Clinical, in vitro, and in vivo evidence of WAPL as a cohesinopathy-associated gene and phenotypic driver of 10q22.3q23.2 genomic disorder.

American journal of human genetics

Authors	Philip Boone Serkan Erdin Abucar Mohamed Sadegheh Haghshenas Kamli Faour Emeline Kao Jack Fu Chiara Auwerx Ricardo Harripaul Bimal Jana Danielle Springer Grey Hallstrom Celine De Esch Erica Denhoff Lauren Holmes Kiana Mohajeri John Lemanski Jennifer Kerkhof Haley McConkey Jessica Rzasa Madison McCune Michael Levy Julia Grafstein Matthew Larson Zsabre Wright Roberta Beauchamp Diane Lucente Rami Jamra Neena Agrawal Pankaj Agrawal Erica Andersen Emanuela Argilli Renee Araiza Sonia Ballal Megan Baxter Gaber Bergant Astrid Bertsche Riya Bhavsar Debora Bortola Viktoria Bothe Charlotte Brasch-Andersen Dominique Braun Ange-Line Bruel Catherine Buchanan Nicholas Burt Laura Carvalho Luigi Chiriatti Benjamin Cogné Ryan Collins Amy Crunk Benjamin Currall Andree Delahaye-Duriez Julian Delanne Anne-Sophie Denommé-Pichon Koenraad Devriendt Aloysius Domingo Laura Duncan Laurence Faivre Laura Famularo Anne Fulton Casie Genetti Tamar Harel Marketa Havlovicova Jenny Higgs Marine Houlier Maria Iascone LaDonna Immken Bertrand Isidor Frank Kaiser Kaycee Karbone Margaret Kenna Amjad Khan Lara Kimmig Tjitske Kleefstra Eva-Maria Kraus Ana Krepischi V Ilona Krey Roger Ladda Louise Lanoue Cédric Le Caignec Zoe Lewis Gloria Lima Sally Lynch Milan Macek Olivier Maier Silvia Maitz Alison Male Marcela Malikova Victoria McKay Oana Moldovan Danielle Monteil Mariana Oliveira Jeeva Munasinghe Sachiko Nakamori Sonja Neuser Mathilde Nizon Xander Nuttle Kathryn O'Keefe Laura Orec Ilaria Parenti Borut Peterlin Rolph Pfundt Jill Pouncey Francesca Radio Leema Robert Lance Rodan Hallel Rosenberg-Fogler Jill Rosenfeld Hana Safraou Monica Salani Sophia Schliesske Eleanor Seaby Susan Sell Eliot Shearer Elliott Sherr Amelle Shillington Dorothea Siebold Margje Sinnema Laura Smith Alexander Stegmann Cathy Stevens Servi Stevens Eric Surette Marco Tartaglia Jenny Taylor Michelle Thompson Pernille Tørring Frederic Them Olga Tsoulaki Muhammad Umair Els Vanhoutte Marie Vincent Antonio Vitobello Lydia von Wintzingerode Amy Watt Marketa Wayhelova Ingrid Wentzensen William Wilson Monica Wojcik Bo Yuan Giuseppe Zampino Siddharth Srivastava Dominik Westphal Korbinian Riedhammer Eric Joyce Rachita Yadav James Gusella Derek Tai Bekim Sadikovic Karl Pfeifer Michael Talkowski
Keywords	PDS5A PDS5B WAPL cohesin release factor Transcription
Abstract	Cohesin orchestrates gene expression via three-dimensional chromosome folding. Genes encoding cohesin and cohesin loaders have been associated with Mendelian disorders, whereas genes encoding cohesin release factors, including WAPL and its binding partners PDS5A and PDS5B, have not. We explored the relevance of cohesin release factors in Mendelian disease by phenotyping individuals with heterozygous predicted damaging variants in WAPL (n = 27), PDS5A (n = 8), and PDS5B (n = 8), by modeling WAPL deficiency in human cells and mice, and by aggregating disease association statistics from consortia studies. We identified a WAPL-related disorder featuring developmental delay, intellectual disability, and risk of other developmental anomalies. Similarities between individuals with damaging WAPL variants and those with large, recurrent 10q22.3q23.2 (10q) deletions encompassing WAPL nominate WAPL as a driver gene within this genomic disorder region. While individuals with PDS5A or PDS5B variants exhibited features of developmental disorders, neither cohort-based statistics nor subject phenotyping associated these genes with specific phenotypes. We used CRISPR to generate truncating variants in WAPL and 10q deletion or duplication in human induced pluripotent stem cells (iPSCs) and induced neurons. Transcriptomics identified significant overlap between WAPL haploinsufficiency and 10q deletion differentially expressed genes. Mice with 50% Wapl expression exhibited mild deficits of growth and learning/memory, whereas those with 25% residual Wapl displayed birth defects and postnatal lethality, revealing a dosage liability threshold below the level of heterozygosity. In summary, we delineated a genetic condition caused by cohesin release factor deficiency, nominated WAPL as a driver gene within a genomic disorder region, and further illuminated dosage sensitivity of human cohesin.
Year of Publication	2026
Journal	American journal of human genetics
Date Published	07/2026
ISSN	1537-6605
DOI	10.1016/j.ajhg.2026.06.012
PubMed ID	42431198
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