Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct genetic disorders caused by lack of expression of paternally (PWS) or maternally (AS) imprinted genes in the 15q11—15q13 region, which is known as the Prader-Willi/Angelman syndrome critical region (PWASCR). Angelman syndrome patients often exhibit severe intellectual and developmental disabilities; sleep disturbances, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanour. Alternatively, Prader-Willi syndrome patients often have low muscle tone, short stature, cognitive disabilities, behaviour problems, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity.


Even though the symptoms of each disease are strikingly different, the disorders are an outcome of aberrations in the same region. In about 1% of PWS patients and 2—4% of AS patients, the disease is due to aberrant imprinting or gene silencing, or both. Further, some of these patients were found to have a mosaic methylation pattern of the Prader-Willi/Angelman syndrome critical region.


To further understand the mechanism of pathogenesis and phenotype of patients with mosaic methylation pattern, Mayo Clinic researchers studied 10 patients with mosaic methylation pattern tested between June 2007 and June 2013 at the Mayo Clinic Clinical Molecular Genetics and Clinical Cytogenetics Laboratories. All patients were younger, ranging from two to 11 years old. The study was published in Molecular Cytogenetics.


All of the cases, except for two, had normal copy number and heterozygosity of chromosome 15 as detected by chromosomal microarray (CMA). In the other two cases, absence of heterozygosity was identified. According to Umut Aypar, Ph.D., FACMG, Co-Director of the Mayo Clinic Cytogenetics Laboratory and first author on this paper, these cases were of particular interest to the team.


Case 1 was a four-year-old boy with mild developmental delays, mild hand tremors, and clumsiness. CMA testing revealed absence of heterozygosity spanning the entire chromosome 15, suggesting uniparental isodisomy 15.


By Umut Aypar, PhD, Co-Director, Clinical Cytogenetics Laboratory, Mayo Clinic, and Kelley Schreiber, Public Affairs, Mayo Clinic


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