Mutations in the LEP gene, which is responsible for encoding the hormone leptin, are a rare but well-documented cause of severe early-onset obesity in humans. Patients with congenital leptin deficiency due to homozygous or heterozygous LEP mutations display rapid and uncontrolled weight gain in early childhood, often followed by serious hyperphagia and significant metabolic disorders. Many clinical studies have reported that such mutations impair leptin production or function, disrupting hypothalamic regulation of appetite and satiety and leading to profound changes in energy balance and obesity. Patients with LEP gene mutations typically have low or undetectable levels of leptin in serum and may develop complications such as metabolic syndrome, fatty liver disease, or hypogonadism (Strobel et al., 1998; Fischer-Posovszky et al., 2010; Yupanqui-Lozno et al., 2019). It is notable that leptin replacement therapy in these patients can effectively reduce food intake, normalize body weight, and correct associated metabolic disorders, underscoring the central role of the LEP gene in human energy homeostasis (Dayal et al., 2018; Zhao et al., 2014).

The mutations in the LEPR gene (which encode the leptin receptor) are known to cause monogenic severe early-onset obesity. Patients with biallelic pathogenic LEPR gene mutations typically manifest marked hyperphagia and fast weight gain beginning in infancy or early childhood. These types of mutation have the ability to disrupt the binding or signal transduction function of the leptin receptor and cause leptin resistance; although the presence of leptin is higher in the blood, the appetite-regulating pathways in the hypothalamus do not respond to the satiety signal, resulting in uncontrolled food intake and severe obesity. Other clinical features which are shown to be commonly associated with LEPR deficiency include hypogonadotropic hypogonadism and, to varying degrees, changes in pubertal development or hormonal disorders, while metabolic pathway complications such as type 2 diabetes may also occur (Kleinendorst et al., 2020). Recent studies reported that MC4R agonists such as setmelanotide can significantly decrease weight and hunger in patients with confirmed LEPR mutations, underscoring the importance of accurate genetic diagnosis for personalized treatment strategies (Chaves et al., 2022; Nunziata et al., 2019; Supti et al., 2024).

The gene POMC is known to encode pro-opiomelanocortin, and mutations of the POMC gene are shown to cause rare but severe forms of monogenic obesity (Künzel et al., 2025). This type of obesity is characterized by rapid, early-onset weight gain, intense hyperphagia, and pronounced endocrine disorders. Patients with homozygous or heterozygous POMC mutations usually develop severe obesity within the first year of life, as well as secondary adrenal insufficiency due to ACTH (adrenocorticotropic hormone) deficiency and distinctive traits such as pale skin and red hair arise from inadequate levels of melanocyte-stimulating hormones, resulting in reduced melanin production in the hair and skin. These findings underscore the critical role of POMC-derived peptides in regulating many processes in the body such as appetite, energy homeostasis, adrenal function, and pigmentation via the leptin-melanocortin signaling pathway (Yeo et al., 2021). Comprehensive reviews and literature searches often highlight the importance of considering POMC deficiency in cases of severe, early-onset obesity combined with adrenal insufficiency even when characteristic changes in pigmentation are absent, as phenotypic expression can vary widely in individuals with similar genetic mutations (Çetinkaya et al., 2018; Dubern et al., 2008; Mendiratta et al., 2011).

