The Frequency of Uniparental Disomy in Prader-Willi Syndrome

Mascari, Maria J.; Gottlieb, Wayne; Rogan, Peter K.; Butler, Merlin G.; Waller, David; Armour, John A.L.; Jeffreys, Alec J.; Ladda, Roger L.; Nicholls, Robert D.

doi:10.1056/nejm199206113262404

Cited by 244 publications

(140 citation statements)

References 39 publications

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“…[1][2][3] Approximately 70% of PWS cases are due to a paternal deletion on chromosome 15 (15q11-q13 region), 25% of PWS cases have maternal uniparental disomy (UPD) of chromosome 15 and the remaining cases result from genetic imprinting defects. [4][5][6][7][8] Much interest now revolves around the role of adipose tissue as an endocrine organ, capable of producing hormones and cytokines such as tumor necrosis factor-a, plasminogen activating inhibitor-1, leptin, interleukin-6, resistin and, more recently, adiponectin. [9][10][11][12] Adiponectin is abundant in the circulation of nondiabetic humans, but is decreased in patients with obesity, type 2 diabetes and cardiovascular disease and higher in women than in men.…”

Section: Introductionmentioning

confidence: 99%

Circulating adiponectin levels, body composition and obesity-related variables in Prader–Willi syndrome: comparison with obese subjects

et al. 2005

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Background: People with obesity and/or the metabolic syndrome have an increased risk for developing diabetes and cardiovascular disease and may have low adiponectin levels. The obesity associated with Prader-Willi syndrome (PWS) would be expected to have similar complications. However, it was recently reported that, despite their adiposity, people with PWS have reduced visceral fat and are less likely to develop diabetes mellitus or the metabolic syndrome compared with people with simple obesity. Objective: To determine if plasma adiponectin levels and other variables relevant to diabetes and cardiovascular risk are different in a cohort of PWS subjects with known genetic subtypes compared with age-, sex-and weight-matched control subjects. Results: Fasting plasma glucose, C-peptide, triglycerides, leptin and cholesterol levels were similar in PWS and obese subjects. Our 20 PWS subjects (mean age ¼ 27.7 years) had higher percent body fat (54.1 vs 48.5%) determined by DEXA measurements and lower percent lean mass (45.9 vs 51.5%) compared with 14 obese controls (mean age ¼ 26.9 year). Plasma adiponectin levels were significantly higher in PWS (15.578.2 mg/ml) than in obese controls (7.572.7 mg/ml). A significant positive correlation was found with insulin sensitivity in PWS subjects (r ¼ 0.75, P ¼ 0.0003) but not in obese controls (r ¼ 0.36, P ¼ 0.20). Discussion: Our study confirmed an earlier observation of higher adiponectin levels in PWS subjects and less insulin resistance proportionate to their obesity status than found in subjects with simple obesity. Furthermore, no differences were seen in PWS subjects with the chromosome 15 deletion or maternal disomy 15. The reported excessive visceral adiposity in subjects with simple obesity compared with PWS may be associated with decreased production and lower circulating levels of adiponectin.

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Section: Introductionmentioning

confidence: 99%

Circulating adiponectin levels, body composition and obesity-related variables in Prader–Willi syndrome: comparison with obese subjects

et al. 2005

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“…In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in <2%, it is the result of a mutation, deletion, or other defect in the imprinting center. [3][4][5][6][7][8] Clinical diagnostic criteria were established by consensus in 1993. 1 Subsequently, definitive molecular genetic testing became available for laboratory diagnosis of PWS.…”

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confidence: 99%

“…In approximately 70% of cases this is the result of deletion of this region from the paternal chromosome 15. In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in Ͻ2%, it is the result of a mutation or deletion in the imprinting center [3][4][5][6][7][8] or other imprinting defect.…”

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The Changing Purpose of Prader-Willi Syndrome Clinical Diagnostic Criteria and Proposed Revised Criteria

