DNA methylation episignature for Smith-Magenis and Potocki-Lupski syndromes: a mirror perspective

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal genomic disorders caused by deletions and duplications of the 17p11.2 chromosomal region, respectively. This study aimed to identify and validate DNA methylation episignatures specific to SMS and PTLS, and to investigate their reciprocal relationship and shared molecular features with other neurodevelopmental disorders. Genome-wide DNA methylation was analyzed in individuals with an SMS (n = 26) or PTLS (n = 27) phenotype associated with copy number variation, and SMS patients with RAI1 sequence variants using the Infinium EPIC array. Differentially methylated CpG sites were identified and used to develop support vector machine (SVM)-based classifiers, which demonstrated high sensitivity and specificity for both syndromes. The analysis revealed a mirror-like episignature, with SMS showing predominant hypomethylation and PTLS displaying hypermethylation at shared loci. Functional correlation with other neurodevelopmental disorders highlighted significant overlap with known episignatures, including those associated with MEF2C-related disorders. Notably, individuals with RAI1 sequence variants did not exhibit the same DNA methylation patterns, suggesting that the epigenetic alterations are primarily driven by copy number changes. These findings establish SMS and PTLS as distinct yet interconnected epigenetic entities, offering valuable diagnostic biomarkers and insights into the molecular pathophysiology of 17p11.2-associated neurodevelopmental disorders.