Prader–Willi syndrome: clinical genetics, cytogenetics and molecular biology (original) (raw)
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ABSTRACT Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder caused by inherited deletion of paternally expressed genes on human chromosome 15q11-q13 via different genetic mechanisms including paternal deletion of this region (65–75% of individuals), maternal uniparentaldisomy (20–30%), and an imprinting defect (1–3%), which is able to change the phenotype of PWS include low birth weight, severe hypotonia, feeding difficulties, hyperphagia and obesity. Many of the characteristic features of PWS results from the loss of function of the paternally imprinted genes including SNURF-SNRPN, NDN, MKRN3, MAGEL and a cluster of snoRNAs. Their silencing on the maternal chromosome is mainly attributed to DNA methylation and histone modifications at PWS imprinting center (IC) of this region. However, the mechanism of imprinted genes is currently unclear for the changes in the phenotypes of PWS. The purpose of this review article explains the aberrations of imprinted genes on chromosome 15q11-q13 region contributed to PWS phenotypes and different therapeutic models established to treatment of PWS.
Prader-Willi Syndrome - Clinical Genetics, Diagnosis and Treatment Approaches: An Update
Current Pediatric Reviews
Background: Prader-Willi Syndrome (PWS) is a neurodevelopmental genomic imprinting disorder with lack of expression of genes inherited from the paternal chromosome 15q11-q13 region usually from paternal 15q11-q13 deletions (about 60%) or maternal uniparental disomy 15 or both 15s from the mother (about 35%). An imprinting center controls the expression of imprinted genes in the chromosome 15q11-q13 region. Key findings include infantile hypotonia, a poor suck, failure to thrive and hypogonadism/hypogenitalism. Short stature and small hands/feet due to growth and other hormone deficiencies, hyperphagia and marked obesity occur in early childhood, if uncontrolled. Cognitive and behavioral problems (tantrums, compulsions, compulsive skin picking) are common. Objective: Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS. This report will describe an accurate diagnosis with determination of specific genetic subtypes, appropriate medical ...
Imprinting-Mutation Mechanisms in Prader-Willi Syndrome
The American Journal of Human Genetics, 1999
Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in 15q11-q13 during gametogenesis. We have identified a larger series of cases of familial PWS, including one case with a deletion of only 7.5 kb, that narrows the PWS critical region to !4.3 kb spanning the SNRPN gene CpG island and exon 1. Identification of a strong DNase I hypersensitive site, specific for the paternal allele, and six evolutionarily conserved (humanmouse) sequences that are potential transcription-factor binding sites is consistent with this region defining the SNRPN gene promoter. These findings suggest that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. We also identified three patients with sporadic PWS who have an imprinting mutation (IM) and no detectable mutation in the IC. An inherited 15q11-q13 mutation or a transfactor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental spermatogenesis. These studies allow a better understanding of a novel mechanism of human disease, since the epigenetic effect of an IM in the parental germ line determines the phenotypic effect in the patient.
Does the Genetic Cause of Prader-Willi Syndrome Explain the Highly Variable Phenotype?
Maedica, 2016
Prader-Willi syndrome (PWS) is characterized by extensive clinical and genetic variability caused by lack of expression of imprinted genes of the chromosomal region 15q11.2-q13. The genotye-phenotype correlation has not been yet fully elucidated. To analyze these correlations in order to determine the role of specifi c geneic alterations in the development of clinical symptoms in PWS. We retrospectively analyzed data routinely collected as part of the clinical care of 52 patients with clinical suspicion of PWS. FISH test was performed in all patients; in case of negative results, methylation test was performed. PWS was confi rmed in 35 patients that were divided in two groups according to the genetic cause of PWS: group A-21 patients with 15q11-q13 region deletion, mean age at evaluation 8.1 years (SD= 5.6) and mean of clinical score 9.4 ± 1.8; group B-14 patients with positive methylation test, with mean age at evaluation 6.7 years (SD= 4.6) and mean of clinical score 10.1 ± 1.9. F...
An interstitial 15q11-q14 deletion: Expanded Prader-Willi syndrome phenotype
American Journal of Medical Genetics Part A, 2010
We present an infant girl with a de novo interstitial deletion of the chromosome 15q11-q14 region, larger than the typical deletion seen in Prader-Willi syndrome (PWS). She presented with features seen in PWS including hypotonia, a poor suck, feeding problems and mild micrognathia. She also presented with features not typically seen in PWS such as preauricular ear tags, a high arched palate, edematous feet, coarctation of the aorta, a PDA and a bicuspid aortic valve. G-banded chromosome analysis showed a large de novo deletion of the proximal long arm of chromosome 15 confirmed using FISH probes (D15511 and GABRB3). Methylation testing was abnormal and consistent with the diagnosis of PWS. Because of the large appearing deletion by karyotype analysis, an array comparative genomic hybridization (CGH) was performed. A 12.3 Mb deletion was found which involved the 15q11-q14 region containing approximately 60 protein coding genes. This rare deletion was approximately twice the size of the typical deletion seen in PWS and involved the proximal breakpoint BP1 and the distal breakpoint was located in the 15q14 band between previously recognized breakpoints BP5 and BP6. The deletion extended slightly distal to the AVEN gene including the neighboring CHRM5 gene. There is no evidence that the genes in the 15q14 band are imprinted; therefore, their potential contribution in this patient's expanded Prader-Willi syndrome phenotype must be a consequence of dosage sensitivity of the genes or due to altered expression of intact neighboring genes from a position effect.
Early Human Development, 2007
Background: Imprinted genes are considered to play an important role in growth and early development but much of the research is based on animal studies. Aim: This study reports clinical data from a French population concerning prenatal, perinatal and postnatal complications in Prader-Willi syndrome (PWS), a genetically imprinted neurodevelopmental disorder associated with growth retardation, intellectual impairment and obesity. Study design: Data from family health records concerning prenatal, perinatal and postnatal complications were collected from 52 French people with the deletion form (DEL), and 34 French people with the maternal disomy form of PWS (UPD) and compared against national norms and between groups. Results: Significant findings include: a history of miscarriage, high rate of polyhydramnios (12/34 UPD, 11/52 DEL), a high rate of induced labour, a high rate of Caesarian section (20/34 UPD, 26/ 52 DEL), small gestational age (10/34 UPD, 22/52 DEL), hypotonia (34/34 UPD, 49/52 DEL), and suckling deficit (25/34 UPD, 46/52 DEL). Significant differences between genetic subtypes include a higher rate of induced labour in UPD (27/34 UPD, 25/52 DEL), an increased risk of premature term in UPD (9/34 UPD vs. 4/52 DEL), raised maternal age in UPD (36.4 years vs. 29.3 years), low birth weight for newborns with a deletion form of PWS (girls 2.8 kg, boys 2.7 kg), a positive correlation between parental weight and offspring birth weight only for patients with UPD (UPD maternal: r = 0.62, paternal: r = 0.51). Conclusion: The results indicate significant intrauterine disturbance in PWS, particularly in PWS due to UPD, but a more significant weight disturbance for PWS due to deletion.
Clinical Trials in Prader–Willi Syndrome: A Review
International Journal of Molecular Sciences
Prader–Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clin...