**3. Syndromic obesity**

hyperphagia have been reported in a patient with a balanced translocation disrupting *SIM1* [55] and multiple heterozygous missense mutations (6q16.3; OMIM \*603128) [56]. However, some mutations of *SIM1* have incomplete penetrance and variable phenotype [57]. The similar phenotype between patients with SMI1 and MC4‐R deficiency suggests that some effects of SIM1 are mediated by altered melanocortin signaling. On the other hand, some children with *SIM1* mutations have neuro‐behavioral disorders including autism spectrum and "Prader‐

In mice, hyperphagia associated with SIM1 deficit can be improved by the administration of oxytocin, a neurotransmitter involved in the modulation of emotion (impaired oxytocinergic

Mutations of the *BDNF* (*brain‐derived neurotrophic factor*, OMIM \*113505, mapped at 11p14.1) and its receptor TrKb (*tyrosin kinase B receptor*, OMIM \*600456, mapped at 9q21.33) are rare causes of monogenic obesity acting downstream signal cascade of MC4‐R and blocking

BDNF's role in energy homeostasis emerged in the 1990s with the observation that intracere‐ broventricular BDNF administration suppresses appetite and induces weight loss in ro‐ dents, and *Bdnf* heterozygous knockout mice exhibit hyperphagia and obesity [60]. Complete lack of BDNF during embryologic development is perinatally lethal, but haploinsufficiency for BDNF or inactivating mutations of the BDNF receptor was associated with increased ad libitum food intake, severe early‐onset obesity, hyperactivity, and cognitive impairment [60, 61]. Multiple genome‐wide association studies of obesity in children and adults of different racial and ethnic populations have found associations for single‐nucleotide polymorphisms (SNPs) at the BDNF locus and BMI, in particular for *G196A* variant (*rs6265*), which leads to a valine to methionine substitution at the 66th amino acid position (*Val66Met*) of the N‐terminal prodomain of pro‐BDNF. Furthermore, modifying factors—particularly sex, lifestyle behav‐ iors, and psychotropic medication use—appear to be important confounders for the associa‐ tion between rs6265 and BMI [60–62]. In addition, the minor C allele of intronic *rs12291063*

*NTRK2* (*TrkB*) mutation (which interferes with receptor autophosphorylation) causes the same symptoms of BDNF deficiency such as hyperphagia, obesity, impaired nociception, and intellectual disability [64, 65]. Recently, a *de novo* mutations in *TrkB* was found in a boy with severe obesity and impairment in learning, memory and nociception, and in a girl with

Another cause of non‐syndromic monogenic obesity is due to a gene mutation of *CART* (*cocaine‐ and amphetamine‐regulated transcript*, OMIM \*602606), mapped at 5q13.2. CART is an anorexigenic peptide produced by specific hypotalamic neurons in response to the stimulus of leptin. It would appear to mediate the termogenetic effects and energy expenditures characteristic of leptin. It has been shown that mutations in the *CART* gene are associated with

signaling is also one possible mechanism implicated in the obesity) [58].

SNP was associated with lower BDNF expression and higher BMI [63].

hyperphagia and severe obesity [66].

Willi‐like" phenotype (**Figure 2**) [3, 12].

222 Adiposity - Omics and Molecular Understanding

translation [59].

**2.8. Other types of non‐syndromic genetic obesity**

To date have been identified syndromic forms (e.g., Prader‐Willi Syndrome) in which obesity can be associated with other signs and symptoms, such as intellectual disability, dysmorfic features and unusual behaviors.

In these syndromes, obesity can be caused by hyperphagia because are involved genes related to central nervous system appetite control centers.

Recently, the genetic bases for some of these syndromes have been elucidated and are begin‐ ning to provide insights into the pathogenesis of the derangements of energy homeostasis.

**Table 2** reports the main syndromic forms of obesity. High‐throughput technologies, and in particular copy number variants (CNVs) detection, are likely to result in the identification and recognition of multiple new syndromes where obesity and developmental delay are closely associated [12].



**Table 2.** Main forms of syndromic obesity.