Gene mutations in MC4R are a common form of monogenic obesity (Giannopoulou et al., 2026) and are characterized by early-onset severe obesity, hyperphagia (increased appetite), and metabolic disorders such as hyperinsulinemia and dyslipidemia. The gene MC4R encodes the melanocortin-4 receptor, a G-protein-coupled receptor that plays a pivotal role in many signaling pathways such as hypothalamic leptin-melanocortin, which is responsible for regulation of energy balance by suppressing food intake and increasing energy expenditure (Imangaliyeva et al., 2025). Both heterozygous and homozygous mutations in the MC4R gene have been documented; patients with homozygous mutations frequently experience a significantly more severe clinical presentation compared to those with heterozygous variants. Individuals with MC4R mutations often show rapid weight gain, impaired satiety, and increased linear growth in infancy or early childhood. The variable penetrance and expressivity of MC4R gene mutations have shown to influence clinical severity, but the primary features remain consistent. Targeted therapies such as the MC4R gene agonist setmelanotide have been reported to offer clinical benefit by reducing hyperphagia and promoting weight loss in affected individuals. Despite great advances, treatment remains multifaceted and includes lifestyle interventions and new pharmacotherapies tailored to genetic diagnosis (Doulla et al., 2014; Imangaliyeva et al., 2025; Sridhar and Gumpeny, 2024; Wade et al., 2021).

The PCSK1 gene is responsible for producing the enzyme proprotein convertase 1/3 (PC1/3). Mutations in the PCSK1 gene are responsible for rare but severe forms of monogenic early-onset obesity (Verde et al., 2025). This type of enzyme is crucial for the proteolytic processing of various neuropeptides and prohormones, including those involved in the regulation of appetite, energy balance, and glucose metabolism, such as proopiomelanocortin and proinsulin. The PCSK1 p.Asn221Asp (c.661 A > G) variants have been associated with metabolic pathways, fatty acid oxidation, and hormone processing, increasing the risk of obesity (Verde et al., 2025). Loss-of-function mutations in the PCSK1 gene result in impaired cleavage of these hormone precursors, leading to hyperphagia, severe obesity, and multiple discordance of the endocrinopathies, such as adrenal insufficiency, hypogonadism, and malabsorptive diarrhea in infancy. Both homozygous and heterozygous mutations can cause a spectrum of clinical features, ranging from extreme obesity with neuroendocrine dysfunction to milder phenotypes in heterozygous carriers. These findings underscore the crucial role of PCSK1 in energy homeostasis and endocrine regulation in humans (Löffler et al., 2017; Ramos-Molina et al., 2016; Stijnen et al., 2016).

SIM1 gene mutations are responsible for rare forms of monogenic obesity (Mohammed et al., 2026), characterized by early-onset severe obesity, hyperphagia, and, frequently, neurological behavioral abnormalities such as developmental delays, intellectual disability, and autism. The SIM1 gene is responsible for encoding a transcription factor which is essential for neuronal development in the paraventricular nucleus of the hypothalamus, a brain region critical for the regulation of appetite and energy balance (Mohammed et al., 2026). Loss-of-function mutations reduce SIM1 transcription activity, leading to hypothalamic dysfunction, increased food intake, and, thus, severe obesity. Some affected individuals show features of Prader-Willi syndrome, such as hypotonia and facial dysmorphia, although this phenotype is variable. Many family studies shave shown that rare SIM1 gene variants contribute significantly to familial obesity risk, with mutation severity and environmental factors influencing phenotypic expression. These findings confirm the central role of SIM1 in neurodevelopment and energy homeostasis and mark it as a key gene for genetic screening in early-onset obesity (Bonnefond et al., 2013; Ramachandrappa et al., 2013; Stanikova et al., 2017).

The gene NTRK2 is responsible for the encoding of tropomyosin receptor kinase B (TrkB) (Roussel-Gervais et al., 2023), and mutations in this gene have been associated with severe early-onset obesity characterized by hyperphagia and a disturbed energy balance. The receptor kinase TrkB plays a pivotal role in the brain-derived neurotrophic factor (BDNF) signaling pathway, particularly in hypothalamic neurons that regulate appetite and energy expenditure (Roussel-Gervais et al., 2023). Loss-of-function mutations or deletions of the NTRK2 gene in key hypothalamic regions such as the paraventricular nucleus increase food intake, decrease physical activity, and cause rapid weight gain. Functional studies of human NTRK2 mutations, such as the Y722C variant, show impaired receptor signaling and neuronal function, which may contribute to deficits in hypothalamic neurogenesis and pronounced obesity phenotypes. Furthermore, selective deletion of Ntrk2 in hypothalamic neurons of mice reproduces hyperphagic obesity, underscoring the important role of the NTRK2/TrkB signaling pathway in energy homeostasis (An et al., 2020; Berger et al., 2025). The NTRK2 gene may explain the severe obesity observed in obesity carriers (Köroğlu et al., 2024).

