Introduction: Maternal uniparental disomy (matUPD) has been identified as the molecular cause of 36% of the cases with Prader-Willi Syndrome (PWS). Trisomic rescue is discussed as the primary mechanism in the development of matUPD, which corrects a non-disjunction error in meiosis I or II by discarding one chromosome of a trisomic zygote. These non-disjunction errors have been linked to advanced maternal age (AMA). Evidence for this mechanism was provided by the detection of mosaicism for trisomy in affected individuals with uniparental disomy (UPD) or placental tissue. For PWS, eight cases have been published so far, detecting mosaic trisomy 15 (MT15) in fetal tissue or blood of individuals with matUPD. Only in two of the cases MT15 has been detected in peripheral blood samples. According to the literature, a more severe phenotype has been discussed for individuals with concurrent MT15 and matUPD 15. This thesis presents the case report of the second documented case of a live-born infant with matUPD in PWS, in which MT15 was found in peripheral blood. Consistent with this finding, further matUPD and paternal uniparental disomy (patUPD) cases were examined for the presence of MT15, under the assumption that its occurrence might be higher than previously reported. Methods: Genetic testing was performed on the infant’s lymphocytes extracted from peripheral blood at eight days of age. Methylation-specific multiplex ligationdependent probe amplification (MS MLPA) was performed initially. Subsequently, a trio genotype analysis (infant and both parents) was performed using single nucleotide polymorphism (SNP) array. Cytogenetic analysis was performed at 16 months of age. The performed retrospective study involved surveying individuals with a previous diagnosis of PWS and Angelman Syndrome (AS) with an abnormal methylation on chromosome 15, resulting in the inclusion of four probands (three with matUPD 15 and one with patUPD 15). Peripheral blood samples were analysed for the presence of the MT15 utilising SNP array and classical cytogenetics. Results: MS MLPA indicated hypermethylation in the Prader-Willi critical region on chromosome 15 and a normal copy number, ruling out a deletion. Trio-genotype and SNP array yielded a complete heterodisomic matUPD 15 as well as a low-grade (approximately 10%) MT15. Cytogenetic analysis demonstrated a normal male karyotype, with no indication of trisomy. The boy was born to a 38-year-old primiparous woman and presented with a relatively mild phenotype. He presented age-appropriate development for PWS, with no severe congenital anomalies. In the retrospective study, MT15 was not identified in any of the four probands, either by cytogenetic analysis or by SNP array. Discussion: The case report provides further evidence for a trisomic rescue after meiotic errors being the primary mechanism in the development of matUPD 15. A link between AMA and matUPD was also present. It also demonstrates that infants with MT15 and matUPD 15 found in peripheral blood may not present with a more severe phenotype or congenital anomalies, as previously suggested in the literature. This finding further supports the efficacy of SNP array analysis in detecting MT15. The current case report supports the recommendation for additional array analysis in future UPD 15 cases to detect a possible MT15. This is required to determine the actual frequency of MT15 in UPD 15 and further phenotypic characteristics in affected individuals in the future.
Mosaic trisomy 15 in Prader-Willi Syndrome with maternal uniparental disomy- A case report and retrospective study on the occurrence of mosaic trisomy 15 in additional cases
Pitzl, S. S. (Author). 2026
Student thesis: Diploma thesis