American journal of human genetics · 2026

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

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Boone Philip M, Erdin Serkan, Mohamed Abucar, Haghshenas Sadegheh, Faour Kamli N W, Kao Emeline, Fu Jack, Auwerx Chiara, Harripaul Ricardo, Jana Bimal, Springer Danielle, Hallstrom Grey, de Esch Celine E F, Denhoff Erica, Holmes Lauren, Mohajeri Kiana, Lemanski John, Kerkhof Jennifer, McConkey Haley, Rzasa Jessica, McCune Madison J, Levy Michael A, Grafstein Julia, Larson Matthew, Wright Zsabre, Beauchamp Roberta L, Lucente Diane, Jamra Rami Abou, Agrawal Neena, Agrawal Pankaj B, Andersen Erica F, Argilli Emanuela, Araiza Renee, Ballal Sonia, Baxter Megan F, Bergant Gaber, Bertsche Astrid, Bhavsar Riya, Bortola Debora R, Bothe Viktoria, Brasch-Andersen Charlotte, Braun Dominique, Bruel Ange-Line, Buchanan Catherine, Burt Nicholas D, Carvalho Laura M L, Chiriatti Luigi, Cogne Benjamin, Collins Ryan, Crunk Amy, Currall Benjamin, Delahaye-Duriez Andree, Delanne Julian, Denommé-Pichon Anne-Sophie, Devriendt Koenraad, Domingo Aloysius, Duncan Laura, Faivre Laurence, Famularo Laura, Fulton Anne, Genetti Casie A, Harel Tamar, Havlovicova Marketa, Higgs Jenny, Houlier Marine, Iascone Maria, Immken LaDonna, Isidor Bertrand, Kaiser Frank J, Karbone Kaycee, Kenna Margaret, Khan Amjad, Kimmig Lara Kristina, Kleefstra Tjitske, Kraus Eva-Maria, Krepischi Ana C V, Krey Ilona, Ladda Roger L, Lanoue Louise, Le Caignec Cedric, Lewis Zoe K, Lima Gloria, Lynch Sally Ann, Macek Milan, Maier Olivier, Maitz Silvia, Male Alison, Malikova Marcela, McKay Victoria, Moldovan Oana, Monteil Danielle, Oliveira Mariana Moysés, Munasinghe Jeeva, Nakamori Sachiko, Neuser Sonja, Nizon Mathilde, Nuttle Xander, O'Keefe Kathryn, Orec Laura, Parenti Ilaria, Peterlin Borut, Pfundt Rolph, Pouncey Jill, Radio Francesca Clementina, Robert Leema, Rodan Lance, Rosenberg-Fogler Hallel, Rosenfeld Jill A, Safraou Hana, Salani Monica, Schliesske Sophia, Seaby Eleanor G, Sell Susan L, Shearer A Eliot, Sherr Elliott, Shillington Amelle, Siebold Dorothea, Sinnema Margje, Smith Laura, Stegmann Alexander P A, Stevens Cathy A, Stevens Servi J C, Surette Eric, Tartaglia Marco, Taylor Jenny C, Thompson Michelle L, Tørring Pernille M, Tran Mau Them Frederic, Tsoulaki Olga, Umair Muhammad, Vanhoutte Els, Vincent Marie, Vitobello Antonio, von Wintzingerode Lydia, Watt Amy, Wayhelova Marketa, Wentzensen Ingrid M, Wilson William, Wojcik Monica H, Yuan Bo, Zampino Giuseppe, Srivastava Siddharth, Westphal Dominik S, Riedhammer Korbinian M, Joyce Eric, Yadav Rachita, Gusella James F, Tai Derek J C, Sadikovic Bekim, Pfeifer Karl E, Talkowski Michael E

Аннотация

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.

Предметные рубрики MeSH

Humans Animals Cell Cycle Proteins Mice Cohesins Chromosomal Proteins, Non-Histone Phenotype Nuclear Proteins Chromosomes, Human, Pair 10 Female Male DNA-Binding Proteins Intellectual Disability Developmental Disabilities Carrier Proteins Proto-Oncogene Proteins Transcription Factors

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

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Аннотация

Предметные рубрики MeSH