There is a range of genetic disorders arising from altered DNA methylation at cytosine residues, known as imprinting defects. This category This group includes Prader-Willi syndrome (PWS) and Angelman syndrome (AS), both of which are linked to the 15q11.2 chromosomal region. PWS is due to a deletion or methylation defect on the paternal allele, while AS occurs when the maternal allele is affected. Historically, locus-specific FISH probes were the standard diagnostic tool for these syndromes, though they detected only about 70% of cases, primarily those involving microdeletions.
In the mid-1990s, methylation-specific PCR (MS-PCR) emerged as a more effective method, capable of identifying other causes such as uniparental disomy and imprinting defects. This technique improved diagnostic accuracy, explaining approximately 99% of PWS cases and around 80% of causative changes in AS.
MS-PCR operates by converting unmethylated cytosine residues to uracil using sodium bisulfite and employing primers that distinguish between unmodified maternal DNA and methylation-modified paternal DNA. However, in recent years, MS-PCR has largely been superseded by methylation-specific MLPA (MS-MLPA). This newer method evaluates the methylation status of individual CpG sites at multiple positions within a differentially methylated region (DMR). By doing so, it minimizes the likelihood of false-positive or false-negative results caused by SNPs or technical issues. MS-PCR, on the other hand, is limited to the CpGs at the primer binding site(s).
| Genetic change | PWS | AS |
| Microdeletion 15q11.2-q13 | 75-80% | 70-75% |
| Uniparental disomy | 20-25% | 3-7% |
| Imprinting center mutations | 1% | 2-3% |
| Pathogenic variants in the UBE3A gene | – | 10% |
| Unknown | – | ca. 15% |
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