Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Mar 22:9:26.
doi: 10.1186/s13039-016-0233-0. eCollection 2016.

Patients with mosaic methylation patterns of the Prader-Willi/Angelman Syndrome critical region exhibit AS-like phenotypes with some PWS features

Umut Aypar  1 , Nicole L Hoppman  1 , Erik C Thorland  1 , D Brian Dawson  1
Affiliations

Patients with mosaic methylation patterns of the Prader-Willi/Angelman Syndrome critical region exhibit AS-like phenotypes with some PWS features

Umut Aypar et al. Mol Cytogenet. .

Abstract

Background: Loss of expression of imprinted genes in the 15q11.2-q13 region is known to cause either Prader-Willi syndrome (PWS) or Angelman syndrome (AS), depending on the parent of origin. In some patients (1 % in PWS and 2-4 % in AS), the disease is due to aberrant imprinting or gene silencing, or both.

Results: We report here a 4-year-old boy on whom a chromosomal microarray (CMA) was performed due to mild hand tremors, mild developmental delays, and clumsiness. CMA revealed absence of heterozygosity (AOH) spanning the entire chromosome 15, suggesting uniparental isodisomy 15. The patient had no definitive phenotypic features of PWS or AS. Methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) was performed to determine the parent of origin of the uniparental disomy (UPD) by examining methylation status at maternally imprinted sites. Interestingly, our patient had a mosaic methylation pattern. We identified nine additional previously tested patients with a similar mosaic methylation pattern. CMA was performed on these individuals retrospectively to test whether patients with mosaic methylation are more likely to have UPD of chromosome 15. Of the nine patients, only one had regions of AOH on chromosome 15; however, this patient had numerous regions of AOH on multiple chromosomes suggestive of consanguinity.

Conclusion: The patients with mosaic methylation had milder or atypical features of AS, and the majority also had some features characteristic of PWS. We suggest that quantitative methylation analysis be performed for cases of atypical PWS or AS. It is also important to follow up with methylation testing when whole-chromosome isodisomy is detected.

Keywords: 15q11.2-q13; Chromosomal microarray; MS-MLPA; Mosaic methylation; PWASCR.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Results of Methylation-Sensitive Multiplex Ligation-Dependent Probe Amplification in Cases With Mosaic Methylation Pattern of the Prader-Willi/Angelman Syndrome Critical Region. Copy number peak ratios are determined by comparing patients with normal controls (2 copies/2 copies = 1.0), in this case no deletion is observed (a). The methylation probes are designed to hybridize to maternally imprinted loci; therefore, when compared to normal controls, in the absence of a deletion, patients with Angelman syndrome are expected to have no methylation (plotting to zero), while patients with Prader-Willi syndrome should have 2 methylated copies (ratio of 2). Interestingly, our patient (case 1) had a ratio slightly below 0.5 on average (b)
Fig. 2
Fig. 2
Results of Chromosomal Microarray in Case 1. Smooth signal is plotted at 2, indicating that two copies of the chromosome 15q arm are present without any deletion or duplication of the Prader-Willi/Angelman syndrome critical region. Allele peaks show the genotype calls. Genotype calls and allele dosage normalization are performed as follows: the formula for allele peaks is A – B, where A is the signal of the A allele and B is the signal of the B allele. The allele peaks are normalized such that AA = 1, AB = 0, and BB = −1. Therefore, the absence of heterozygosity would be observed as loss of the AB allele peaks (plotted at 0) with only AA (plotted at 1) and BB (plotted at −1) allele peaks present, as shown with case 1
See this image and copyright information in PMC

References

    1. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15(1):70–3. doi: 10.1038/ng0197-70. - DOI - PubMed
    1. Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004;15(1):12–20. doi: 10.1016/j.tem.2003.11.003. - DOI - PubMed
    1. Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet. 2003;40(2):87–95. doi: 10.1136/jmg.40.2.87. - DOI - PMC - PubMed
    1. Buiting K, Dittrich B, Gross S, Lich C, Farber C, Buchholz T, et al. Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet. 1998;63(1):170–80. doi: 10.1086/301935. - DOI - PMC - PubMed
    1. Buiting K, Gross S, Lich C, Gillessen-Kaesbach G, el-Maarri O, Horsthemke B. Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet. 2003;72(3):571–7. doi: 10.1086/367926. - DOI - PMC - PubMed

LinkOut - more resources