenylate cyclase 3 (ADCY3) gene alterations have been found to be associated with obesity. However, few patients with homozygous mutations have been reported so far, and the follow-up procedure and treatment options have not been clarified. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 µIU/mL, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A(p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient's weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount's disease and acanthosis nigricans were distinctive, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur even at young ages. More data regarding the follow-up process and treatment of these patients are needed.

Novel homozygous leptin receptor mutation in an infant with monogenic obesity.

Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed by the leptin gene and its receptor. Leptin receptor (LEPR) gene mutation is an extremely rare endocrine disease characterized by early-onset obesity, hyperphagia in addition to pituitary hormone deficiency, and metabolic abnormalities. We report the case of a 12-month-old male infant born of a non-consanguineous marriage. He presented to us with rapid weight gain from 2 months of age along with hyperphagia. Biochemistry revealed a deranged lipid profile, elevated transaminases, and markedly raised serum leptin levels. On genetic analysis, a novel mutation was detected, which was a homozygous variation In exon 12 of the LEPR gene (chr1:g.65608901G>A) that resulted in the synonymous amino acid change of lysine at codon 584 proximal to donor splice site (p.Lys584). The in silico prediction of the variant was 'damaging' by MutationTaster2. The mutation was classified as a 'variant of uncertain significance' due to a lack of published literature and had to be correlated carefully with the clinical symptoms. It was recommended to do Sanger sequencing of the parents and other family members. However, due to financial constraints, the family could not afford the same. At the time of writing, funds were being arranged for procuring setmelanotide, which is a novel and effective therapy for monogenic obesity due to LepR mutation.

High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor.

The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n = 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations. We report a very high mortality in children with LEP (26%) or LEPR deficiency (9%), mainly due to severe pulmonary and gastrointestinal infections. In addition, 40% of surviving children with LEP or LEPR deficiency experience life-threatening episodes of lung or gastrointestinal infections. Although precision drugs are currently available for LEP and LEPR deficiencies, as yet, they are not accessible in Pakistan. An appreciation of the severe impact of LEP or LEPR deficiency on morbidity and early mortality, educational attainment, and the attendant stigmatization should spur efforts to deliver the available life-saving drugs to these children as a matter of urgency.

Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach.

Obesity represents a major health problem in the pediatric population with an increasing prevalence worldwide, associated with cardiovascular and metabolic disorders, and due to both genetic and environmental factors. Rare forms of obesity are mostly monogenic, and less frequently due to polygenic influence. Polygenic form of obesity is usually the common obesity with single gene variations exerting smaller impact on weight and is commonly non-syndromic.Non-syndromic monogenic obesity is associated with variants in single genes typically related to the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation, thus body weight control. Patients with these genetic defects usually present with hyperphagia and early-onset severe obesity. Significant progress in genetic diagnostic testing has recently made for early identification of patients with genetic obesity, which guarantees prompt intervention in terms of therapeutic management of the disease. What is Known: • Obesity represents a major health problem among children and adolescents, with an increasing prevalence worldwide, associated with cardiovascular disease and metabolic abnormalities, and it can be due to both genetic and environmental factors. • Non-syndromic monogenic obesity is linked to modifications in single genes usually involved in the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation. What is New: • The increasing understanding of rare forms of monogenic obesity has provided significant insights into the genetic causes of pediatric obesity, and our current knowledge of the various genes associated with childhood obesity is rapidly expanding. • A useful diagnostic algorithm for early identification of genetic obesity has been proposed, which can ensure a prompt intervention in terms of therapeutic management of the disease and an early prevention of the development of associated metabolic conditions.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases.

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Genetic Obesity Disorders: Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population.

OBJECTIVE: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. STUDY DESIGN: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated. RESULTS: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity. CONCLUSIONS: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.

Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.