{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T03:34:45Z","timestamp":1778729685381,"version":"3.51.4"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009187","name":"RCUK | MRC | Medical Research Foundation","doi-asserted-by":"publisher","award":["MR\/Y011813\/1"],"award-info":[{"award-number":["MR\/Y011813\/1"]}],"id":[{"id":"10.13039\/501100009187","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identical twin brothers presenting with spontaneous pneumothoraces in adulthood, leading to a diagnosis of Tatton-Brown-Rahman syndrome (TBRS), a DNMT3A-related overgrowth disorder not previously associated with pneumothorax. Both individuals exhibited tall stature, mild intellectual disability, hypermobility, and cardiac abnormalities. Whole genome sequencing identified a rare de novo DNMT3A missense variant (c.1585\u2009G\u2009&gt;\u2009A, p.D529N) absent from population databases and predicted to be damaging. Methylation profiling confirmed genome-wide hypomethylation consistent with impaired DNMT3A function, supporting pathogenicity. No variants were found in known familial pneumothorax genes. Apical blebs observed at surgery and connective tissue features suggest a mechanistic link between TBRS and pneumothorax, analogous to other monogenic connective tissue disorders. This case expands the phenotypic spectrum of TBRS and highlights the importance of genetic evaluation in familial pneumothorax. Diagnosis enables personalised care, including surveillance for extrapulmonary complications such as aortic root dilatation and haematological malignancy. Our findings suggest that TBRS should be considered in patients presenting with pneumothorax, tall stature, and neurodevelopmental features. Further cases are needed to confirm this association and refine clinical management strategies.<\/jats:p>","DOI":"10.1038\/s41431-026-02034-9","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:52:36Z","timestamp":1772023956000},"page":"723-726","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Familial pneumothorax in twins with Tatton-Brown-Rahman DNMT3A overgrowth syndrome"],"prefix":"10.1038","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0446-3435","authenticated-orcid":false,"given":"Sarju G.","family":"Mehta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8314-5816","authenticated-orcid":false,"given":"Simon","family":"Holden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Babar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumit","family":"Karia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2924-7587","authenticated-orcid":false,"given":"Maria T. A.","family":"Wetscherek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4660-9978","authenticated-orcid":false,"given":"Allanah P.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-3268","authenticated-orcid":false,"given":"Sunwoo Liv","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Foster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-6918","authenticated-orcid":false,"given":"Eamonn R.","family":"Maher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8472-7183","authenticated-orcid":false,"given":"Stefan J.","family":"Marciniak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"2034_CR1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1136\/thoraxjnl-2017-211169","volume":"73","author":"RM Scott","year":"2018","unstructured":"Scott RM, Henske EP, Raby B, Boone PM, Rusk RA, Marciniak SJ. Familial pneumothorax: towards precision medicine. Thorax. 2018;73:270\u20136.","journal-title":"Thorax"},{"key":"2034_CR2","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1164\/rccm.201807-1212CI","volume":"199","author":"PM Boone","year":"2019","unstructured":"Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA. The genetics of pneumothorax. Am J Respir Crit Care Med. 2019;199:1344\u201357.","journal-title":"Am J Respir Crit Care Med"},{"key":"2034_CR3","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1183\/13993003.00952-2015","volume":"46","author":"JE Chambers","year":"2015","unstructured":"Chambers JE, Dalton LE, Subramanian DN, Gooptu B, Balan A, Park SM, et al. Spontaneous pneumothorax can be associated with TGFBR2 mutation. Eur Respir J. 2015;46:1832\u20135.","journal-title":"Eur Respir J"},{"key":"2034_CR4","doi-asserted-by":"crossref","unstructured":"Grimes HL, Holden S, Babar J, Karia S, Wetscherek MTA, Barker A, et al. Combining clinical, radiological and genetic approaches to pneumothorax management. Thorax. 2021. thoraxjnl-2021-217210","DOI":"10.1136\/thoraxjnl-2021-217210"},{"key":"2034_CR5","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1513\/AnnalsATS.201712-968CC","volume":"15","author":"R Lim","year":"2018","unstructured":"Lim R, Marciniak SJ, Marcadier J, Rassl D, Mitchell PD. Time Is of the Essence: A Young Man with Recurrent Pneumothorax and Cavitating Lung Lesions. Ann Am Thorac Soc. 2018;15:988\u201391.","journal-title":"Ann Am Thorac Soc"},{"key":"2034_CR6","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.4530893.v5","author":"M Caulfield","year":"2017","unstructured":"Caulfield M, Davies J, Dennys M, Elbahy L, Fowler T, Hill S, et al. Natl Genomics Res Healthc Knowledgebase. 2017. https:\/\/doi.org\/10.6084\/m9.figshare.4530893.v5. figshare. Dataset.","journal-title":"Natl Genomics Res Healthc Knowledgebase"},{"key":"2034_CR7","doi-asserted-by":"publisher","first-page":"k1687","DOI":"10.1136\/bmj.k1687","volume":"361","author":"C Turnbull","year":"2018","unstructured":"Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N, Pretty FB, et al. The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ. 