2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Variants in Cohesin Release Factors WAPL, PDS5A, and PDS5B Define a New Class of Cohesinopathies

Variants in Cohesin Release Factors WAPL, PDS5A, and PDS5B Define a New Class of Cohesinopathies
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This study investigates the phenotypic consequences of mutations in cohesin release factors WAPL, PDS5A, and PDS5B. Cohesin plays a crucial role in organizing the genome and gene expression through the formation of topologically associating domains (TADs). Mutations in cohesin and its positive regulator NIPBL are known to cause Cornelia de Lange syndrome (CdLS), a neurodevelopmental disorder. However, the impact of mutations in the negative regulators WAPL, PDS5A, and PDS5B is unknown. The researchers used multiple databases to identify individuals with variants in WAPL, PDS5A, PDS5B, and the genomic region 10q22q23. They recruited and phenotyped these individuals. Additionally, they edited human induced pluripotent stem cells (iPSCs) using CRISPR/Cas9 to contain specific mutations and performed genomic analysis. The results show that WAPL mutations are associated with developmental delay/intellectual disability, although the syndrome is milder than CdLS. WAPL is also implicated in some phenotypes of the 10q22q23 deletion syndrome. Damaging PDS5A/B variants are associated with neurological problems, but more cases are needed for a consensus phenotype. Overall, these findings suggest a new class of disorders characterized by defective cohesin release. The authors propose further research to study the TAD architecture and gene expression in cellular models and perform methylation analysis on additional cases. This study provides valuable insights into the phenotypic consequences of mutations in cohesin release factors and expands our understanding of cohesinopathies.

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Co-Author - Philip Boone, M.D., Ph.D.; Presenting Author - Kamli N. Faour, BA; Co-Author - Kiana Mohajeri, PhD; Co-Author - John Lemanski, BS; Co-Author - Bimal Jana, PhD; Co-Author - Jack Fu, PhD; Co-Author - Jennifer Kerkhof, BSc; Co-Author - Haley McConkey, MSc; Co-Author - Ryan Collins, PhD; Co-Author - Diane Lucente, MS, LCGC; Co-Author - Celine de Esch, PhD; Co-Author - Mariana Moysés-Oliveira, PhD; Co-Author - Alexander Nuttle, PhD; Co-Author - Aloysius Domingo, MD, PhD; Co-Author - Serkan Erdin, PhD; Co-Author - Maris Hanley, BA; Co-Author - Amy Watt, BS; Co-Author - Eric Surette, BS; Co-Author - Gloria Lima, BA; Co-Author - Laura Smith, BS; Co-Author - Monica Salani, PhD; Co-Author - Rachita Yadav, PhD; Co-Author - Ricardo Harripaul, PhD; Co-Author - Kathryn O’Keefe, BS; Co-Author - Nicholas D. Burt, BS; Co-Author - Matthew Larson, HSD; Co-Author - Riya Bhavsar, MS; Co-Author - Benjamin Currall, PhD; Co-Author - Susan Sell, MS, LCGC; Co-Author - Roger L. Ladda, MD; Co-Author - LaDonna L. Immken, MD; Co-Author - Catherine Buchanan, MS, CGC; Co-Author - Bo Yuan, PhD, FACMG; Co-Author - Sally A. Lynch, MD; Co-Author - Christian Gilissen, PhD; Co-Author - Rolph Pfundt, PhD; Co-Author - Charlotte Ockeloen, MD PhD; Co-Author - Tjitske Kleefstra, MD, PhD; Co-Author - Els Vanhoutte, MD, PhD; Co-Author - Margje Sinnema, MD, PhD; Co-Author - Sander Stegmann, PhD; Co-Author - Servi Stevens, MSc; Co-Author - Maria Iascone, PhD; Co-Author - Silvia Maitz, MD; Co-Author - Benjamin Cogne, PharmD, PhD; Co-Author - Cedric Le Caignec, MD, PhD; Co-Author - Marie Vincent, MD; Co-Author - Mathilde Nizon, MD; Co-Author - Alison Male, FRCP, MBBS; Co-Author - Pankaj Agrawal, MD, MSSc; Co-Author - Michelle L. Thompson, PhD; Co-Author - Pernille M. Torring, MD, PhD; Co-Author - Charlotte Brasch-Andersen, ErCLG, MSc, PhD; Co-Author - Laurence Faivre, MD, PhD; Co-Author - Ange-Line Bruel, PhD; Co-Author - Bertrand Isidor, MD, PhD; Co-Author - Christophe Philippe, PhD; Co-Author - Manuela Morleo, MSc, PhD; Co-Author - Monica H. Wojcik, MD, MPH, FAAP, FACMG; Co-Author - Casie Genetti, CGC; Co-Author - Siddharth Srivastava, MD; Co-Author - Sonia Ballal, MD; Co-Author - Sophia Schließke, Medical Student; Co-Author - Rami Abou Jamra, MD; Co-Author - Andree Delahaye, MD; Co-Author - Lydia von Wintzingerode, MS; Co-Author - Viktoria Bothe, MS; Co-Author - Marine Houlier, MD; Co-Author - Timothy Stout, MD, PhD; Co-Author - Gaber Bergant, MD; Co-Author - Borut Peterlin, MD, PhD; Co-Author - Oana Moldovan, MD; Co-Author - Núria Martínez-Gil, PhD; Co-Author - Emanuela Argilli, PhD; Co-Author - Elliott Sherr, MD, PhD; Co-Author - Tamar Harel, MD, PhD; Co-Author - Hallel Rosenberg-Fogler, Undergraduate Student; Co-Author - Jill Rosenfeld, MS, CGC; Co-Author - Ingrid M. Wentzensen, MD, FACMG; Co-Author - Dominik S. Westphal, MD; Co-Author - Korbinian M. Riedhammer, MD; Co-Author - Laura Orec, MD; Co-Author - James F. Gusella, PhD; Co-Author - Bekim Sadikovic, PhD, FACMG; Co-Author - Derek J. Tai, PhD; Co-Author - Michael E. Talkowski, Ph.D;

