Prader-Willi and Angelman Syndromes and the Implications of Genomic Imprinting in Their Etiology

1996 ◽  
Vol 45 (1-2) ◽  
pp. 15-16
Author(s):  
S.B. Cassidy
Keyword(s):  
Genomic Imprinting ◽  
Hypogonadotropic Hypogonadism ◽  
Uniparental Disomy ◽  
Failure To Thrive ◽  
Chromosome 15 ◽  
Sleep Regulation ◽  
Obsessive Compulsive ◽  
Maternal Uniparental Disomy ◽  
Normal Human ◽  
Human Disorder

The unfolding of the genetic story of Prader-Willi and Angelman syndromes provided the first recognition of human genomic imprinting. These disorders, which are clinically very distinct, are related through their genomic proximity and the inverse direction of the imprinting which affects them. Both are interesting disorders in themselves, especially in that both have distinctive behavioral patterns among their clinical features that may teach us much about normal human behavior.Prader-Willi syndrome (PWS) is a complex multi-system condition whose major features include infantile hypotonia with decreased arousal, poor suck and failure-to-thrive; characteristic dysmorphic facial features; hypopigmentation; childhood onset of obesity due to lack of satiety; hypogonadotropic hypogonadism with genital hypoplasia and delayed and incomplete puberty; short stature for genetic background; developmental delay and usually mild mental retardation; and a characteristic behavioral disturbance with temper tantrums and obsessive-compulsive behavior. PWS occurs in about 1/15,000 people. Since its first description in 1956, it has been apparent that many of these features arise from insufficient function of the hypothalamus, and recent identification of neurosecretory growth hormone insufficiency and temperature and sleep regulation abnormalities support this. However, no visible gross or microscopic abnormalities of the hypothalamus are seen on neuropathology. The finding of a chromosome 15q 11-13 deletion in a proportion of patients with PWS by Ledbetter and colleagues in 1981 was the first window to the exciting genetic discoveries of the past decade, including recognition (initially by Butler and Palmer) that the deletion is always on the paternally-derived chromosome 15 in PWS, and the finding by Nicholls and coworkers that the vast majority of the remainder of patients had normal chromosomes but had maternal uniparental disomy (UPD). Nearly all patients with clinically typical PWS have either 15q deletion (about 75%) or maternal UPD (about 25%). This is the first human disorder that was recognized to result from uniparental disomy, and lead to many insights into imprinting.

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

2019 ◽  
Vol 32 (8) ◽  
pp. 879-884 ◽  
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.

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

2006 ◽  
Vol 52 (6) ◽  
pp. 1005-1013 ◽  
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.

Loss of Heterozygosity on the Distal Long Arm of Chromosome 15: An Allusion for Prader-willi Syndromes?

2021 ◽  
Author(s):  
Yang-Li Dai ◽  
Ke Huang ◽  
Ming-Qiang Zhu ◽  
Mian-Ling Zhong ◽  
Guan-Ping Dong ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Loss Of Heterozygosity ◽  
Critical Region ◽  
Neutral Loss ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Maternal Uniparental Disomy ◽  
Specific Pcr ◽  
Dependent Probe

Abstract BackgroundPrader-Willi syndrome (PWS) is a rare neurodevelopmental disorder that is partially caused by maternal uniparental disomy (UPD) of chromosome 15. Copy-neutral loss of heterozygosity (CN-LOH) observed on the distal long arm of chromosome 15 may be an indicator of UPD and may require additional genetic testing as chromosome 15 is known to harbor imprinted genes.MethodsChromosome microarray (CMA) was performed for two children with developmental disabilities or congenital anomalies. The results showed CN-LOH on the distal long arm of chromosome 15. Thereafter, methylation-specific PCR (MS-PCR) or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to confirm the diagnosis of PWS.ResultsMS-PCR did not detect an unmethylated allele for the SNRPN gene or MS-MLPA hypermethylation in 15q11.2-q13.1 region, supporting the diagnosis of PWS.ConclusionsThese data suggested that LOH on chromosome 15, and even the critical region of 15q11.2q13.1 was not involved, perhaps due to partial heterodisomy and partial isodisomy UPD15. Hence, other genetic tests are warranted for the diagnosis of PWS.

Prader-Willi syndrome due to maternal uniparental disomy of chromosome 15 in a boy with a balanced 3;21 translocation

2001 ◽  
Vol 100 (1) ◽  
pp. 85-86 ◽  
Author(s):  
Lori L. Bassett ◽  
Ron C. Michaelis ◽  
Mary Holland Geiger ◽  
Jack Tarleton ◽  
C. Lynn Moore ◽  
...  
Keyword(s):  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy

Mosaic maternal uniparental disomy of chromosome 15 in Prader-Willi syndrome: Utility of genome-wide SNP array

