**1. Introduction**

The World Health Organization defines being overweight and obesity as a "clinical condition characterized by an abnormal or excessive fat accumulation that may impair health" [1]. In 2014, an estimated 41 million children under the age of 5 were overweight or obese [1]. Once considered a problem only in high‐income countries, being overweight and obesity are now dramatically on the rise in low‐ and middle‐income countries, particularly in urban settings [1].

Therefore, obesity is considered a global epidemic and can cause serious health repercussions. In fact, in addition to causing a significant morbidity and premature mortality and to have psychological and social consequences, it is associated with medical conditions, such as type II diabetes (non‐insulin‐dependent diabetes mellitus or NIDDM), hypertension, coronary artery disease and many forms of cancer [2].

In order to create the best management programs and to determine novel therapeutic targets, it has become essential to understand the factors causing today's rising epidemic of childhood obesity [3].

Obesity is a complex condition, caused by multiple factors. It is characterized by an altered energy system, determined by the interaction of biological, social, and behavioral factors that cause an increase in food intake and a reduction in energy expenditure [4].

This global epidemic and the increase of its prevalence show that this condition is the result not only of genetic causes, but also of environmental factors (high availability of palatable and energy dense foods) [4]. However, some individuals manage to maintain a healthy body weight in an "obesogenic" environment, but the weight gain may be determined by their genetic susceptibility [4].

Recently, major advances in obesity research emerged concerning the molecular mechanisms contributing to the obese condition. However, several studies and data concerning the genetics and other important factors in the susceptibility risk of developing obesity are became increasingly evident [5]; in fact, available data suggest that 40–77% of the observed variance in human body weight can be accounted for, by inherited factors [6–8].

The strongest risk factor for childhood and adolescent obesity is parental obesity [9]. The risk becomes especially elevated if both parents are obese [10]. On the contrary, the pattern of inheritance of monogenic obesity is different (which may or may not be related to specific syndromes). In fact, they are attributable to a Mendelian model which recognizes a rare causative mutation to load a single gene that can be expressed in the heterozygous and homozygous state [11].

literature search will be entered in all combinations. Searches will be augmented by manually reviewing the reference lists of all original articles and all systematic review

**Keywords:** obesity, children, adolescence, next‐generation sequencing, array CGH,

The World Health Organization defines being overweight and obesity as a "clinical condition characterized by an abnormal or excessive fat accumulation that may impair health" [1]. In 2014, an estimated 41 million children under the age of 5 were overweight or obese [1]. Once considered a problem only in high‐income countries, being overweight and obesity are now dramatically on the rise in low‐ and middle‐income countries, particularly in urban settings [1].

Therefore, obesity is considered a global epidemic and can cause serious health repercussions. In fact, in addition to causing a significant morbidity and premature mortality and to have psychological and social consequences, it is associated with medical conditions, such as type II diabetes (non‐insulin‐dependent diabetes mellitus or NIDDM), hypertension, coronary

In order to create the best management programs and to determine novel therapeutic targets, it has become essential to understand the factors causing today's rising epidemic of childhood

Obesity is a complex condition, caused by multiple factors. It is characterized by an altered energy system, determined by the interaction of biological, social, and behavioral factors that

This global epidemic and the increase of its prevalence show that this condition is the result not only of genetic causes, but also of environmental factors (high availability of palatable and energy dense foods) [4]. However, some individuals manage to maintain a healthy body weight in an "obesogenic" environment, but the weight gain may be determined by their genetic

Recently, major advances in obesity research emerged concerning the molecular mechanisms contributing to the obese condition. However, several studies and data concerning the genetics and other important factors in the susceptibility risk of developing obesity are became increasingly evident [5]; in fact, available data suggest that 40–77% of the observed variance

The strongest risk factor for childhood and adolescent obesity is parental obesity [9]. The risk becomes especially elevated if both parents are obese [10]. On the contrary, the pattern of inheritance of monogenic obesity is different (which may or may not be related to specific syndromes). In fact, they are attributable to a Mendelian model which recognizes a rare

cause an increase in food intake and a reduction in energy expenditure [4].

in human body weight can be accounted for, by inherited factors [6–8].

articles, with each study being evaluated for inclusion.

pediatrics, diabetes, hyperphagia

214 Adiposity - Omics and Molecular Understanding

artery disease and many forms of cancer [2].

**1. Introduction**

obesity [3].

susceptibility [4].

Patients can be affected by monogenic forms, in which obesity is the predominant feature but it is not associated with malformations, or by syndromic obesity: in the latter case, they show also a pattern of clinical features, including developmental delay, dysmorphic features, and/or other developmental abnormalities [12].

Furthermore, historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. Many of the initial findings emerged from studying families who displayed a classical Mendelian pattern of inheritance; however, more comprehensive genetic approaches, such as genome‐wide studies, array CGH, and next‐generation sequencing examinations, have highlighted more complex models of inheritance, and ever more candidate genes were identified [13]. In broad terms, most cases of patients with genetic forms of obesity are oligogenic, determined by interaction between genetic and environmental factors. In these cases, the genetic make‐up influences weight and the individual responses to nutrition and physical activity. In addition to this form of obesity, there are others caused by a single gene or it appears to be related to a specific syndrome. Monogenic obesity typically is caused by a single gene mutation with severe obesity as the main symptom; syndromic obesity, on the other hand, has many characteristics, of which obesity is one symptom [13].

The increase of knowledge about the functional and physiological features of these different obesity forms may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is frequently a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments.

The comprehension of the molecular mechanisms of obesity progressed enormously in the last years thanks to the development of faster and more precise genetic screening tools applied in cohort studies or in examinations with focus on subjects and their families.

Several clinical presentations in obesity depend on the genes involved:


Rare genetic forms of obesity are important to be detected clinically because it allows to progress in understanding the physiopathology of obesity. On the other hand, there is a specific management of these forms of obesity provided by specialized and multidisciplinary teams.
