Rare genetic forms of obesity


Obesity is a condition in which a person has an excess of body fat and weight. With its complications, obesity is a major global public health concern. It has a multifactorial etiology that includes genetic, environmental, socioeconomic, and behavioral or psychological influences. Whereas polygenic forms of common obesity can explain up to 40% of the heritability for obesity, monogenic obesity causally relates to a subset of early forms of severe obesity which account for at least 5%-8% of obesity cases worldwide. These rare genetic forms are caused by pathogenic variants in different genes. Most of these cases are due to deficiency in genes of the leptin-melanocortin signaling pathway, which is a master regulator of energy balance.


Detailed clinical description

Obesity occurs when a person has an excess of body fat and weight. A parameter called Body Mass Index (BMI) is usually used to define the condition of obesity. It takes into account a person's weight and height to evaluate the total body fat. Obesity in adults occurs when the BMI is higher than 30 Kg/m2. Severe obesity is present in adults if the BMI is higher than 40 Kg/m2. Choosing a BMI value to define obesity in children is more complex than in adults because growth parameters vary widely throughout childhood and adolescence. However, there is a general agreement in defining obesity status in children with a BMI higher than 35 kg/m2.
Obesity is reported to be a major health burden in developed and developing countries and one of the most common preventable diseases. As it is a major risk factor for diabetes mellitus type II, cardiovascular disease, hypertension, and metabolic syndrome, obesity is a central contributor to mortality in the general population. At least 2.8 million people die each year as a consequence of being overweight or obese, and its incidence among children is increasing.
Obesity results from an imbalance between energy intake and energy expense with a chronic positive energy balance. This disequilibrium is maintained by complex interactions between endocrine tissues and the central nervous system, which leads to a pathologic accumulation of adipose tissue.
Obesity in humans results from a combination of environmental influences and genetic factors. Polygenic forms of common obesity can explain up to 40% of the heritability for the disease, but relatively severe cases presenting with an early age of onset are typically associated with highly penetrant rare genetic variants. Major forms of genetic obesity were classified as syndromic obesity and monogenic non-syndromic obesity:
1- syndromic obesity includes patients with neurodevelopmental disorders or malformative features such as in Prader Willi, Bardet-Biedl syndromes, Alport syndrome, which are the most frequently observed forms.
2- monogenic non-syndromic obesity is characterized by excess adiposity as a predominant trait with hyperphagia, and includes patients with variants in genes commonly involved in the leptin/melanocortin pathway. These monogenic forms account at least for 5%-8% of the total cases of obesity.


The prevalence of obesity in adults (>20 years of age and with a BMI ≥ 30 kg/m2) reached 30.5% in 2000 and 39.8% in 2015. The situation is just as alarming in youth (age 2-19 years old), as the prevalence increased from 13.9% in 2000 to 18.5% in 2016.

Molecular genetics

Around 5%-8% of obesity cases are monogenic forms caused by mutations in single genes, but some studies suggest that they are probably underdiagnosed in some countries and could be more frequent in specific populations, reaching up to 30% in some areas. The most studied and common mutated genes associated with monogenic obesity belong to the leptin/melanocortin pathway, which includes the MC4R, LEP, LEPR, POMC, PCSK1, SIM1 and NCOA1 genes. These genes are all associated with monogenic forms of severe obesity with childhood-onset.

What is the leptin/melanocortin pathway?
In the melanocortin system, hormones of the ‘fed state’ (i.e.: when the body is digesting the food and absorbing the nutrients) such as leptin and insulin, released in the bloodstream by adipocytes and by the β-cells of the pancreas, respectively, cross the blood-brain barrier to bind to leptin and insulin receptors on the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH), which signals to decrease energy intake. In the fed state, leptin also binds to leptin receptors to inhibit secretion of AgRP and of neuropeptide Y, which regulate eating behavior. Conversely, in the ‘starved state’ AgRP/NPY neuron activity is increased by decreased circulation of leptin and insulin. In the melanocortin pathway to regulate feeding, hypothalamic POMC neurons receive inhibitory signals from cholinergic neurons localized to the dorsomedial hypothalamus.

