Abstract
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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Acknowledgements
We gratefully acknowledge the participation and provision of information provided by the families at the University of Florida and in the Rare Disease Natural History Study. We thank Krista Garner and Christy Lynn for their expert assistance in clinical assessments, Drs Karin Buiting and Bernhard Horsthemke for sharing their MLPA protocol, and Dr Robert Nicholls for critical comments on parts of this manuscript. This work was supported in part by the Hayward Foundation (DJD), the National Institutes of Health (NIH) U54 HD061222 and RR019478 (SJK; JLM; ALB; TXS; DJD), and the NIH/National Center for Research Resources CTSA Grant 1UL 1RR029890. SJK is supported in part by 2007 NARSAD young investigator award, 2008 PWSA (USA) Research Award, NIH R03MH083673 and NIH K23MH082883 awards.
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Kim, SJ., Miller, J., Kuipers, P. et al. Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes. Eur J Hum Genet 20, 283–290 (2012). https://doi.org/10.1038/ejhg.2011.187
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DOI: https://doi.org/10.1038/ejhg.2011.187
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