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Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next\u2010generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on <jats:italic>N<\/jats:italic>\u2009=\u2009120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total\u201410 germline and 1 somatic\u2014variants in cohesin genes. Data of <jats:italic>N<\/jats:italic>\u2009=\u2009205 brain tumors were extracted by bioinformatic analysis of data from open\u2010source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13\u2009years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline <jats:italic>NIPBL<\/jats:italic> variants in CdLSp, whereas <jats:italic>RAD21<\/jats:italic> and <jats:italic>STAG1\/2<\/jats:italic> are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches.<\/jats:p>","DOI":"10.1002\/ajmg.a.64076","type":"journal-article","created":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T01:05:00Z","timestamp":1743901500000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cohesins: Crossroad Between Cornelia de Lange Spectrum and Cancer Predisposition"],"prefix":"10.1002","volume":"197","author":[{"given":"Laura","family":"Rigotti","sequence":"first","affiliation":[{"name":"Department of Pediatrics Mariani Foundation Center for Fragile Children, ASST\u2010Lariana, Sant'Anna Hospital  Como 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