Abstract
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS.
Highlights
AND HISTORICAL REVIEWPrader-Willi syndrome (PWS) is a complex neurodevelopmental genetic condition due to paternal loss of imprinted genes on chromosome 15 and characterized by a range of mental and physical findings including obesity that can be life-threatening [1, 2]
The Prader-Willi Syndrome Association (USA) estimates that 17,000–22,000 individuals live in the United States [3]
The remaining PWS individuals result from maternal disomy 15, genomic imprinting defects due to microdeletions or epimutations of the imprinting center located in the 15q11-q13 region in less than 3% of cases, or chromosome 15 translocations or rearrangements [1, 2, 6, 7, 10, 11]
Summary
Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic condition due to paternal loss of imprinted genes on chromosome 15 and characterized by a range of mental and physical findings including obesity that can be life-threatening [1, 2]. It affects an estimated 350,000–400,000 people worldwide. Using Southern hybridization of polymorphic DNA markers isolated from the 15q11–q13 region, Nicholls, Butler, and others reported in 1989 [10] that individuals with PWS and normal-appearing chromosomes inherited both chromosome 15s from the mother and none from the father This previously unreported observation was referred to as maternal uniparental disomy 15 or maternal UPD 15. The individuals with the Type I deletion had more behavioral and cognitive problems when compared to those with the smaller Type II deletion or maternal disomy 15
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