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The frequency of uniparental disomy in Prader-Willi syndrome. Implications for molecular diagnosis
M J Mascari1, W Gottlieb, P K Rogan
1Department of Pediatrics, Milton S. Hershey Medical Center, College of Medicine, Pennsylvania State University, Hershey 17033.
Insights
Maternal uniparental disomy, inheriting both copies of chromosome 15 from the mother, causes Prader-Willi syndrome in about 20% of cases. Molecular and cytogenetic tests identify the genetic cause in most patients.
Area of Science:
- Genetics
- Molecular Biology
- Pediatrics
Background:
- Prader-Willi syndrome (PWS) is a complex genetic disorder affecting infants and children, presenting with hypotonia, obesity, hypogonadism, and intellectual disability.
- Clinical diagnosis of PWS can be challenging in early childhood.
- Genetic basis typically involves a deletion in the paternally derived chromosome 15 (15q11q13), present in about two-thirds of patients.
Purpose of the Study:
- To investigate the frequency of maternal uniparental disomy (UPD) in Prader-Willi syndrome patients lacking a detectable cytogenetic deletion.
- To utilize molecular genetic techniques to identify alternative genetic causes of PWS.
Main Methods:
- Molecular analyses were performed on DNA markers within the 15q11q13 region and other parts of chromosome 15.
- The study included 30 PWS patients without visible deletions and their parents.
- Three PWS patients with cytogenetic deletions were included as controls.
Main Results:
- Maternal uniparental disomy for chromosome 15 was identified in 60% (18/30) of PWS patients without cytogenetic deletions, with an association with advanced maternal age.
- Large molecular deletions were found in 27% (8/30) of these patients.
- Normal biparental inheritance was observed in 13% (4/30) of patients, with three exhibiting atypical clinical features.
Conclusions:
- Maternal uniparental disomy accounts for approximately 20% of all Prader-Willi syndrome cases.
- Combining cytogenetic and molecular techniques allows for the identification of the genetic basis in up to 95% of PWS patients.
Background:
Prader-Willi syndrome is a genetic disorder characterized by infantile hypotonia, obesity, hypogonadism, and mental retardation, but it is difficult to diagnose clinically in infants and young children. In about two thirds of patients, a cytogenetically visible deletion can be detected in the paternally derived chromosome 15 (15q11q13). Recently, patients with Prader-Willi syndrome have been described who do not have the cytogenetic deletion but instead have two copies of the 15q11q13 region that are inherited from the mother (with none inherited from the father). This unusual form of inheritance is known as maternal uniparental disomy. Using molecular genetic techniques, we sought to determine the frequency of uniparental disomy in Prader-Willi syndrome.
Methods:
We performed molecular analyses using DNA markers within 15q11q13 and elsewhere on chromosome 15 in 30 patients with Prader-Willi syndrome who had no cytogenetically visible deletion. We also studied their parents. Three patients with Prader-Willi syndrome who had a cytogenetic deletion served as controls.
Results:
In 18 of the 30 patients without a cytogenetic deletion (60 percent), we demonstrated the presence of maternal uniparental disomy for chromosome 15 and its association with advanced maternal age. In another eight patients (27 percent), we identified large molecular deletions. The remaining four patients (13 percent) had evidence of normal biparental inheritance for chromosome 15; three of these patients were the only ones in the study who had some atypical clinical features.
Conclusions:
In about 20 percent of all cases, Prader-Willi syndrome results from the inheritance of both copies of chromosome 15 from the mother (maternal uniparental disomy). With the combined use of cytogenetic and molecular techniques, the genetic basis of Prader-Willi syndrome can be identified in up to 95 percent of patients.