2018;361:k1687.","journal-title":"BMJ"},{"key":"2034_CR8","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1136\/jmedgenet-2015-103638","volume":"53","author":"C Tlemsani","year":"2016","unstructured":"Tlemsani C, Luscan A, Leulliot N, Bieth E, Afenjar A, Baujat G, et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016;53:743\u201351.","journal-title":"J Med Genet"},{"key":"2034_CR9","doi-asserted-by":"publisher","first-page":"2488","DOI":"10.1056\/NEJMoa1408617","volume":"371","author":"S Jaiswal","year":"2014","unstructured":"Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488\u201398.","journal-title":"N Engl J Med"},{"key":"2034_CR10","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","volume":"100","author":"Q Li","year":"2017","unstructured":"Li Q, Wang K. InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines. Am J Hum Genet. 2017;100:267\u201380.","journal-title":"Am J Hum Genet"},{"key":"2034_CR11","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41431-023-01474-x","volume":"32","author":"T Husson","year":"2024","unstructured":"Husson T, Lecoquierre F, Nicolas G, Richard AC, Afenjar A, Audebert-Bellanger S, et al. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders. Eur J Hum Genet. 2024;32:190\u20139.","journal-title":"Eur J Hum Genet"},{"key":"2034_CR12","doi-asserted-by":"publisher","first-page":"3123","DOI":"10.1093\/hmg\/ddad079","volume":"32","author":"S Lee","year":"2023","unstructured":"Lee S, Menzies L, Hay E, Ochoa E, Docquier F, Rodger F, et al. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders. Hum Mol Genet. 2023;32:3123\u201334.","journal-title":"Hum Mol Genet"},{"key":"2034_CR13","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/s41431-023-01422-9","volume":"31","author":"S Lee","year":"2023","unstructured":"Lee S, Ochoa E, Badura-Stronka M, Donnelly D, Lederer D, Lynch SA, et al. Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome. Eur J Hum Genet. 2023;31:1040\u20137.","journal-title":"Eur J Hum Genet"},{"key":"2034_CR14","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ng.2917","volume":"46","author":"K Tatton-Brown","year":"2014","unstructured":"Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46:385\u20138.","journal-title":"Nat Genet"},{"key":"2034_CR15","doi-asserted-by":"publisher","first-page":"46","DOI":"10.12688\/wellcomeopenres.14430.1","volume":"3","author":"K Tatton-Brown","year":"2018","unstructured":"Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, Aksglaede L, et al. The Tatton-Brown-Rahman Syndrome: a clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 2018;3:46.","journal-title":"Wellcome Open Res"},{"key":"2034_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24800-7","volume":"12","author":"AM Smith","year":"2021","unstructured":"Smith AM, LaValle TA, Shinawi M, Ramakrishnan SM, Abel HJ, Hill CA, et al. Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nat Commun. 2021;12:4549.","journal-title":"Nat Commun"},{"key":"2034_CR17","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1038\/s41431-023-01459-w","volume":"31","author":"C Kumps","year":"2023","unstructured":"Kumps C, D\u2019Haenens E, Kerkhof J, McConkey H, Alders M, Sadikovic B, et al. Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown-Rahman syndrome. Eur J Hum Genet. 2023;31:1350\u20134.","journal-title":"Eur J Hum Genet"},{"key":"2034_CR18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1136\/thorax-2024-221738","volume":"80","author":"B Yngvadottir","year":"2025","unstructured":"Yngvadottir B, Richman L, Andreou A, Woodley J, Luharia A, Lim D, et al. Inherited predisposition to pneumothorax: estimating the frequency of Birt-Hogg-Dube syndrome from genomics and population cohorts. Thorax. 2025;80:553\u20135.","journal-title":"Thorax"},{"key":"2034_CR19","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1056\/NEJMoa1005143","volume":"363","author":"TJ Ley","year":"2010","unstructured":"Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424\u201333.","journal-title":"N Engl J Med"},{"key":"2034_CR20","doi-asserted-by":"publisher","first-page":"537","DOI":"10.2217\/epi-2021-0521","volume":"14","author":"S Lee","year":"2022","unstructured":"Lee S, Ochoa E, Barwick K, Cif L, Rodger F, Docquier F, et al. Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders. Epigenomics. 2022;14:537\u201347.","journal-title":"Epigenomics"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02034-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02034-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02034-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T14:35:10Z","timestamp":1778682910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-026-02034-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,25]]},"references-count":20,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["2034"],"URL":"https:\/\/doi.org\/10.1038\/s41431-026-02034-9","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,25]]},"assertion":[{"value":"26 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 January 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Ethical approval was provided by the South Birmingham Research Ethics Committee for the Molecular Pathology of Human Genetic Disease (HumGenDis) study, 100,000 Genomes Project Bioresource REC approval 14\/EE\/1112. The study was approved by the University of Cambridge Human Biology Research Ethics Committee HBREC.2020.28.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent for publication of individual details and images was obtained from each individual.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}