Does the Genetic Cause of Prader-Willi Syndrome Explain the Highly Variable Phenotype? (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, cytogenetics and molecular biology
Expert Reviews in Molecular Medicine, 2005
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11-q13 region. PWS is considered the most common syndromal cause of life-threatening obesity and is estimated at 1 in 10,000 to 20,000 individuals. A de novo paternally derived chromosome 15q11-q13 deletion is the cause of PWS in about 70% of cases, and maternal disomy 15 accounts for about 25% of cases. The remaining cases of PWS result either from genomic imprinting defects (microdeletions or epimutations) of the imprinting centre in the 15q11-q13 region or from chromosome 15 translocations. Here, we describe the clinical presentation of PWS, review the current understanding of causative cytogenetic and molecular genetic mechanisms, and discuss future directions for research.
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 ...
American Journal of Medical Genetics Part A, 2007
Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype-phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty-nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as ''deleted'' and ''non-deleted.'' An increased maternal age was found in the UPD group. Four of Holm's criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full-Scale IQ (FSIQ) !70, while 61.53% of subjects without deletion had FSIQ !70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations !10% in the deleted group (P ¼ 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes.
Epigenetic approach of Prader-Willi syndrome diagnosis in Romanian population
Romanian Biotechnological Letters
This work aimed to compare the clinical validity of a newly developed assay for Prader-Willi syndrome diagnosis in Romanian population, as compared to an existing assay. This syndrome is a complex multisystem, genetic and epigenetic disorder, which arises from a defect in imprinted genes regulation and contribution. So far, a molecular cytogenetic method (fluorescence in situ hybridization) has been the most frequently used assay in primary diagnosis, but because it is targeted towards genetic factors it only covers deletional cases in this pathology. However, gene expression control is realized both through physical presence of the corresponding DNA sequence and through specific methylation patterns on parental alleles of the given gene: normal healthy state is defined by unmethylated (expressed) paternal allele, in the presence of methylated (repressed) maternal allele; by contrast, the pathological condition is defined by the presence of only methylated (repressed) maternal allel...
This work aimed to compare the clinical validity of a newly developed assay for Prader-Willi syndrome diagnosis in Romanian population, as compared to an existing assay. This syndrome is a complex multisystem, genetic and epigenetic disorder, which arises from a defect in imprinted genes regulation and contribution. So far, a molecular cytogenetic method (fluorescence in situ hybridization) has been the most frequently used assay in primary diagnosis, but because it is targeted towards genetic factors it only covers deletional cases in this pathology. However, gene expression control is realized both through physical presence of the corresponding DNA sequence and through specific methylation patterns on parental alleles of the given gene: normal healthy state is defined by unmethylated (expressed) paternal allele, in the presence of methylated (repressed) maternal allele; by contrast, the pathological condition is defined by the presence of only methylated (repressed) maternal allele, thus the lack of unmethylated (contributing) paternal allele. This is the first report presenting a methylation mapping assay, based on methylation specific amplification, for Prader-Willi syndrome in Romanian population, suggesting it might be used as primary diagnosis tool based on its costefficiency and covering ability of almost entire Prader-Willi syndrome etiology (deletions, unimaternal disomy, imprinting defect).
Prader-Willi syndrome: Methylation study or fluorescence in situ hybridization first?
Indian Journal of Human Genetics, 2010
Prader-Willi syndrome (PWS) is neurogenetic disorder involving the imprinting mechanism at 15q11-13 region. We report a 4-year-old girl who was referred to our laboratory to be investigated for clinical obesity, mental deficiency and respiratory problems. The patient was born for nonconsanguineous and healthy biological parents. After normal pregnancy, the patient was delivered by cesarean section at full term, with a birth weight of 2500 g, and the height and head circumference were unknown. In neonatal stage, she presented severe hypotonia with feeding problems. Her developmental progress was delayed. She walked and developed speech at the age of 3 years. Since the age of 3 years, she presented severe dental problems. Methylation study had confirmed the diagnosis, and for detecting etiology, fluorescence in situ hybridization using probes for small nuclear ribonucleoprotein polypeptide N (SNRPN), which map inside the chromosomal region 15q11-15q13, was necessary to confirm the 15q11-15q13 deletion of paternal chromosome 15, which is the predominant genetic defect in PWS. In conclusion, we report this case with an objective to reinforce the necessity of analysis of DNA methylation within the 15q11-13 region, which is an important tool for the correct diagnosis among children presenting with neonatal hypotonia, mental deficiency and obesity.
Prader-Willi Syndrome and diagnostic protocols: a preliminary study in Romania
Revista Romana de Medicina de Laborator
Prader Willi Syndrome (PWS) is a neurometabolic genetic disorder affecting 1/12.000-1/15.000 new-borns. Molecular mechanisms that could lead to this disorder include chromosomal deletions, uniparental disomy (UPD), intragenic mutations, and epigenetic modifications in the process of imprinting and rarely reciprocal translocations. A common defect is noticed in all cases: loss of parental contribution for the functioning of specific genes in normal conditions, due to genetic instability of the critical region 15q11-q13. Objectives of the study concerned the implementation of molecular genetic/epigenetic methods of investigation and development of an interdisciplinary clinical investigation algorithm specific for the disease (geneticist, pediatrician, endocrinologist, psychiatrist, neurologist, psychologist, orthopedist, pneumologist, nutritionist) aiming for early recognition of the clinical features, resulting in early diagnosis and early intervention. Materials and methods: a multi...
Prenatal Diagnosis, 2020
ObjectivesPrader‐Willi syndrome (PWS) is a neurogenetic disorder characterized by mental retardation, morbid obesity, and endocrine and behavior disorders. We previously showed in a small group of patients that PWS may have a unique prenatal phenotype. We aimed to characterize clinical and ultrasonic features in a larger series of pregnancies with a PWS fetus.MethodsWe retrospectively interviewed all mothers of children with PWS followed in the Israel national multidisciplinary PWS clinic. We compared details of the PWS pregnancy with the pregnancies of healthy siblings and with data from the general population. Medical records including ultrasound reports, obstetric records, and genetic results were analyzed.ResultsDistinct prenatal features of PWS pregnancies included abnormal fetal growth [fetal growth restriction (FGR) (37.3%), increased head to abdominal circumference ratio (44.8%), decreased abdominal circumference (49.2%)], markedly decreased fetal movements (DFM) (80.4%), an...