{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T09:10:06Z","timestamp":1792919406628,"version":"4.5.0"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001786","name":"The University of Adelaide","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001786","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pituitary"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Introduction<\/jats:title>\n            <jats:p>X-linked acrogigantism (X-LAG; OMIM: 300942) is a rare X-linked dominant, fully penetrant form of infancy-onset pituitary gigantism caused by Xq26.3 tandem duplications involving the <jats:italic>GPR101<\/jats:italic> gene. All previously reported X-LAG-associated duplications disrupt the integrity of the resident topologically associating domain (TAD). This creates a neo-TAD, permitting ectopic chromatin interactions between <jats:italic>GPR101<\/jats:italic> and centromeric pituitary enhancers postulated to lie between <jats:italic>RBMX<\/jats:italic> and <jats:italic>VGLL1<\/jats:italic>, and culminating in pituitary <jats:italic>GPR101<\/jats:italic> misexpression and growth hormone excess. Conversely, none of the few previously reported cases of Xq26.3 duplications in unaffected individuals include the tissue-invariant TAD border that shields <jats:italic>GPR101<\/jats:italic> from its centromeric enhancers. Preservation of this boundary has thus been considered synonymous with non-penetrance of X-LAG.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We examined a series of four family members from the same kindred with an incidentally detected <jats:italic>GPR101<\/jats:italic>-containing Xq26.3 duplication involving the invariant TAD border.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Chromosome microarray demonstrated an interstitial chromosome Xq26.3 duplication: arr[GRCh37] Xq26.3(135,954,223\u2009\u2212\u2009136,224,319)x2, including <jats:italic>GPR101<\/jats:italic>, the TAD invariant border and <jats:italic>RBMX<\/jats:italic>, but not <jats:italic>VGLL1<\/jats:italic>. None of the relatives with the Xq26.3 duplication exhibited evidence of growth hormone excess, making this the first unaffected family with a <jats:italic>GPR101<\/jats:italic>-containing Xq26.3 duplication involving the invariant TAD border. The predicted neo-TAD in this kindred excludes the <jats:italic>VGLL1<\/jats:italic> region, which is present in all previously described X-LAG patients and absent in all previously described unaffected individuals with Xq26.3 duplications.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our clinical findings suggest that TAD border involvement is not sufficient for X-LAG to develop, and implicates the <jats:italic>VGLL1<\/jats:italic> region as likely the sole pituitary enhancer responsible for <jats:italic>GPR101<\/jats:italic> misexpression and the X-LAG phenotype. Pending corroborative studies, this new insight into X-LAG pathogenesis may guide interpretation of future Xq26.3 duplications and counselling of families in whom such duplications are found.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11102-025-01559-4","type":"journal-article","created":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T09:37:56Z","timestamp":1753004276000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Non-penetrant Xq26.3 duplication involving the invariant TAD border: clinical evidence for the VGLL1 region as the GPR101 pituitary enhancer of X-linked acrogigantism"],"prefix":"10.1007","volume":"28","author":[{"given":"Cathie","family":"Hilditch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Cotton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"LeBlanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0127-6482","authenticated-orcid":false,"given":"Sunita","family":"De Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,20]]},"reference":[{"issue":"25","key":"1559_CR1","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1056\/NEJMoa1408028","volume":"371","author":"G Trivellin","year":"2014","unstructured":"Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg J-H, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy P, Ferrante E, Strebkova N, Mazerkina N, Zatelli M, Lodish M, Horvath A, de Alexandre R, Manning A, Levy I, Keil M, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves L, Jamar M, Bours V, Wu T, Choong C, Bertherat J, Chanson P, Kamenick\u00fd P, Farrell W, Barlier A, Quezado M, Bjelobaba I, Stojilkovic S, Wess J, Costanzi S, Liu P, Lupski J, Beckers A, Stratakis C (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 371(25):2363\u20132374","journal-title":"N Engl J Med"},{"issue":"5","key":"1559_CR2","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1210\/endrev\/bnae014","volume":"45","author":"AF Daly","year":"2024","unstructured":"Daly AF, Beckers A (2024) The genetic pathophysiology and clinical management of the tadopathy, X-Linked acrogigantism. Endocr Rev 45(5):737\u2013754","journal-title":"Endocr Rev"},{"issue":"4","key":"1559_CR3","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.ajhg.2022.02.002","volume":"109","author":"M Franke","year":"2022","unstructured":"Franke M, Daly AF, Palmeira L, Tirosh A, Stigliano A, Trifan E, Faucz FR, Abboud D, Petrossians P, Tena JJ, Vitali E, Lania AG, G\u00f3mez-Skarmeta JL, Beckers A, Stratakis CA, Trivellin G (2022) Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism. Am J Hum Genet 109(4):553\u2013570","journal-title":"Am J Hum Genet"},{"issue":"1","key":"1559_CR4","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40478-016-0328-1","volume":"4","author":"D Iacovazzo","year":"2016","unstructured":"Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernandez-Ramirez LC, Kapur S, Caimari F, Evanson J, Ferrau F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramirez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M (2016) Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun 4(1):56","journal-title":"Acta Neuropathol Commun"},{"key":"1559_CR5","doi-asserted-by":"publisher","first-page":"102622","DOI":"10.1016\/j.sbi.2023.102622","volume":"81","author":"JA da Costa-Nunes","year":"2023","unstructured":"da Costa-Nunes JA, Noordermeer D, TADs (2023) Dynamic structures to create stable regulatory functions. Curr Opin Struct Biol 81:102622","journal-title":"Curr Opin Struct Biol"},{"issue":"1","key":"1559_CR6","doi-asserted-by":"publisher","first-page":"4752","DOI":"10.1038\/s41467-020-18500-x","volume":"11","author":"D Abboud","year":"2020","unstructured":"Abboud D, Daly AF, Dupuis N, Bahri MA, Inoue A, Chevign\u00e9 A, Ectors F, Plenevaux A, Pirotte B, Beckers A, Hanson J (2020) GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of G(s) and G(q\/11). Nat Commun 11(1):4752","journal-title":"Nat Commun"},{"issue":"1","key":"1559_CR7","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13073-024-01378-5","volume":"16","author":"AF Daly","year":"2024","unstructured":"Daly AF, Dunnington LA, Rodriguez-Buritica DF, Spiegel E, Brancati F, Mantovani G, Rawal VM, Faucz FR, Hijazi H, Caberg JH, Nardone AM, Bengala M, Fortugno P, Del Sindaco G, Ragonese M, Gould H, Cannav\u00f2 S, P\u00e9trossians P, Lania A, Lupski JR, Beckers A, Stratakis CA, Levy B, Trivellin G, Franke M (2024) Chromatin conformation capture in the clinic: 4\u00a0C-seq\/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus. Genome Med 16(1):112","journal-title":"Genome Med"},{"key":"1559_CR8","doi-asserted-by":"crossref","unstructured":"De Sousa SMC, Lenders NF, Lamb LS, Inder WJ, McCormack A (2023) Pituitary tumours: molecular and genetic aspects. J Endocrinol.;257(3)","DOI":"10.1530\/JOE-22-0291"},{"issue":"2","key":"1559_CR9","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.ajhg.2014.12.017","volume":"96","author":"S Newman","year":"2015","unstructured":"Newman S, Hermetz KE, Weckselblatt B, Rudd MK (2015) Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. Am J Hum Genet 96(2):208\u2013220","journal-title":"Am J Hum Genet"}],"container-title":["Pituitary"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-025-01559-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11102-025-01559-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-025-01559-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T15:51:01Z","timestamp":1757260261000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11102-025-01559-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,20]]},"references-count":9,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["1559"],"URL":"https:\/\/doi.org\/10.1007\/s11102-025-01559-4","relation":{},"ISSN":["1386-341X","1573-7403"],"issn-type":[{"value":"1386-341X","type":"print"},{"value":"1573-7403","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,20]]},"assertion":[{"value":"11 July 2025","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2025","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Written consent to publish patient related data was obtained from subjects II-4, III-3, IV-1 and IV-2.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"85"}}