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DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.

European journal of human genetics : EJHG

Authors: Quentin Sabbagh, Camille Cenni, Sadegheh Haghshenas, Jean-Luc Alessandri, Mads Bak, Allan Bayat, Mouna Barat-Houari, Alfredo Brusco, Tiffany Busa, Anaïs Calaya, Paige Calvert, Valérie Cormier-Daire, Christine Coubes, Yannis Duffourd, Giovanni B Ferrero, Anne Guimier, Damien Haye, Tina Duelund Hjortshøj, Laetitia Lambert, Karen Bonde Larsen, Carolyn Lauzon-Young, Gaetan Lesca, Nicolas Chatron, Michael A Levy, Diego Lopergolo, Henri Margot, Haley McConkey, Pauline Monin, Godelieve Morel, Sophie Naudion, Mathilde Nizon, Sylvie Odent, Lucile Pinson, Linda Pons, Audrey Putoux, Marlène Rio, Massimiliano Rossi, Lucie Rouaux, Flavien Rouxel, Nathalie Ruiz-Pallares, Elodie Sanchez, Stefano Pagano, Filippo M Santorelli, Clément Sauvestre, Jennifer C Schymick, Victoria Mok Siu, Marta Spodenkiewicz, Matthew Tedder, Mylène Tharreau, Frédéric Tran Mau-Them, Zeynep Tümer, Irene Valenzuela, Julien Van Gils, Marjolaine Willems, Aron Kirchhoff, Peter Krawitz, Jennifer Kerkhof, Janneke H M Schuurs-Hoeijmakers, Bekim Sadikovic, David Geneviève

PACS1-related disorder (PACS1-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C > T p.(Arg203Trp) gain-of-function variant. Although core clinical features have been delineated, systematic data on developmental milestones, growth parameters, and clinical variability remain limited. We assembled a series of 24 previously unreported, unrelated individuals with PACS1-RD and compared their clinical and molecular features with 84 individuals from the literature. Genome-wide DNA methylation profiling was performed on peripheral blood DNA using bisulfite sequencing, interrogating ~860,000 CpG sites. Our study expands the phenotypic spectrum of PACS1-RD by reporting median age at independent walking and first spoken words (both 24 months), cross-sectional growth parameters, and previously undescribed clinical features, including congenital kidney malformations (25%) and feeding difficulties (75%). Compared with the literature, our series showed a higher prevalence of cryptorchidism (77.8%), congenital heart defect (45.8%), and hypotonia (75%). Methylation analysis identified a specific episignature for PACS1-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant. This episignature further enabled PACS1-RD diagnosis in one unsolved individual initially suspected of Kabuki syndrome. These findings refine the clinical delineation of PACS1-RD and establish an episignature that will support diagnosis in unresolved neurodevelopmental disorders and guide pathogenicity assessment of non-recurrent PACS1 variants.

© 2026. The Author(s), under exclusive licence to European Society of Human Genetics.

PMID: 41882293

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