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Prader–Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2–q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.

Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65–75% of individuals), maternal uniparental disomy 15 (20–30%), or an imprinting defect (1–3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116 , seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available. Genet Med 2012:14(1):10–26.

Purpose: The purpose of this study was to test the hypothesis that deletions of varying sizes in de novo apparently balanced chromosome rearrangements are a significant cause of phenotypic abnormalities. Methods: A total of fifteen patients, with seemingly balanced de novo rearrangements by routine cytogenetic analysis but with phenotypic anomalies, were systematically analyzed. We characterized the breakpoints in these fifteen cases (two of which were ascertained prenatally), using a combination of high-resolution GTG-banding, fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BACs), and data from the Human Genome Project. Results: Molecular cytogenetic characterization of the 15 patients revealed nine with deletions, ranging in size from 0.8 to 15.3 Mb, with the number of genes lost ranging from 15 to 70. In five of the other six cases, a known or putative gene(s) was potentially disrupted as a result of the chromosomal rearrangement. In the remaining case, no deletions were detected, and no known genes were apparently disrupted. Conclusions: Our study suggests that the use of molecular cytogenetic techniques is a highly effective way of systematically delineating chromosomal breakpoints, and that the presence of deletions of varying size is an important cause of phenotypic abnormalities in patients with “balanced” de novo rearrangements.

There is an assumption of parsimony with regard to the number of chromosomes involved in rearrangements and to the number of breaks within those chromosomes. Highly complex chromosome rearrangements are thought to be relatively rare, with the risk for phenotypic abnormalities increasing as the number of chromosomes and chromosomal breaks involved in the rearrangement increases. We report here five cases of de novo complex chromosome rearrangements, each with a minimum of four breaks. Deletions were found in four cases, and in at least one case, a number of genes or potential genes might have been disrupted. This study highlights the importance of the detailed delineation of complex rearrangements, beginning with high-resolution chromosome analysis, and emphasizes the utility of fluorescence in situ hybridization in combination with the data available from the Human Genome Project as a means to delineate such rearrangements.

The speech and language of 55 individuals (27 males and 28 females) with Prader-Willi syndrome (PWS), aged from 6 months to 42 years, were examined through standardized testing and spontaneous speech sample analysis. While great variability was noted in speech and language abilities, most subjects presented with speech sound errors characterized by imprecise articulation (85%), and oral motor difficulties (91%). Hypernasality was noted in 62% and hyponasality in 14%. Other speech characteristics included a slow speaking rate, flat intonation patterns, abnormal pitch of the voice, and harsh/hoarse voice quality. Narrative retelling abilities were poor, with specific deficits in sequencing of story events. Individuals with PWS as a result of deletions of chromosome 15 did not differ significantly in speech and language from individuals with PWS as a result of uniparental disomy.

Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial appearance, obesity, hypogonadism, and short stature. Obesity and the behavioural problems are the major causes of morbidity and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted region of proximal 15q and results from absence of the normally active paternal genes in this region. Such absence results from paternal interstitial deletion, maternal uniparental disomy, or a mutation or other abnormality in the imprinting process. Diagnostic identification of all causes has become available in recent years, permitting early detection and institution of appropriate management. This testing has permitted recent identification of some phenotypic differences among affected subjects of different race and between those with deletions and uniparental disomy as a cause.