MC4R. Rare heterozygous or bi-allelic loss-of-function mutations in this gene are reported in about 4%-5% of children and in 1% of adults with severe obesity. They are related to severe forms of childhood obesity with autosomal dominant or recessive transmission and variable penetrance. The disease is characterized by hyperinsulinemia and increased risk of type 2 diabetes, hyperphagia that decreases with age, and increased bone mineral density and content. The increased body weight is observable within the first year of life in most patients. Usually, MC4R-related obesity is not associated with specific endocrine anomalies. Bi-allelic carriers of MC4R mutations are very rare and obesity is more severe. Heterozygous carriers of MC4R mutations are more common and result in obesity occurring at a later age than bi-allelic carriers. Recent studies seem to confirm that gain-of-function variants in the MC4R gene are associated with resistance to obesity. Other studies suggest a possible cumulative pathogenic effect due to the presence of other variants in genes involved in the MC4R. However, the results do not allow us to get a clear picture of these functional effects. Genome-wide association studies (GWAS) have demonstrated a consistent association between frequent variants in MC4R and both BMI and fat mass.
LEPR. Bi-allelic mutations in the LEPR gene are reported in less than 2%-3% of patients with severe early-onset obesity. They are related to severe obesity with autosomal recessive transmission, and the disease is characterized by severe and uncontrolled hyperphagia and gonadotropic, thyrotropic, and somatotropin insufficiency with alteration of the immune function and metabolic dysfunction. Due to the hypogonadotropic hypogonadism, patients can show delayed pubertal development, with a recovery of hormonal functions in some cases.
LEP. Bi-allelic mutations in the LEP gene are described in rare cases and the related pathological phenotype overlaps with LEPR-related obesity.
POMC. Bi-allelic mutations in the POMC gene are described in very few cases worldwide and they cause early-onset obesity, adrenal insufficiency, and red hair, which is an autosomal recessive endocrine disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair in caucasian individuals, and secondary hypocortisolism. In the neonatal period, affected individuals are prone to be affected by hypoglycemia, hyperbilirubinemia, and cholestasis.
PCSK1. Bi-allelic mutations in the PCSK1 gene cause proprotein convertase 1/3 deficiency, which is an autosomal recessive rare severe childhood obesity with hyperphagia, malabsorption, diarrhea, postprandial hypoglycemia and adrenal, gonadotropic, somatotropin, and thyrotrophic insufficiency. The phenotype is variable and small intestine biopsy shows villous atrophy. Genome-wide association studies (GWAS) have demonstrated a consistent association between frequent variants in PCSK1 and both BMI and fat mass.
SIM1. Heterozygous mutations in the SIM1 gene cause monogenic forms of severe obesity in very few cases. They cosegregate with obesity in extended family studies with variable penetrance. Additional features include hypopituitarism and neurobehavioral abnormalities. Within the hypothalamus, SIM1 is a transcription factor expressed during the development of the paraventricular nucleus, that contains the melanocortin 4 receptor (MC4R), a key component of appetite regulation and energy homeostasis. Even if SIM1 mutations are a well-known cause of monogenic syndromic obesity, the underlying pathophysiology remains to be fully understood.
NCOA1 (also known as SRC-1). In a cohort of 2548 European ancestry individuals with severe early-onset obesity, one study identified by Whole Exome Sequencing fifteen rare heterozygous variants observed only in patients with severe and early-onset obesity. These variants were not present in 1117 ancestry-matched individuals. Supported by functional studies and by a knock-in mouse model of the most severe loss of function human SRC-1 variants, the authors suggested a pathogenic role for these mutations and show that steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription.

Out of the leptin/melanocortin pathway
CELA2A and DYRK1B. Heterozygous mutations in the CELA2A and DYRK1B genes cause two forms of the abdominal obesity-metabolic syndrome. The disease is characterized by abdominal obesity, high triglycerides, low levels of high-density lipoprotein cholesterol, high blood pressure, and elevated fasting glucose levels, often resulting in early-onset coronary artery disease and myocardial infarction.
CEP19. A homozygous stop-gain mutation has been reported in the CEP19 gene as causative for a form of severe obesity with spermatogenic failure in several individuals from a single Arabian family. The disease is characterized by obesity, hypertension, fatty liver disease, and insulin resistance. Some of the patients display developmental delay. Observed spermatogenic failure includes oligospermia and azoospermia.
NR0B2. A first study reported an association between a polymorphism and mild to moderate early-onset obesity cases in a cohort of Japanese with early-onset diabetes. The results of subsequent studies were inconsistent and the association remained uncertain. However, another study reported a stronger association between rare variants with variable penetrance in this gene and early-onset severe obesity in a cohort of obese Danish men.
PPARG. This gene is a master regulator of fat cell formation. It is required for the accumulation of adipose tissue and hence contributes to obesity. Several studies have focused on the association between PPARG polymorphism and obesity, and a recent study suggest that at least one highly-penetrant rare variant in this gene can be associated with non-syndromic early-onset obesity.
ADCY3. In two different studies, rare homozygous loss-of-function mutations (splicing, frameshift variants, and one missense mutation) have been reported in patients from two different populations with severe obesity and risk of type 2 diabetes. Genome-wide association studies (GWAS) have demonstrated a consistent association between frequent variants in ADCY3 and both BMI and fat mass.
BDNF. In a study investigating the relationship between genotype and BMI in a cohort of 33 patients with the chromosome 11p13 deletion syndrome, it was found that haploinsufficiency for the BDNF gene was strongly associated with a subtype of the syndrome characterized by childhood-onset obesity. All 19 patients with deletions that involved any portion of the BDNF gene became obese by 10 years of age, whereas in each patient who had normal weight during childhood, the BDNF gene was intact. In a subsequent study, a rare missense variant in the same gene has been reported as pathogenic for a monogenic form of obesity.
SH2B1. A study from 2010 identified five patients with SH2B1-containing deletions among a cohort of 300 Caucasians with severe early-onset obesity. Two of them had a larger deletion that also included an additional proximal 600-kb 16p11.2 region. The latter two patients also showed a developmental delay in addition to obesity. Subsequently, different studies reported large deletions on chromosome 16p11.2, always encompassing the SH2B1 gene, associated with a highly penetrant form of isolated severe early-onset obesity as well as obesity with developmental delay.


Genetic testing strategy

A multigene panel that includes the known genes related to monogenic forms of nonsyndromic obesity is most likely to identify a genetic cause of these forms of obesity at the most reasonable cost.

Panel testing recommended at Breda Genetics for this condition:



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