{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T10:44:52Z","timestamp":1772102692291,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>\n<jats:italic>SETD2<\/jats:italic> has an essential role in epigenetic regulation. <jats:italic>SETD2<\/jats:italic> pathogenic variants cause neurodevelopmental disorders (<jats:italic>SETD2<\/jats:italic>\u2010NDDs) that most commonly include various degrees of intellectual disability and behavioral disorders, macrocephaly, brain malformations, and generalized overgrowth. A distinctive DNA methylation episignature has been identified for Luscan\u2013Lumish syndrome. A less common phenotype, denoted <jats:italic>SETD2<\/jats:italic>\u2010NDD with multiple congenital anomalies, failure to thrive, and profound intellectual disability, has been reported in association with a particular pathogenic variant (p.Arg1740Trp). To date, about 50 patients have been described in the literature with <jats:italic>SETD2<\/jats:italic> causative variants. We report here an individual with a phenotype distinct from <jats:italic>SETD2<\/jats:italic>\u2010NDDs, including normal cognition, distinctive facial features, and multiple tumor histories, including a sacral osteoblastoma at age 7, a benign femoral bone tumor at age 17, a peritoneal pseudomyxoma at age 27, and a hypophyseal macroadenoma and a low\u2010grade optochiasmatic glioma at age 37\u2009years. Trio exome sequencing identified a de novo heterozygous missense variant of unknown significance (p.Ser1658Leu) in the <jats:italic>SETD2<\/jats:italic> gene. DNA methylation study by EpiSign assay confirmed the presence of an episignature profile compatible with <jats:italic>SETD2<\/jats:italic>\u2010related disorders. Given the implication of somatic <jats:italic>SETD2<\/jats:italic> variants in benign and malignant tumors, the implication of these <jats:italic>SETD2<\/jats:italic> constitutional variants in tumorigenesis is discussed.<\/jats:p>","DOI":"10.1002\/ajmg.a.64043","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T09:22:07Z","timestamp":1742376127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Abnormal <scp>DNA<\/scp> Methylation Profile Suggests the Extension of the Clinical Spectrum of the <scp><i>SETD2<\/i><\/scp>\u2010Related Disorders to a Syndromic Multiple Tumor Phenotype"],"prefix":"10.1002","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3634-1765","authenticated-orcid":false,"given":"Marie","family":"Lucain","sequence":"first","affiliation":[{"name":"Unit\u00e9 Fonctionnelle Innovation en Diagnostic G\u00e9nomique Des Maladies Rares CHU 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