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By Umut Aypar, PhD, Co-Director, Clinical Cytogenetics Laboratory, Mayo Clinic, and Kelley Schreiber, Public Affairs, Mayo Clinic, 16 January 2017
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 demeanor. Alternatively, Prader-Willi syndrome patients often have low muscle tone, short stature, cognitive disabilities, behavior 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.
“Case 1 was unique because even though the CMA testing suggested uniparental isodisomy 15, the patient had no definitive phenotypic features of Prader-Willi or Angelman syndrome,” said Dr. Aypar. “Further, methylation testing showed a mosaic methylation pattern.”
After the test results were received, researchers obtained additional clinical information, which showed that the patient was much less severely affected than expected for Angelman syndrome.
“While the patient had features similar to those of Angelman syndrome, such as essential tremors and clumsiness (ataxia), he had no seizures, dysmorphic features, or obesity. These findings weren’t traditional with previous research,” added Dr. Aypar.
To identify the difference, researchers identified nine additional previously tested patients with a similar mosaic methylation pattern. Researchers utilised CMA to test whether patients with mosaic methylation were more likely to have uniparental disomy of chromosome 15.
“Of the nine patients, only one (case two, which was an 11-year-old girl with developmental delay, speech delay, and hypotonia) had regions of absence of heterozygosity on chromosome 15,” said Dr. Aypar. “However, this patient had numerous other regions of absence of heterozygosity on multiple chromosomes, suggesting consanguinity.”
Based on the results, patients with mosaic methylation patterns don’t always have absence of heterozygosity spanning the entire chromosome 15. They tend to have milder or atypical Angelman syndrome, and the majority have features that resemble Prader-Willi syndrome.
“We recommend that quantitative methylation analysis be performed for cases of atypical Prader-Willi syndrome or Angelman syndrome,” said Dr. Aypar. “It is also important to follow up with methylation testing when whole-chromosome isodisomy is detected.”
The article was used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.