Known Clinical Epigenetic Disorders with an Obesity Phenotype: Prader–Willi Syndrome and the GNAS Locus

Abstract

Prader–Willi syndrome (PWS) was the first example in humans of genomic imprinting, an epigenetic phenomenon mediated through modifications of DNA and histones by methylation without altering the DNA sequence. Epigenetics is heritable but reversible depending on the parent of origin. PWS is a neurodevelopmental disorder characterized by hypotonia, feeding difficulties, hypogonadism, growth failure, learning/behavioral problems, and hyperphagia in early childhood leading to morbid obesity if uncontrolled. PWS is considered the most common known cause of life-threatening obesity and estimated to occur in 1 in 10,000–20,000 individuals. A de novo paternal deletion of the chromosome 15q11–q13 region is the cause in 70% of PWS subjects, maternal disomy 15 accounts for about 25%, and the remaining cases are due to an imprinting defect (microdeletions or epimutations) of the imprinting center or from chromosome 15 translocations. Predisposition of adipogenesis and obesity is present before birth and controlled by epigenetics in PWS and other obesity-related disorders. Specific information about clinical epigenetic disorders with obesity will be discussed, including PWS, along with epigenetic defects involving the complex GNAS gene locus on chromosome 20 causing Albright hereditary osteodystrophy (pseudohypoparathyroidism – PHP and pseudopseudohypoparathyroidism – PPHP) in which obesity is a major manifestation, and McCune–Albright syndrome.