There is a range of genetic disorders arising from altered DNA methylation at cytosine residues, known as imprinting defects. This category This group includes and , 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 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 bisulphite 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 However, in recent years, MS-PCR has largely been superseded by methylation-specific MLPA (MS-MLPA).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).