DNA methylation signature and clinical delineation of PACS1-related disorder in 24 unreported individuals.
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Sabbagh Quentin, Cenni Camille, Haghshenas Sadegheh, Alessandri Jean-Luc, Bak Mads, Bayat Allan, Barat-Houari Mouna, Brusco Alfredo, Busa Tiffany, Calaya Anaïs, Calvert Paige, Cormier-Daire Valérie, Coubes Christine, Duffourd Yannis, Ferrero Giovanni B, Guimier Anne, Haye Damien, Hjortshøj Tina Duelund, Lambert Laetitia, Larsen Karen Bonde, Lauzon-Young Carolyn, Lesca Gaetan, Chatron Nicolas, Levy Michael A, Lopergolo Diego, Margot Henri, McConkey Haley, Monin Pauline, Morel Godelieve, Naudion Sophie, Nizon Mathilde, Odent Sylvie, Pinson Lucile, Pons Linda, Putoux Audrey, Rio Marlène, Rossi Massimiliano, Rouaux Lucie, Rouxel Flavien, Ruiz-Pallares Nathalie, Sanchez Elodie, Pagano Stefano, Santorelli Filippo M, Sauvestre Clément, Schymick Jennifer C, Siu Victoria Mok, Spodenkiewicz Marta, Tedder Matthew, Tharreau Mylène, Mau-Them Frédéric Tran, Tümer Zeynep, Valenzuela Irene, Van Gils Julien, Willems Marjolaine, Kirchhoff Aron, Krawitz Peter, Kerkhof Jennifer, Schuurs-Hoeijmakers Janneke H M, Sadikovic Bekim, Geneviève David
Аннотация
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.