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

Fiche publication

Date publication

juillet 2026

Journal

American journal of human genetics

Auteurs

Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence

Tous les auteurs :
Boone PM, Erdin S, Mohamed A, Haghshenas S, Faour KNW, Kao E, Fu J, Auwerx C, Harripaul R, Jana B, Springer D, Hallstrom G, de Esch CEF, Denhoff E, Holmes L, Mohajeri K, Lemanski J, Kerkhof J, McConkey H, Rzasa J, McCune MJ, Levy MA, Grafstein J, Larson M, Wright Z, Beauchamp RL, Lucente D, Jamra RA, Agrawal N, Agrawal PB, Andersen EF, Argilli E, Araiza R, Ballal S, Baxter MF, Bergant G, Bertsche A, Bhavsar R, Bortola DR, Bothe V, Brasch-Andersen C, Braun D, Bruel AL, Buchanan C, Burt ND, Carvalho LML, Chiriatti L, Cogne B, Collins R, Crunk A, Currall B, Delahaye-Duriez A, Delanne J, Denommé-Pichon AS, Devriendt K, Domingo A, Duncan L, Faivre L, Famularo L, Fulton A, Genetti CA, Harel T, Havlovicova M, Higgs J, Houlier M, Iascone M, Immken L, Isidor B, Kaiser FJ, Karbone K, Kenna M, Khan A, Kimmig LK, Kleefstra T, Kraus EM, Krepischi ACV, Krey I, Ladda RL, Lanoue L, Le Caignec C, Lewis ZK, Lima G, Lynch SA, Macek M, Maier O, Maitz S, Male A, Malikova M, McKay V, Moldovan O, Monteil D, Oliveira MM, Munasinghe J, Nakamori S, Neuser S, Nizon M, Nuttle X, O'Keefe K, Orec L, Parenti I, Peterlin B, Pfundt R, Pouncey J, Radio FC, Robert L, Rodan L, Rosenberg-Fogler H, Rosenfeld JA, Safraou H, Salani M, Schliesske S, Seaby EG, Sell SL, Shearer AE, Sherr E, Shillington A, Siebold D, Sinnema M, Smith L, Stegmann APA, Stevens CA, Stevens SJC, Surette E, Tartaglia M, Taylor JC, Thompson ML, Tørring PM, Tran Mau Them F, Tsoulaki O, Umair M, Vanhoutte E, Vincent M, Vitobello A, von Wintzingerode L, Watt A, Wayhelova M, Wentzensen IM, Wilson W, Wojcik MH, Yuan B, Zampino G, Srivastava S, Westphal DS, Riedhammer KM, Joyce E, Yadav R, Gusella JF, Tai DJC, Sadikovic B, Pfeifer KE, Talkowski ME

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42431198

Résumé

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.