SH2B1 encodes an adapter protein that amplifies the signaling pathways of several hormones crucial for energy homeostasis, including leptin and insulin. Mutations in the SH2B1 gene have shown to have a significant impact on obesity, particularly severe early-onset forms characterized by hyperphagia and insulin resistance. Loss-of-function mutations in the SH2B1 gene disrupt the leptin signaling pathway in the hypothalamus, causing impaired regulation of appetite and energy expenditure, which also results in increased food intake and rapid weight gain. In other words, these types of mutations contribute to insulin resistance and type 2 diabetes, further complicating the metabolic profile of affected individuals. Behavioral abnormalities such as social isolation and aggression have also been observed in patients with SH2B1 gene mutations, suggesting a broader role for SH2B1 gene in neurological function. Mouse models with targeted deletion on the gene SH2B1 replicate many human phenotypes, such as hyperphagia, obesity, and glucose intolerance, underscoring the critical regulatory role of the gene in metabolism and energy balance (Chermon and Birk, 2024; Doche et al., 2012; Rui, 2014).

Deletions in chromosome 6q16 (including the SIM1 gene), 11p13 (including the BDNF gene), and distal 16p11.2 (including the SH2B1 gene; OMIM #613444) are associated with obesity. (Chung et al., 2021; D’Angelo et al., 2018; Han et al., 2008; Faivre et al., 2002). A study by da Silva et al., showed the same deletion (three genomic deletions at the 16p11.2) in the same region in patients with severe obesity from Brazil. Based on this report, clinical and genetic testing should be carried out to identify patients with the genetic form of severe obesity. This will support specific medical treatment, genetic counselling, and targeted therapeutic intervention (Da Silva Assis et al., 2025).

Mutations and the most common genetic variants in the FTO gene (associated with fat mass and obesity) are associated with an increased risk of obesity through different mechanisms that influence energy balance and fat tissue function. The gene FTO is responsible for encoding the RNA demethylase enzyme, in which influences mRNA processing and regulates genes involved in adipogenesis, appetite control, and energy metabolism. Important single nucleotide polymorphisms (SNPs) in the FTO gene, such as rs9939609 and rs1421085, have been shown to be associated with a higher risk for high BMI, increased fatty mass, and altered dietary habits, including a tendency to consume energy-dense and high-fat foods. Mechanistically, these variants influence the expression of neighboring regulatory genes such as IRX3 and IRX5, which are responsible for the differentiation of adipocytes from energy-consuming beige cells to energy-storing white fatty cells, alongside reducing mitochondrial thermogenesis and promoting lipid accumulation. Functional studies also show that FTO gene variants have a great influence on appetite by modulating hypothalamic circuits and increasing ghrelin expression. Together, these molecular and behavioral effects contribute to a positive energy balance and increased susceptibility to obesity. The FTO gene offers potential targets for targeted therapeutic interventions (Kumar et al., 2022; Lan et al., 2020; Poosri et al., 2024; Yang et al., 2017).

Mutations in the MC4R gene not only influence obesity risk through rare, highly effective variants that cause monogenic obesity (see above) but also interact with polygenic susceptibility to modulate obesity outcomes in broader populations. Recent large-scale studies show that carriers of obesity-associated MC4R mutations can exhibit highly diverse phenotypes depending on their polygenic risk score (PRS) for obesity. Individuals with high polygenic risk who also carry MC4R mutations have a significantly higher BMI and a higher risk of obesity than mutation carriers with low polygenic risk who remain normal weight or show only slight weight gain. This suggests that the polygenic background can either increase or attenuate the effect of MC4R gene mutations. Thus, polygenic susceptibility interacts with MC4R gene mutation status and influences the severity and penetrance of obesity. This underscores the complex genetic architecture of this common disease and the importance of integrating information about rare and common variants for personalized risk assessment and treatment strategies (Adamska-Patruno et al., 2021; Chami et al., 2020; Mohn et al., 2025; Wang et al., 2022).

