Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

Abstract Background Chromosome abnormalities are a frequent finding in prenatal invasive testing for fetal malformations and/or growth retardation. Case presentation We present a case of low level (8%) mosaic trisomy 15 detected on amniocentesis after fetal heart anomalies and IUGR (intrauterine growth retardation) were found on routine scan. Postnatal karyotype confirmed a very low level (2%) mosaicism in the skin but not in blood lymphocytes or in the urine. Methylation specific testing of chromosome 15 showed maternal uniparental disomy and consequently the newborn was diagnosed with Prader-Willi syndrome (PWS). Conclusions This case illustrates the need of further genetic testing in all trisomy 15 mosaicisms detected in prenatal invasive testing in order to screen for PWS, a more frequent entity than trisomy 15, altogether providing appropriate genetic counseling and adequate clinical management. The recommendation is applicable to prenatally detected mosaic trisomies of other chromosomes carrying imprinted genes, such as 7, 11 and 14.

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Generation of patient-specific induced pluripotent stem cells (KSCBi007-A) derived from a patient with Prader–Willi syndrome retain maternal uniparental disomy (UPD)

Stem Cell Research ◽

10.1016/j.scr.2019.101647 ◽

2019 ◽

Vol 41 ◽

pp. 101647

Author(s):

Bo-Young Kim ◽

Jin-Sung Lee ◽

Yong-Ou Kim ◽

Mi-Hyun Park ◽

Soo Kyung Koo

Keyword(s):

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Uniparental Disomy ◽

Patient Specific ◽

Prader Willi Syndrome ◽

Maternal Uniparental Disomy ◽

Induced Pluripotent

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Exclusion of maternal uniparental disomy of chromosome 14 in patients referred for Prader-Willi syndrome using a multiplex methylation polymerase chain reaction assay

Journal of Medical Genetics ◽

10.1136/jmg.40.4.e46 ◽

2003 ◽

Vol 40 (4) ◽

pp. 46e-46 ◽

Cited By ~ 16

Author(s):

L G Dietz

Keyword(s):

Polymerase Chain Reaction ◽

Polymerase Chain Reaction Assay ◽

Uniparental Disomy ◽

Prader Willi Syndrome ◽

Chromosome 14 ◽

Chain Reaction ◽

Maternal Uniparental Disomy ◽

Polymerase Chain

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Safety and effectiveness of growth hormone therapy in infants with Prader-Willi syndrome younger than 2 years: a prospective study

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0539 ◽

2019 ◽

Vol 32 (8) ◽

pp. 879-884 ◽

Cited By ~ 3

Author(s):

Raquel Corripio ◽

Carla Tubau ◽

Laura Calvo ◽

Carme Brun ◽

Núria Capdevila ◽

...

Keyword(s):

Growth Hormone ◽

Prospective Study ◽

Mixed Model ◽

Standard Deviation Score ◽

Uniparental Disomy ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Gh Treatment ◽

Maternal Uniparental Disomy ◽

A Prospective Study

Abstract Background There is little evidence of the effects of early treatment with growth hormone (GH) in infants with Prader-Willi syndrome (PWS). A prospective study was conducted to assess the safety of GH therapy in infants younger than 2 years of age with PWS. Methods A total of 14 patients with PWS started treatment with GH under the age of 2 years and were followed over a 2-year period. A deletion of chromosome 15 was present in nine infants (64.3%) and maternal uniparental disomy 15 in five infants (35.7%). The median age at start of GH treatment was 9.6 months (interquartile range [IQR] 9.0–18.3 months). Changes in height standard deviation score (SDS), body mass index (BMI) SDS and subcapsular and tricipital skinfolds in the follow-up period were evaluated with a mixed-model regression analysis using the Package R. Results There were no fatal adverse events. A significant decrease (p < 0.001) in tricipital and subcapsular skinfold thickness, with an upward trend of height SDS and a downward trend of BMI SDS, was observed. Infants who started GH before 15 months of age started walking at a median of 18.0 [17.0–19.5] months vs. 36.6 [36.3–37.8] months for those who began treatment with GH after 15 months of age (p = 0.024). Conclusions GH treatment in infants with PWS less than 2 years of age is safe and improved body composition. Infants who received GH before the age of 15 months started to walk earlier.

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Sleep-Related Breathing Disorders in Young Adults With Prader-Willi Syndrome: A Placebo-Controlled, Crossover GH Trial

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00391 ◽

2019 ◽

Vol 104 (9) ◽

pp. 3931-3938

Author(s):

Stephany H Donze ◽

Al W de Weerd ◽

Renilde A S van den Bossche ◽

Koen F M Joosten ◽

Anita C S Hokken-Koelega

Keyword(s):

Young Adults ◽

Adult Height ◽

Uniparental Disomy ◽

Apnea Hypopnea Index ◽

Prader Willi Syndrome ◽

Double Blind ◽

Sleep Related Breathing Disorders ◽

Maternal Uniparental Disomy ◽

Breathing Disorders ◽

Obstructive Sleep

Abstract Context Sleep-related breathing disorders (SRBD) are common in people with Prader-Willi syndrome (PWS). Young adults with PWS benefit from GH continuation after attaining adult height by maintaining the improved body composition obtained during childhood. There are, no studies about the effects of GH on SRBD in young adults with PWS who were treated with GH during childhood. Objective Investigate the effects of GH vs placebo on SRBD in young adults with PWS who were treated with GH during childhood and had attained adult height. Design Two-year, randomized, double-blind, placebo-controlled, crossover study in 27 young adults with PWS, stratified for sex and body mass index. Setting Dutch PWS Reference Center. Intervention Crossover intervention with GH (0.67 mg/m2/d) and placebo, both over one year. Main Outcome Measures Apnea hypopnea index (AHI), obstructive apnea index (OAI), central apnea index (CAI), measured by polysomnography. Results Compared with placebo, GH did not increase AHI, CAI, or OAI (P > 0.35). The effect of GH vs placebo was neither different between men and women, nor between patients with a deletion or maternal uniparental disomy/imprinting center defect. After two years, there was no difference in AHI, CAI, or OAI compared with baseline (P > 0.18). Two patients (7%) fulfilled the criteria of obstructive sleep apnea regardless of GH or placebo. Conclusions GH compared with placebo does not cause a substantial increase in AHI, CAI, or OAI in adults with PWS who were treated with GH during childhood and have attained adult height. Our findings are reassuring and prove that GH can be administered safely.

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Quantitative Analysis of SRNPN Gene Methylation by Pyrosequencing as a Diagnostic Test for Prader–Willi Syndrome and Angelman Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2005.065086 ◽

2006 ◽

Vol 52 (6) ◽

pp. 1005-1013 ◽

Cited By ~ 49

Author(s):

Helen E White ◽

Victoria J Durston ◽

John F Harvey ◽

Nicholas CP Cross

Keyword(s):

Diagnostic Test ◽

Angelman Syndrome ◽

Uniparental Disomy ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Maternal Uniparental Disomy ◽

Cpg Sites ◽

Specific Pcr ◽

Small Nuclear Ribonucleoprotein ◽

Maternal Contribution

Abstract Background: Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (∼70%) or maternal uniparental disomy (UPD; ∼30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (∼70%) or by paternal UPD (∼5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Methods: Sodium bisulfite–treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol. Results: The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol. Conclusions: Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS.

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