{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T15:47:02Z","timestamp":1793029622754,"version":"4.5.0"},"reference-count":42,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2014,4,28]]},"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in <jats:italic>NSD1<\/jats:italic> and <jats:italic>EZH2<\/jats:italic>, respectively. NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers catalyse two specific post-translational modifications of histones: methylation of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no <jats:italic>NSD1<\/jats:italic> or <jats:italic>EZH2<\/jats:italic> abnormalities.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analysed the coding sequences of 14 H3K27 methylation-related genes and eight H3K36 methylation-related genes using a targeted next-generation sequencing approach in three Sotos, 11 \u2018Sotos-like\u2019 and two Weaver syndrome patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified two heterozygous mutations in the <jats:italic>SETD2<\/jats:italic> gene in two patients with \u2018Sotos-like\u2019 syndrome: one missense p.Leu1815Trp de novo mutation in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is non-redundantly responsible for H3K36 trimethylation. The two probands shared similar clinical features, including postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results illustrate the power of targeted next-generation sequencing to identify rare disease-causing variants. We provide a compelling argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by loss-of-function mutations of epigenetic writers of the H3K36 histone mark.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2014-102402","type":"journal-article","created":{"date-parts":[[2014,5,22]],"date-time":"2014-05-22T23:37:58Z","timestamp":1400801878000},"page":"512-517","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":122,"title":["Mutations in <i>SETD2<\/i> cause a novel overgrowth condition"],"prefix":"10.1136","volume":"51","author":[{"given":"Armelle","family":"Luscan","sequence":"first","affiliation":[{"name":"EA7331, Universit\u00e9 Paris Descartes, Sorbonne Paris Cit\u00e9, Facult\u00e9 des Sciences Pharmaceutiques et Biologiques, Paris, France"},{"name":"Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, Assistance Publique-H\u00f4pitaux de Paris, H\u00f4pital Cochin, Paris, 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