Genetic variants near the SEC16B gene have been shown to be linked to polygenic obesity and an increased BMI in several populations, including Japanese and Caucasians. The SEC16B genes play a pivotal role in encoding a key protein involved in vesicle transport between the endoplasmic reticulum and the Golgi apparatus, which may have an influence on adipocyte function and energy regulation, although its specific metabolic role has not yet been fully elucidated. The common SNPs such as rs10913469 in SEC16B gene show a significant association with obesity risk, likely through the modulation of protein transport on an intracellular level and secretion pathways that influence fat storage and metabolism. These genetic effects add to other obesity-associated loci and thus contribute to the polygenic architecture of obesity. Further functional studies are needed to elucidate the precise biological mechanisms by which SEC16B variants influence obesity and metabolic homeostasis (Hotta et al., 2009; Sahibdeen et al., 2018; Shi et al., 2023).

Variants in the gene LINC02702 have been associated with polygenic obesity, where they influence obesity phenotypes, particularly through their potential regulatory functions during adipogenesis and lipid metabolism. Using a GWAS, the SNP rs486394 within LINC02702 was identified as significantly associated with increased BMI and metabolic traits related to obesity. Interestingly, the genetic results of this SNP differ between metabolically healthy obesity phenotypes and metabolically unhealthy obesity phenotypes, suggesting that LINC02702 influences not only obese individuals but also the metabolic health status of obese individuals. Long intergenic non-protein-coding RNAs (lncRNAs) such as LINC02702 gene are increasingly being recognized for their role in the regulation of gene expression and provide insights into complex genetic interactions underlying polygenic obesity (Jo et al., 2024).

Variants in the GNPDA2 gene have been consistently associated with polygenic obesity and an increased BMI in various population studies through GWAS. The GNPDA2 gene encodes glucosamine-6-phosphate deaminase 2, which is involved in the hexosamine biosynthesis pathway that may influence adipogenesis and glucose metabolism. Studies of gene function suggest that altered GNPDA2 expression influences lipid accumulation and adipocyte differentiation, thereby contributing to increased fat mass. In addition, GNPDA2 is expressed in important metabolic tissues such as the hypothalamus, where it may play a role in nutrient sensing and energy balance regulation. The obesity-associated SNP rs10938397 near GNPDA2 shows a strong correlation with measures of central obesity such as waist circumference and waist-to-height ratio, underscoring its role in obesity distribution. These findings underscore the importance of GNPDA2 gene as a crucial gene contributing to the polygenic risk for fat mass through modulation of both metabolic and central nervous system signaling pathways (Gutierrez-Aguilar et al., 2021; Wu et al., 2019).

Mutations and polymorphisms in the BDNF gene are associated with polygenic obesity due to their influence on energy balance, appetite regulation, and neurodevelopment. The common polymorphism Val66Met (SNP rs6265) in the BDNF gene alters the intracellular transport and secretion of the protein after maturation, thereby influencing hypothalamic signaling pathways that are critical for satiety and food intake control. Several studies from different research groups have confirmed an association between the Met allele and an increased BMI, an increased risk of obesity, and altered metabolic profiles, although the effects differ depending on the population studies and gender. In other words, the regulatory variants are very highly conserved regions of the BDNF gene and modulate its expression in the hypothalamus, thus influencing appetite control and energy homeostasis. The functional impact of these BDNF variants can also be influenced by other factors such as environmental factors, diet, and physical activity, which further contribute to the complex genetic architecture of polygenic obesity (Honarmand et al., 2021; McEwan et al., 2024; Miksza et al., 2023).

