TY - JOUR
T1 - DNA methylation episignature for Smith-Magenis and Potocki-Lupski syndromes
T2 - a mirror perspective
AU - van der Laan, Liselot
AU - Karimi, Karim
AU - Rooney, Kathleen
AU - Alders, Mariëlle
AU - Brusco, Alfredo
AU - Lasa-Aranzasti, Amaia
AU - Brunetti-Pierri, Nicola
AU - Cueto-Gonzalez, Anna M
AU - DuPont, Barbara R
AU - Cappuccio, Gerarda
AU - Dubourg, Christele
AU - Everman, David
AU - Gatinois, Vincent
AU - Ganne, Benjamin
AU - Genevieve, David
AU - Ferrero, Giovanni Battista
AU - Kempers, Marlies
AU - Levy, Michael A
AU - Niceta, Marcello
AU - Novelli, Antonio
AU - Orlando, Valeria
AU - Odent, Sylvie
AU - Patterson, Wesley G
AU - Polstra, Abeltje M
AU - Roscioli, Tony
AU - Ruiz-Pallares, Nathalie
AU - Sabbagh, Quentin
AU - Trajkova, Slavica
AU - Tartaglia, Marco
AU - Tedder, Matthew A
AU - Toutain, Annick
AU - Koehler, Udo
AU - Valenzuela, Irena
AU - van Hagen, Johanna M
AU - van der Kevie-Kersemaekers, Anne-Marie
AU - Henneman, Peter
AU - Mannens, Marcel M A M
AU - Sadikovic, Bekim
AU - van Haelst, Mieke M
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to European Society of Human Genetics 2025.
PY - 2026/1
Y1 - 2026/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105017478890
U2 - 10.1038/s41431-025-01956-0
DO - 10.1038/s41431-025-01956-0
M3 - Article
C2 - 41028553
SN - 1018-4813
VL - 34
SP - 90
EP - 98
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 1
ER -