2012 ◽  
Vol 161 (1) ◽  
pp. 166-171 ◽  
Author(s):  
Kosuke Izumi ◽  
Avni B. Santani ◽  
Matthew A. Deardorff ◽  
Holly A. Feret ◽  
Tanya Tischler ◽  
...  
Keyword(s):  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Genome Wide

scholarly journals Maternal uniparental disomy of chromosome 15 and concomitant STRC and CATSPER2 deletion-mediated deafness-infertility syndrome

2017 ◽  
Vol 173 (5) ◽  
pp. 1436-1439 ◽  
Author(s):  
Lisa Karger ◽  
Wahab A. Khan ◽  
Rafaela Calabio ◽  
Ram Singh ◽  
Bixia Xiang ◽  
...  
Keyword(s):  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Maternal Uniparental Disomy

scholarly journals Methylation-Sensitive High-Resolution Melting-Curve Analysis of the SNRPN Gene as a Diagnostic Screen for Prader-Willi and Angelman Syndromes

2007 ◽  
Vol 53 (11) ◽  
pp. 1960-1962 ◽  
Author(s):  
Helen E White ◽  
Victoria J Hall ◽  
Nicholas CP Cross
Keyword(s):  
High Resolution ◽  
High Resolution Melting ◽  
Uniparental Disomy ◽  
Melting Curve ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Chromosome 15 ◽  
Maternal Uniparental Disomy ◽  
Small Nuclear Ribonucleoprotein ◽  
High Resolution Melting Curve

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. Lack of paternal contribution results in PWS either by paternal deletion (approximately 70%) or maternal uniparental disomy (UPD) (approximately 25%). Most cases of AS result from the lack of a maternal contribution from this same region, by maternal deletion (70%) or paternal UPD (approximately 5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus differentiates the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Methods: Methylation-sensitive high-resolution melting-curve analysis (MS-HRM) using the DNA binding dye EvaGreen was used to analyze methylation differences at the SNRPN locus in anonymized DNA samples from individuals with PWS (n = 39) or AS (n = 31) and from healthy control individuals (n = 95). Results from the MS-HRM assay were compared to those obtained by use of a methylation-specific PCR (MSP) protocol that is used commonly in diagnostic practice. Results: With the MS-HRM assay 97.6% of samples were unambiguously assigned to the 3 diagnostic categories (AS, PWS, normal) by use of automated calling with an 80% confidence percentage threshold, and the failure rate was 0.6%. One PWS sample showed a discordant result for the MS-HRM assay compared to MSP data. Conclusions: MS-HRM is a simple, rapid, and robust method for screening methylation differences at the SNRPN locus and could be used as a diagnostic screen for PWS and AS.

scholarly journals Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility.

2021 ◽  
Author(s):  
Anna Kaitlyn Victor ◽  
Martin Donaldson ◽  
Daniel Johnson ◽  
Winston Miller ◽  
Lawrence Reiter
Keyword(s):  
Behavioral Problems ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Autism Spectrum ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Mitochondrial Defects ◽  
Mitochondrial Transcripts ◽  
Global Reduction

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by chromosome 15 maternal uniparental disomy (PW-UPD). Children with PW-UPD are at higher risk for developing autism spectrum disorder (ASD) than the neurotypical population. In this study, we used expression analysis of PW-UPD neurons to try to identify the molecular cause for increased autism risk. Methods: Dental pulp stem cells (DPSC) from neurotypical control and PWS subjects were differentiated to neurons for mRNA sequencing. Significantly differentially expressed transcripts among all groups were identified. Downstream protein analysis including immunocytochemistry and immunoblots were performed to confirm the transcript level data and pathway enrichment findings. Results: We identified 9 transcripts outside of the PWS critical region (15q11.2-q13.1) that may contribute to core PWS phenotypes. Moreover, we discovered a global reduction in mitochondrial transcripts in the PW-UPD +ASD group. We also found decreased mitochondrial abundance along with mitochondrial aggregates in the cell body and neural projections of +ASD neurons. Conclusions: The 9 transcripts we identified common to all PWS subtypes may reveal PWS specific defects during neurodevelopment. Importantly, we found a global reduction in mitochondrial transcripts in PW-UPD +ASD neurons versus control and other PWS subtypes. We then confirmed mitochondrial defects in neurons from individuals with PWS at the cellular level. Quantification of this phenotype supports our hypothesis that the increased incidence of ASD in PW-UPD subjects may arise from mitochondrial defects in developing neurons.

scholarly journals Prader-Willi syndrome: reflections on seminal studies and future therapies

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200195
Author(s):  
Michael S. Chung ◽  
Maéva Langouët ◽  
Stormy J. Chamberlain ◽  
Gordon G. Carmichael
Keyword(s):  
Genomic Imprinting ◽  
Angelman Syndrome ◽  
Cpg Island ◽  
Uniparental Disomy ◽  
Large Deletion ◽  
Paternal Allele ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Uniparental Disomy ◽  
Parental Allele

Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from the SNURF-SNRPN/SNHG14 may be the primary cause of PWS. Patients with small atypical deletions of the paternal SNORD116 cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.

Sign in / Sign up

Export Citation Format

Share Document