Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes

Department of Psychiatry, University of Florida, Gainesville, FL, USA.
European journal of human genetics: EJHG (Impact Factor: 4.35). 11/2011; 20(3):283-90. DOI: 10.1038/ejhg.2011.187
Source: PubMed


Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n=5) or larger (n=2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in ∼8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

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    • "The smallest was 2.46 Mb and stretched from BP2 to ATP10A. This patient had an atypical presentation with tall stature, macrocephaly and large hands and feet [Kim et al., 2012]. "
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    ABSTRACT: Genetic analyses were performed in a male patient with suspected Prader-Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromosome analysis showed a normal male karyotype. Further analysis with array-CGH identified a mosaic 847 kb deletion in 15q11-q13, including SNURF-SNRPN, the snoRNA gene clusters SNORD116 (HBII-85), SNORD115, (HBII-52), SNORD109 A and B (HBII-438A and B), SNORD64 (HBII-13), and NPAP1 (C15ORF2). MLPA confirmed the deletion and the results were compatible with a paternal origin. Metaphase-FISH verified the mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller deletions in this region have previously been reported in patients with Prader-Willi syndrome phenotype. All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome. Furthermore, it examplifies diagnostic difficulties in atypical cases and illustrates the need for additional testing methods when Prader-Willi syndrome is suspected. © 2013 Wiley Periodicals, Inc.
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    • "Since the distinction between a premutation and a full mutation is related to the methylation status rather than to the exact size of the repeat, in the present study we evaluated the usefulness of the Methylation-Specific Multiplex-Ligation-dependent Probe Amplification (MS-MLPA) assay to assess the methylation status of the promoter of the FMR1 gene for the molecular diagnosis of FXS. In fact MLPA represent a widely used technique in the study of gene copy number but also for the assessment of the methylation status of specific genes [9-14]. This approach was used in a retrospective study on 44 males, 10 Chorionic Villus Sampling (CVS) samples from male foetuses and 10 females in order to verify if MS-MLPA could replace SB in the evaluation of the methylation status of the promoter of FMR1 gene. "
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