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

• Published in: European journal of human genetics : EJHG Vol. 20; no. 3; pp. 283 - 290
• Main Authors: Kim, Soo-Jeong, Miller, Jennifer L, Kuipers, Paul J, German, Jennifer Ruth, Beaudet, Arthur L, Sahoo, Trilochan, Driscoll, Daniel J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.03.2012
• Subjects: Adolescent; Adult; Biological and medical sciences; Breakpoints; Child; Child, Preschool; Chromosome 15; Chromosome Deletion; Chromosomes; Chromosomes, Human, Pair 15; Clonal deletion; Cohort Studies; Copy number; DNA Copy Number Variations; DNA Methylation; Female; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene Order; General aspects. Genetic counseling; Genes; Genetic disorders; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Humans; Imprinting; Infant; Intellectual disabilities; Male; Medical genetics; Medical sciences; Metabolic diseases; Metabolism; Methylation; Molecular and cellular biology; Obesity; Pediatrics; Phenotype; Phenotypes; Prader-Willi syndrome; Prader-Willi Syndrome - diagnosis; Prader-Willi Syndrome - genetics; Psychiatry; Reproducibility of Results; Uniparental disomy; Young Adult; United States > US; Chromosomal aberration; Endocrinopathy; Nervous system diseases; Typing; array CGH; Epilepsy; Diseases of the osteoarticular system; 15q11.2-q13; Genotype; Genetic disease; Cerebral disorder; Phenotype; Convulsion; genotype―phenotype; Central nervous system disease; MS-MLPA; Deletion; Genetics; seizures; Atypical; Prader―Willi syndrome; Complex syndrome; Neurological disorder; Prader Labhart Willi syndrome
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2011.187

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.