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<p><i>PACS1</i>-related disorder (<i>PACS1</i>-RD), also known as Schuurs-Hoeijmakers syndrome, is a rare autosomal dominant neurodevelopmental disorder predominantly caused by the recurrent de novo c.607 C &gt; 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 <i>PACS1</i>-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 <i>PACS1</i>-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 <i>PACS1</i>-RD, consistently observed in individuals carrying either the canonical p.(Arg203Trp) or the non-recurrent p.(Arg203Gln) variant. This episignature further enabled <i>PACS1</i>-RD diagnosis in one unsolved individual initially suspected of Kabuki syndrome. These findings refine the clinical delineation of <i>PACS1</i>-RD and establish an episignature that will support diagnosis in unresolved neurodevelopmental disorders and guide pathogenicity assessment of non-recurrent <i>PACS1</i> variants.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • 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

摘要

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.