Single Gene and Syndromic Causes of Obesity: Illustrative Examples

Abstract

Obesity is a significant health problem in westernized societies, particularly in the United States where it has reached epidemic proportions in both adults and children. The prevalence of childhood obesity has doubled in the past 30 years. The causation is complex with multiple sources, including an obesity promoting environment with plentiful highly dense food sources and overall decreased physical activity noted for much of the general population, but genetic factors clearly play a role. Advances in genetic technology using candidate gene approaches, genome-wide association studies, structural and expression microarrays, and next generation sequencing have led to the discovery of hundreds of genes recognized as contributing to obesity. Polygenic and monogenic causes of obesity are now recognized including dozens of examples of syndromic obesity with Prader-Willi syndrome, as a classical example and recognized as the most common known cause of life-threatening obesity. Genetic factors playing a role in the causation of obesity will be discussed along with the growing evidence of single genes and the continuum between monogenic and polygenic obesity. The clinical and genetic aspects of four classical but rare obesity-related syndromes (ie, Prader-Willi, Alström, fragile X, and Albright hereditary osteodystrophy) will be described and illustrated in this review of single gene and syndromic causes of obesity.

Keywords: Albright hereditary osteodystrophy; Alström syndrome; Prader–Willi syndrome; candidate obesity genes; fragile X syndrome; genomic imprinting; syndromic obesity.

Figure 1

(A) Obesity gene ideogram part A. High resolution human chromosome ideograms (850 band level) with symbols representing recognized genes for obesity positioned at the chromosome band location. The upper “p” and lower “q” arms for each chromosome are separated by the centromere area. (B) Obesity gene ideogram part B. High resolution human chromosome ideograms (850 band level) with symbols representing recognized genes for obesity positioned at the chromosome band location. The upper “p” and lower “q” arms for each chromosome are separated by the centromere area.

Figure 1

(A) Obesity gene ideogram part A. High resolution human chromosome ideograms (850 band level) with symbols representing recognized genes for obesity positioned at the chromosome band location. The upper “p” and lower “q” arms for each chromosome are separated by the centromere area. (B) Obesity gene ideogram part B. High resolution human chromosome ideograms (850 band level) with symbols representing recognized genes for obesity positioned at the chromosome band location. The upper “p” and lower “q” arms for each chromosome are separated by the centromere area.

Figure 2

Frontal and profile view of an 8-year-old male with PWS showing the typical facial features, central obesity, and gastrostomy-tube site located on the abdomen.

Figure 3

Chromosome 15 ideogram showing the location of genes in the 15q11-q13 region. BP1, BP2, and BP3 are the three common chromosome 15 breakpoints in the region at the site of breakage leading to the larger typical Type I deletion between BP1 and BP3 and the smaller Type II deletion between BP2 and BP3. The dark gray (blue in the web version) colored rectangle-shaped symbols represent paternally expressed genes (eg, MAGEL2) which when disturbed leads to PWS. The gray (red in the web version) colored square-shaped symbols represent maternally expressed genes and the UBE3A gene when disturbed causes Angelman syndrome. The light gray (green in the web version) colored rectangle-shaped symbols represent genes (eg, CYFIP1) that are expressed on both the maternal and paternal chromosome 15s.

Figure 4

(A) Chromosome microarray results for PWS deletion subtypes. High resolution chromosome microarray using CNV and SNP probes to identify typical 15q11-q13 deletions in PWS classified as Type I involving breakpoints BP1 and BP3 and Type II involving breakpoints BP2 and BP3. (B) Chromosome Microarray Results for Uniparental Maternal Disomy 15. High resolution chromosome microarray using CNV and SNP probes to identify the maternal disomy 15 subtype (segmental isodisomy 15, isodisomy 15, and heterodisomy 15).

Figure 4

(A) Chromosome microarray results for PWS deletion subtypes. High resolution chromosome microarray using CNV and SNP probes to identify typical 15q11-q13 deletions in PWS classified as Type I involving breakpoints BP1 and BP3 and Type II involving breakpoints BP2 and BP3. (B) Chromosome Microarray Results for Uniparental Maternal Disomy 15. High resolution chromosome microarray using CNV and SNP probes to identify the maternal disomy 15 subtype (segmental isodisomy 15, isodisomy 15, and heterodisomy 15).