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Received on January 26, 2006
Accepted on April 20, 2006
Molecular Diagnostics and Genetics |
1 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT
2 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, and ARUP Laboratories, Salt Lake City, UT, and Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT
* To whom correspondence should be addressed. E-mail: rong.mao{at}aruplab.com.
Background: Approximately 99% of Prader-Willi syndrome (PWS) and 80% of Angelman syndrome (AS) cases have deletions at a common region in chromosome 15q11.2-q13, uniparental disomy for chromosome 15 (UPD15), or imprinting center defects affecting gene expression in this region. The resulting clinical phenotype (PWS or AS) in each class of sequence variation depends on the parent of origin. Both disorders are characterized at the molecular level by abnormal methylation of imprinted regions at 15q11.2-q13. Other rare chromosome 15 rearrangements and a few smaller atypical deletions associated with abnormal methylation patterns also have symptoms overlapping with either PWS or AS.
Methods: We designed a methylation-specific melting analysis (MS-MA) method for a rapid screening of PWS/AS and evaluated methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for diagnosis of PWS/AS associated with deletions, UPD15, or rare duplications. Forty-nine previously genotyped samples were tested by MS-MA. We also tested 26 MS-MA genotyped samples and 1 additional sample with rare duplication of chromosome region 15q11-q12.
Results: PWS/AS genotyping results obtained by MS-MA and by MS-MLPA were fully concordant. In addition, MS-MLPA was superior in detecting deletions/rare duplications, possible UPD15, or imprinting center defects, which were usually determined by a laborious fluorescence in situ hybridization method or by chromosomal segregation analysis for the parental-origin using short-tandem repeat makers.
Conclusions: MS-MA appears to be an efficient primary method to diagnose PWS/AS, and use of the quantitative MS-MLPA method provides detailed information about deletions, rare duplications, and possibly UPD.
The following articles in journals at HighWire Press have cited this article:
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  W. Wang, H.-Y. Law, and S. S. Chong Detection and Discrimination between Deletional and Non-Deletional Prader-Willi and Angelman Syndromes by Methylation-Specific PCR and Quantitative Melting Curve Analysis J. Mol. Diagn., September 1, 2009; 11(5): 446 - 449. [Abstract] [Full Text] [PDF]
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E. Lyon and C. T. Wittwer LightCycler Technology in Molecular Diagnostics J. Mol. Diagn., March 1, 2009; 11(2): 93 - 101. [Abstract] [Full Text] [PDF]
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 A. P. Goldstone, A. J. Holland, B. P. Hauffa, A. C. Hokken-Koelega, M. Tauber, and on behalf of speakers contributors at the Second E Recommendations for the Diagnosis and Management of Prader-Willi Syndrome J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4183 - 4197. [Abstract] [Full Text] [PDF]
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A. O.H. Nygren, S. I. Lens, and R. Carvalho Methylation-Specific Multiplex Ligation-Dependent Probe Amplification Enables a Rapid and Reliable Distinction between Male FMR1 Premutation and Full-Mutation Alleles J. Mol. Diagn., November 1, 2008; 10(6): 496 - 501. [Abstract] [Full Text] [PDF]
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 J. R. Pedersen-White, L. P. Chorich, D. P. Bick, R. J. Sherins, and L. C. Layman The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome Mol. Hum. Reprod., June 1, 2008; 14(6): 367 - 370. [Abstract] [Full Text] [PDF]
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 H. E. White, V. J. Hall, and N. C.P. Cross Methylation-Sensitive High-Resolution Melting-Curve Analysis of the SNRPN Gene as a Diagnostic Screen for Prader-Willi and Angelman Syndromes Clin. Chem., November 1, 2007; 53(11): 1960 - 1962. [Abstract] [Full Text] [PDF]
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C.-C. Hung, C.-P. Chen, S.-P. Lin, S.-C. Chien, C.-N. Lee, W.-F. Cheng, W.-S. Hsieh, M. S. Liu, Y.-N. Su, and W.-L. Lin Quantitative Assay of Deletion or Duplication Genotype by Capillary Electrophoresis System: Application in Prader-Willi Syndrome and Duchenne Muscular Dystrophy Clin. Chem., December 1, 2006; 52(12): 2203 - 2210. [Abstract] [Full Text] [PDF]
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