Prader-Willi Syndrome: Clinical and Genetic Findings

Abstract

Since the initial medical description by Prader, Labhart and Willi in 1956 of individuals with overlapping features, the Prader-Willi syndrome has become recognized as a classical but sporadic genetic syndrome. Prader-Willi syndrome is the most common genetic cause of life-threatening obesity in humans. It is estimated that there are 350,000-400,000 people with this syndrome worldwide. Prader-Willi Syndrome Association USA knows of more than 3,400 persons with Prader-Willi syndrome in the USA out of an approximate 17,000-22,000. Prader-Willi syndrome with an incidence of 1 in 10,000 to 25,000 individuals and Angelman syndrome, an entirely different clinical condition, were the first examples in humans of genetic imprinting. Genetic imprinting or the differential expression of genetic information depending on the parent of origin plays a significant role in other conditions including malignancies.

Figure 1

A prometaphase chromosome 15 ideogram and a representative pair of high-resolution chromosome 15s from a subject with Prader-Willi syndrome and an interstitial deletion of chromosome 15q11-q13. The arrows on the ideogram indicate the deletion breakpoints at bands 15q11 and 15q13. The 15q12 band is indicated by the arrow on the normal chromosome 15 on the right. The deleted chromosome 15 is on the left. Modified from Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Butler MG, Meaney FJ, Palmer CG. Am J Med Genet 23: 793–809. Copyright 1986 by Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Figure 2

Frontal views of two children with Prader-Willi syndrome showing the typical appearance. The 8.5-year-old boy on the left with the 15q11-q13 deletion has hypopigmentation, and the 10.5-year-old boy on the right has normal pigment and maternal disomy 15 with normal-appearing chromosomes. Modified from Prader-Willi syndrome: current understanding of cause and diagnosis. Butler MG. Am J Med Genet 35:319–332. Copyright 1990 by Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Figure 3

The Prader-Willi syndrome (PWS) genetic domain-adapted from Nicholls et al., 1999 [59] (courtesy of J.A. Searl and R.D. Nicholls) a) Human chromosome 15q11-q13 region showing imprinted and non-imprinted genes and deletion breakpoint (BP) hotspots. b) Cartoon showing the structure of the imprinting center (IC) and flanking genes, including locations of microdeletions and balanced translocations reported in PWS subjects c) Mouse chromosome 7C showing the PWS-homologous region. Not drawn to scale.

Figure 4

Representative fluorescence in situ hybridization (FISH) using a SNRPN probe from the proximal chromosome 15q11-q13 region (red color), a centromeric probe from chromosome 15 (green color), and a distal control probe from chromosome 15q (red color) showing the absence of the SNPRN signal close to the centromere on the deleted chromosome 15 from a Prader-Willi syndrome subject.

Figure 5

Polymerase chain reaction amplification of genomic DNA using GABRB3 gene from the 15q11-q13 region from a Prader-Willi syndrome family with normal chromosome studies in the Prader-Willi syndrome individual. The mother (on the left), the Prader-Willi syndrome individual (in the middle) and the father (on the right) each show two DNA bands representing the presence of the GABRB3 gene in each chromosome 15 (non-deleted status). The DNA pattern from the mother and Prader-Willi syndrome individual are identical but no DNA signal from chromosome 15 was inherited from the father. The Prader-Willi syndrome individual has two chromosome 15s from the mother and no chromosome 15 from the father, thus demonstrating uniparental maternal disomy 15 (both 15s from the mother).