Copy Number Variants in Obesity-Related Syndromes: Review and Perspectives on Novel Molecular Approaches

Abstract

In recent decades, obesity has reached epidemic proportions worldwide and became a major concern in public health. Despite heritability estimates of 40 to 70% and the long-recognized genetic basis of obesity in a number of rare cases, the list of common obesity susceptibility variants by the currently published genome-wide association studies (GWASs) only explain a small proportion of the individual variation in risk of obesity. It was not until very recently that GWASs of copy number variants (CNVs) in individuals with extreme phenotypes reported a number of large and rare CNVs conferring high risk to obesity, and specifically deletions on chromosome 16p11.2. In this paper, we comment on the recent advances in the field of genetics of obesity with an emphasis on the genes and genomic regions implicated in highly penetrant forms of obesity associated with developmental disorders. Array genomic hybridization in this patient population has afforded discovery opportunities for CNVs that have not previously been detectable. This information can be used to generate new diagnostic arrays and sequencing platforms, which will likely enhance detection of known genetic conditions with the potential to elucidate new disease genes and ultimately help in developing a next-generation sequencing protocol relevant to clinical practice.

Long-term effects of bariatric surgery in patients with obesity and chromosome 16 p11.2 microdeletion

“…None of the 27 genes within the deletion stands out as a candidate gene for obesity 11 , however studies suggest that several factors together may cause the obese phenotype. This includes changes in brain structures associated with the reward system and eating behavior 12, 13 and changes in satiety response 14 , sweet food intake 15 , and altered expression of obesity associated genes 16 .…”

“…The frequency of the 16p11.2 microdeletion in the surgery group of the SOS study was 0.49%, which is slightly lower than what we 5 and others 20 have previously found in individuals with morbid obesity. A potential explanation is the fact that the chromosome 16p11.2 microdeletion is associated with cognitive deficits 11 and that this may have led to a lower proportion of carriers of the 16p11.2 microdeletion among the candidates for inclusion in the study compared to non-carriers. Also, the exclusion criteria in the SOS study, including psychological problems suspected to result in poor cooperation 10 , might have disfavored selection of deletion carriers.…”

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

“…On the contrary, patients harboring a ~593 kb microduplication share some characteristics with the deletion phenotype, however, confer an increased risk for being underweight indicating that haploinsufficiency and triplosensitivity at the 16p11.2 locus clearly has opposite effects on BMI. To date, no particular candidate gene located within the 593 kb region is pointed forward to clarify the obesity/underweight phenotype . In addition, larger deletions of 1.7 Mb encompassing the 593 kb proximal deletion are also reported in patients harboring similar characteristics supplemented with or without secondary features such as dysmorphism, heart defects or Hirschsprung disease .…”

“…For the distal 16p11.2 deletion (and the overlapping 1.7 Mb deletion) there is increasing evidence that haploinsufficiency of the Sarcoma ( Src ) homology 2B adaptor protein 1 ( SH2B1 ) gene could induce the obesity phenotype seen in the patients as other genes within the 220 kb region might clarify the presence of the additional features . Previous research in a yeast 2‐hybrid system showed that SH2B1 is a Janus kinase 2 (JAK2)‐binding protein .…”

Screening for Hormonal, Monogenic, and Syndromic Disorders in Obese Infants and Children

“…In addition to obesity and developmental delay/intellectual disability, these genetic variants have been associated with autism, schizophrenia, and cardiac and renal anomalies. 29 Continued advances in the field may uncover additional genes implicated in obesity, promoting our understanding of the complex nature of this disorder and leading to the discovery of new obesity-related syndromes.…”