Meta Tag

Chromosome Structure/Function

Exome sequencing

Genotype-Phenotype Correlations

Identification of Disease Genes

Intellectual disability

Malformation

Methylation

Sequencing

Co-Author Philip Boone, M.D., Ph.D.

Co-Author Kiana Mohajeri, PhD

Co-Author John Lemanski, BS

Co-Author Bimal Jana, PhD

Co-Author Jack Fu, PhD

Co-Author Jennifer Kerkhof, BSc

Co-Author Haley McConkey, MSc

Co-Author Ryan Collins, PhD

Co-Author Diane Lucente, MS, LCGC

Co-Author Celine de Esch, PhD

Co-Author Mariana Moysés-Oliveira, PhD

Co-Author Alexander Nuttle, PhD

Co-Author Aloysius Domingo, MD, PhD

Co-Author Serkan Erdin, PhD

Co-Author Maris Hanley, BA

Co-Author Amy Watt, BS

Co-Author Eric Surette, BS

Co-Author Gloria Lima, BA

Co-Author Laura Smith, BS

Co-Author Monica Salani, PhD

Co-Author Rachita Yadav, PhD

Co-Author Ricardo Harripaul, PhD

Co-Author Kathryn O’Keefe, BS

Co-Author Nicholas D. Burt, BS

Co-Author Matthew Larson, HSD

Co-Author Riya Bhavsar, MS

Co-Author Benjamin Currall, PhD

Co-Author Susan Sell, MS, LCGC

Co-Author Roger L. Ladda, MD

Co-Author LaDonna L. Immken, MD

Co-Author Catherine Buchanan, MS, CGC

Co-Author Bo Yuan, PhD, FACMG

Co-Author Sally A. Lynch, MD

Co-Author Christian Gilissen, PhD

Co-Author Rolph Pfundt, PhD

Co-Author Charlotte Ockeloen, MD PhD

Co-Author Tjitske Kleefstra, MD, PhD

Co-Author Els Vanhoutte, MD, PhD

Co-Author Margje Sinnema, MD, PhD

Co-Author Sander Stegmann, PhD

Co-Author Servi Stevens, MSc

Co-Author Maria Iascone, PhD

Co-Author Silvia Maitz, MD

Co-Author Benjamin Cogne, PharmD, PhD

Co-Author Cedric Le Caignec, MD, PhD

Co-Author Marie Vincent, MD

Co-Author Mathilde Nizon, MD

Co-Author Alison Male, FRCP, MBBS

Co-Author Pankaj Agrawal, MD, MSSc

Co-Author Michelle L. Thompson, PhD

Co-Author Pernille M. Torring, MD, PhD

Co-Author Charlotte Brasch-Andersen, ErCLG, MSc, PhD

Co-Author Laurence Faivre, MD, PhD

Co-Author Ange-Line Bruel, PhD

Co-Author Bertrand Isidor, MD, PhD

Co-Author Christophe Philippe, PhD

Co-Author Manuela Morleo, MSc, PhD

Co-Author Monica H. Wojcik, MD, MPH, FAAP, FACMG

Co-Author Casie Genetti, CGC

Co-Author Siddharth Srivastava, MD

Co-Author Sonia Ballal, MD

Co-Author Sophia Schließke, Medical Student

Co-Author Rami Abou Jamra, MD

Co-Author Andree Delahaye, MD

Co-Author Lydia von Wintzingerode, MS

Co-Author Viktoria Bothe, MS

Co-Author Marine Houlier, MD

Co-Author Timothy Stout, MD, PhD

Co-Author Gaber Bergant, MD

Co-Author Borut Peterlin, MD, PhD

Co-Author Oana Moldovan, MD

Co-Author Núria Martínez-Gil, PhD

Co-Author Emanuela Argilli, PhD

Co-Author Elliott Sherr, MD, PhD

Co-Author Tamar Harel, MD, PhD

Co-Author Hallel Rosenberg-Fogler, Undergraduate Student

Co-Author Jill Rosenfeld, MS, CGC

Co-Author Ingrid M. Wentzensen, MD, FACMG

Co-Author Dominik S. Westphal, MD

Co-Author Korbinian M. Riedhammer, MD

Co-Author Laura Orec, MD

Co-Author James F. Gusella, PhD

Co-Author Bekim Sadikovic, PhD, FACMG

Co-Author Derek J. Tai, PhD

Co-Author Michael E. Talkowski, Ph.D

Presenting Author Kamli N. Faour, BA

Keywords

cohesin release factors

WAPL

PDS5A

PDS5B

phenotypic consequences

topologically associating domains

Cornelia de Lange syndrome

neurodevelopmental disorder

genomic analysis

10q22q23 deletion syndrome