et al. 2001

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ABSTRACT. Background. Prader-Willi syndrome (PWS) is a complex, multisystem disorder. Its major clinical features include neonatal hypotonia, developmental delay, short stature, behavioral abnormalities, childhoodonset obesity, hypothalamic hypogonadism, and characteristic appearance. 1,2 The genetic basis of PWS is also complex. It is caused by absence of expression of the paternally active genes in the PWS critical region on 15q11-q13. In approximately 70% of cases this is the result of deletion of this region from the paternal chromosome 15. In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in <2%, it is the result of a mutation, deletion, or other defect in the imprinting center. [3][4][5][6][7][8] Clinical diagnostic criteria were established by consensus in 1993. 1 Subsequently, definitive molecular genetic testing became available for laboratory diagnosis of PWS. However, identification of appropriate patients for testing remains a challenge for most practitioners because many features of the disorder are nonspecific and others can be subtle or evolve over time. For example, hypotonic infants who are still in the failure to thrive phase of the disorder often do not have sufficient features for recognition of PWS and often are not tested. Initial screening with these diagnostic criteria can increase the yield of molecular testing for older children and adults with nonspecific obesity and mental retardation. Therefore, the purpose of clinical diagnostic criteria has shifted from assisting in making the definitive diagnosis to raising diagnostic suspicion, thereby prompting testing.We conducted a retrospective review of patients with PWS confirmed with genetic testing to assess the validity and sensitivity of clinical diagnostic criteria published before the widespread availability of testing for all affected patients 1 and recommend revised clinical criteria.Methods. Charts of all 90 patients with laboratoryconfirmed PWS were reviewed. For each patient, the presence or absence of the major, minor, and supportive features listed in the published diagnostic criteria was recorded. The sensitivity of each criterion, mean of the total number of major and minor criteria, and mean total score for each patient were calculated.Results. There were 68 patients with a deletion (del 15q11-q13), 21 with maternal UPD of chromosome 15, and 1 with a presumed imprinting defect. Age range at the time of the most recent evaluation was 5 months to 60 years (median: 14.5 years; del median: 14 years; range: 5 months-60 years; UPD median: 18 years; range: 5-42 years).The sensitivities of the major criteria ranged from 49% (characteristic facial features) to 98% (developmental delay). Global developmental delay and neonatal hypotonia were the 2 most consistently positive major criteria and were positive in >97% of the patients. Feeding problems in ...

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“…Approximately 70-75% of individuals with PWS and AS have 15q11-q13 deletions, which are of paternal origin in PWS and of maternal origin in AS (Knoll et al, 1989;Magenis et al, 1990). Maternal uniparental disomy (UPD) of chromosome 15 is found in about 25% of PWS patients (Mascari et al, 1992), whereas paternal UPD occurs in only 2-3% of patients with AS (Magenis et al, 1990). About 1-5% of patients with PWS and AS have biparental inheritance of chromosome 15, but show abnormal methylation pattern and gene expression due to mutations in the imprinting center (Buiting et al, 1995;Saitoh et al, 1996;Ohta et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of patients with Prader-Willi and Angelman Syndromes: the importance of an overall investigation

2002

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Seventy-two patients with clinical diagnoses of Prader-Willi (PWS; n = 28 patients) or Angelman syndromes (AS; n = 44 patients) were submitted to chromosome analysis, SNRPN-SNURF exon 1 methylation assay, and microsatellite genotyping. Analysis of the methylation pattern confirmed the PWS diagnosis in 18 out of 28 patients and the AS diagnosis in 20 out of 44 patients. FISH and microsatellite analysis detected a deletion in 30 patients (14 PWS and 16 AS). Eight patients had normal FISH results (4 PWS and 4 AS); microsatellite markers showed that these patients had a uniparental disomy (UPD). Based on this study, we propose a strategy for the routine diagnosis of these syndromes that consists of the following steps: 1) methylation analysis, which does not require parental samples; 2) microsatellite genotyping of patient and parents to differentiate deletions, UPD and imprinting mutations; and 3) FISH for otherwise uninformative cases, and whenever parental samples are not available. Of the 34 patients whose PWS or AS diagnoses were not confirmed by laboratory tests, five presented a small extra marker chromosome, identified in three of them as an inv dup(15). One AS patient carried a balanced t(15;15) translocation associated with paternal UPD. Therefore G-banded chromosome analysis should be performed on all such patients, to detect possible structural rearrangements.

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The Frequency of Uniparental Disomy in Prader-Willi Syndrome

Cited by 244 publications

References 39 publications

Circulating adiponectin levels, body composition and obesity-related variables in Prader–Willi syndrome: comparison with obese subjects

Circulating adiponectin levels, body composition and obesity-related variables in Prader–Willi syndrome: comparison with obese subjects

The Changing Purpose of Prader-Willi Syndrome Clinical Diagnostic Criteria and Proposed Revised Criteria

Diagnosis of patients with Prader-Willi and Angelman Syndromes: the importance of an overall investigation

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