Mutations in the ADCY3 gene have been associated with polygenic obesity due to their influence on neural pathways regulating appetite and energy homeostasis. ADCY3 encodes adenylate cyclase 3, an enzyme that is primarily expressed in the primary cilia of hypothalamic neurons, where it catalyzes the production of cyclic AMP (cAMP), an important secondary messenger for appetite regulation and metabolic control. Variants of the ADCY3 gene that impair its function, especially homozygous loss-of-function mutations, have the ability to disrupt cAMP signaling pathways, which lead to excessive eating, severe obesity beginning in early childhood, insulin resistance, and delays in neurological development. Animal models confirm that loss of ADCY3 function disrupts leptin-melanocortin signaling pathways, particularly through its colocalization and interaction with MC4R in hypothalamic neurons, which are essential for normal body weight regulation. Moreover, certain ADCY3 gene polymorphisms are associated with obesity risk in various human populations, confirming its relation to polygenic obesity susceptibility. These findings emphasize how important ADCY3 is as a crucial genetic factor influencing obesity via central nervous system pathways that control feeding behavior and energy balance (Mohammed et al., 2024; Toumba et al., 2021).

The gene mutations found in the RALGAPA1 gene have been associated with polygenic obesity due to their pivotal role in intracellular signaling pathways that regulate energy balance and obesity. RALGAPA1 is responsible for encoding a GTPase-activating protein involved in the regulation of the Ral signaling pathway, which influences different cellular processes such as vesicle transport and cytoskeletal dynamics. Although direct functional studies on the role of RALGAPA1 in obesity are limited, the GWAS have found variants near or within the gene that correlate with increased BMI and obesity risk. These variants likely contribute with small additive effects within the polygenic architecture of obesity and influence fat accumulation and metabolic regulation. Research findings suggest that RALGAPA1 may interact with other obesity-associated genes to modulate hypothalamic control of appetite and peripheral metabolism, thereby contributing to the complex genetic predisposition observed in general obesity (Hinney and Hebebr, 2008).

Mutations in the IRX3 and IRX5 genes have a significant influence on polygenic obesity, primarily through their regulatory effects on energy homeostasis, adipose tissue function, and hypothalamic appetite control. These genes are located near the FTO locus, the strongest genetic risk region for polygenic obesity, and the expression of IRX3 and IRX5 is modulated by obesity-associated variants within FTO through extensive enhancer-promoter interactions. The increasing expression of IRX3 and IRX5 genes in adipocytes lead to reduced thermogenesis of adipose tissue by promoting the storage of white fat over the formation of beige fat, thereby reducing energy expenditure. Moreover, in mouse models, the inhibition of Irx3 or Irx5 genes leads to lean phenotypes characterized by increased basal metabolic rate, increased adipose browning, decreased food intake, and a resistance to diet-induced obesity. The expression of these genes is also increased in hypothalamic neurons, suggesting their role in the central regulation of feeding behavior. These coordinated peripheral and central effects position IRX3 and IRX5 as important mediators of FTO-associated obesity risk and contribute to the complex polygenic architecture of obesity (Dou et al., 2021; Sobreira et al., 2021; Son et al., 2022).

Variants in the ZNF259 gene are associated with polygenic obesity because they influence lipid metabolism and energy homeostasis. The gene ZNF259 is responsible for encoding a zinc finger protein that participates in regulating lipid profile and cell metabolism. Different genetic studies have identified polymorphisms within or near ZNF259 that are correlated with an increased BMI and dyslipidemia, both of which are risk factors for obesity. These variants contribute to obesity risk by modulating metabolic pathways that influence fat storage, insulin sensitivity, and systemic inflammation. Although the exact mechanisms are still being investigated, the cumulative effect of ZNF259 gene mutations in a polygenic context underscores its role as one of several genes with moderate effects on obesity susceptibility and metabolic dysregulation in affected individuals (Parra et al., 2017; Vázquez-Moreno et al., 2021).