{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:54:15Z","timestamp":1753890855591,"version":"3.41.2"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Luscan-Lumish syndrome (LLS) is currently recognized as a rarely-observed condition featured with overgrowth, macrocephaly, obesity, type I Chiari malformation, and linguistic retardation. So far, there have been only a few LLS cases registered worldwide, but with none of them reported from China. To acquire a deeper understanding on the clinical and genetic features of this disease, a Chinese boy with LLS caused by a heterozygous variant in SETD2 gene was investigated in the present study.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The patient was clinically examined and the medical history of his family was collected. Genetic testing was performed to determine the genetic etiology.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The proband was a boy aged 5-year-7-month-old, who was referred to our hospital due to \u201cbeing a slow learner in kindergarten\u201d. The child had a history of delayed motor and language development in comparison to his peers. After admission, physical examination revealed tall stature and macrocephaly as the major manifestation, in addition to a relatively lower rating in intelligence assessment as well as abnormal MRI images showing a slightly shorter corpus callosum accompanied by a mildly thinner corpus callosum body. Whole exome sequencing (WES) revealed a heterozygous c.2514_2516delTAG (p.Ser838del) variant in SETD2 gene, which was subsequently identified as a novel <jats:italic>de novo<\/jats:italic> variant. According to the standardized genetic variant classification published by the American College of Medical Genetics and Genomics (ACMG), the variant, with a pathogenicity analysis result indicating PS2 + PM2_Supporting + PM4, was determined to be likely pathogenic. Through literature review, the clinical phenotypes of the 15 LLS cases were summarized, including 8 cases of overgrowth (53%), 13 cases of macrocephaly (87%), 11 cases of developmental delay (73%), 8 cases of autism (53%), and 7 cases of special facial features (47%). Besides, abnormal craniocerebral MRI findings were noticed in 7 cases. Despite that the mutation sites of the 15 patients varied from case to case, they showed a uniformly distributed pattern throughout the whole SETD2 gene, including 5 missense mutations, 5 frameshift mutations and 5 non-sense mutations.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> LLS, not having been recognized till recent years, is identified as an autosomal dominant syndrome triggered by SETD2 gene mutation. As the first report of LLS in China, the case in our study was proved to be associated with a unique type of SETD2 gene mutation that has never been reported previously, which is believed to enrich the mutation spectrum of SETD2 gene and also, deepening the clinicians\u2019 understanding on the disease.<\/jats:p>","DOI":"10.3389\/fgene.2023.1081391","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T06:04:51Z","timestamp":1674799491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Clinical and genetic features of luscan-lumish syndrome associated with a novel de novo variant of SETD2 gene: Case report and literature review"],"prefix":"10.3389","volume":"14","author":[{"given":"Yanqing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haozheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqiang","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongmei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingxiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41574-019-0180-z","article-title":"Overgrowth syndromes - clinical and molecular aspects and tumour risk","volume":"15","author":"Brioude","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.urolonc.2018.10.027","article-title":"Mutations in renal cell carcinoma","volume":"38","author":"D'Avella","year":"2020","journal-title":"Urol. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"21283","DOI":"10.1074\/jbc.M116.739375","article-title":"Structure\/function analysis of recurrent mutations in SETD2 protein reveals a critical and conserved role for a SET domain residue in maintaining protein stability and histone H3 lys-36 trimethylation","volume":"291","author":"Hacker","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1136\/gutjnl-2015-309482","article-title":"SETD2 histone modifier loss in aggressive GI stromal tumours","volume":"65","author":"Huang","year":"2016","journal-title":"Gut"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1093\/brain\/awab200","article-title":"Neuronal SETD2 activity links microtubule methylation to an anxiety-like phenotype in mice","volume":"144","author":"Koenning","year":"2021","journal-title":"Brain"},{"key":"B6","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41421-021-00261-6","article-title":"Cryo-EM structure of SETD2\/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations","volume":"7","author":"Liu","year":"2021","journal-title":"Cell Discov."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3764","DOI":"10.1007\/s10803-015-2484-8","article-title":"Brief report: SETD2 mutation in a child with autism, intellectual disabilities and epilepsy","volume":"45","author":"Lumish","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"B8","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1136\/jmedgenet-2014-102402","article-title":"Mutations in SETD2 cause a novel overgrowth condition","volume":"51","author":"Luscan","year":"2014","journal-title":"J. Med. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1002\/ajmg.c.31746","article-title":"SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature","volume":"181","author":"Marzin","year":"2019","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1084\/jem.20160894","article-title":"Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2","volume":"214","author":"Moffitt","year":"2017","journal-title":"J. Exp. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1126\/science.1227764","article-title":"Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders","volume":"338","author":"O'Roak","year":"2012","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/j.cell.2016.07.005","article-title":"Dual chromatin and cytoskeletal remodeling by SETD2","volume":"166","author":"Park","year":"2016","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1038\/leu.2016.134","article-title":"Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia","volume":"30","author":"Parker","year":"2016","journal-title":"Leukemia"},{"key":"B14","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.bbrc.2020.09.025","article-title":"An actin-WHAMM interaction linking SETD2 and autophagy","volume":"558","author":"Seervai","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1016\/S0140-6736(05)62956-X","article-title":"Autism and macrocephaly","volume":"349","author":"Stevenson","year":"1997","journal-title":"Lancet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1210\/clinem\/dgaa893","article-title":"A case of luscan-lumish syndrome: Possible involvement of enhanced GH signaling","volume":"106","author":"Suda","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1002\/ajmg.c.31359","article-title":"The NSD1 and EZH2 overgrowth genes, similarities and differences","author":"Tatton-Brown","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.lungcan.2018.07.011","article-title":"Common cancer-driver mutations and their association with abnormally methylated genes in lung adenocarcinoma from never-smokers","volume":"123","author":"Tessema","year":"2018","journal-title":"Lung Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1136\/jmedgenet-2015-103638","article-title":"SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort","volume":"53","author":"Tlemsani","year":"2016","journal-title":"J. Med. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1002\/ajmg.a.38666","article-title":"Two novel cases expanding the phenotype of SETD2-related overgrowth syndrome","volume":"176","author":"van Rij","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e83","DOI":"10.1158\/1078-0432.CCR-17-0631","article-title":"Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk","volume":"23","author":"Villani","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"jeb220632","DOI":"10.1242\/jeb.220632","article-title":"Remodeling the epigenome and (epi)cytoskeleton: A new paradigm for co-regulation by methylation","volume":"223","author":"Walker","year":"2020","journal-title":"J. Exp. Biol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1081391\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T06:04:55Z","timestamp":1674799495000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1081391\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,27]]},"references-count":22,"alternative-id":["10.3389\/fgene.2023.1081391"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1081391","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2023,1,27]]},"article-number":"1081391"}}