{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:53Z","timestamp":1760144753686,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Rubinstein\u2013Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions.<\/jats:p>","DOI":"10.3390\/genes15060654","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T10:00:11Z","timestamp":1716372011000},"page":"654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Phenotype-Based Approach Can Solve Cold Cases: The Paradigm of Mosaic Mutations of the CREBBP Gene"],"prefix":"10.3390","volume":"15","author":[{"given":"Giulia Bruna","family":"Marchetti","sequence":"first","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano Statale, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3087-8514","authenticated-orcid":false,"given":"Donatella","family":"Milani","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico di Milano, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7653-981X","authenticated-orcid":false,"given":"Livia","family":"Pisciotta","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano Statale, 20122 Milano, Italy"},{"name":"Child Neuropsychiatry Unit, ASST Fatebenefratelli Sacco, 20100 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8111-563X","authenticated-orcid":false,"given":"Laura","family":"Pezzoli","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Marchisio","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Milano Statale, 20122 Milano, Italy"},{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico di Milano, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-5347","authenticated-orcid":false,"given":"Berardo","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (2024, May 01). Rubinstein-Taybi Syndrome. 30 August 2002 [Updated 9 November 2023], GeneReviews\u00ae, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1526\/."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lacombe, D., Bloch-Zupan, A., Bredrup, C., Cooper, E.B., Houge, S.D., Garc\u00eda-Mi\u00f1a\u00far, S., Kayserili, H., Larizza, L., Gonzalez, V.L., and A Menke, L. (2024). Diagnosis and management in Rubinstein-Taybi syndrome: First international consensus statement. J. Med. Genet.","DOI":"10.1136\/jmg-2023-109438"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/376348a0","article-title":"Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP","volume":"376","author":"Petrif","year":"1995","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1086\/429130","article-title":"Genetic heterogeneity in Rubinstein-Taybi syndrome: Mutations in both the CBP and EP300 genes cause disease","volume":"76","author":"Roelfsema","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R254","DOI":"10.1093\/hmg\/ddz174","article-title":"Mendelian disorders of the epigenetic machinery: Postnatal malleability and therapeutic prospects","volume":"28","author":"Fahrner","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/cge.12537","article-title":"Insights into genotype-phenotype correlations from CREBBP point mutation screening in a cohort of 46 Rubinstein-Taybi syndrome patients","volume":"88","author":"Spena","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bentivegna, A., Milani, D., Gervasini, C., Castronovo, P., Mottadelli, F., Manzini, S., Colapietro, P., Giordano, L., Atzeri, F., and Divizia, M.T. (2006). Rubinstein-Taybi Syndrome: Spectrum of CREBBP mutations in Italian patients. BMC Med. Genet., 7.","DOI":"10.1186\/1471-2350-7-77"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.ygeno.2007.07.012","article-title":"High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints","volume":"90","author":"Gervasini","year":"2007","journal-title":"Genomics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/MCD.0000000000000268","article-title":"Tissue-specific mosaicism in a patient with Rubinstein-Taybi syndrome and CREBBP exon 1 duplication","volume":"28","author":"Gucev","year":"2019","journal-title":"Clin. Dysmorphol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/ejhg.2016.14","article-title":"Mosaic CREBBP mutation causes overlapping clinical features of Rubinstein-Taybi and Filippi syndromes","volume":"24","author":"Monroe","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1891\/0730-0832.19.1.17","article-title":"Apgar scoring: Its use and meaning for today\u2019s newborn","volume":"19","author":"Juretschke","year":"2000","journal-title":"Neonatal Netw."},{"key":"ref_12","first-page":"722","article-title":"Duane\u2019s retraction syndrome: Literature review","volume":"71","author":"Gurwood","year":"2000","journal-title":"Optometry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1002\/ajmg.a.40635","article-title":"Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy","volume":"176","author":"Pezzani","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/s41431-022-01091-0","article-title":"Recommendations for reporting results of diagnostic genomic testing","volume":"30","author":"Deans","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104679","DOI":"10.1016\/j.ejmg.2022.104679","article-title":"Bridging the language gap\u2014A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests","volume":"66","author":"Pengelly","year":"2023","journal-title":"Eur. J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1111\/j.1399-0004.2010.01408.x","article-title":"Somatic mosaicism in Cornelia de Lange syndrome: A further contributor to the wide clinical expressivity?","volume":"78","author":"Castronovo","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1136\/jmedgenet-2012-101477","article-title":"High rate of mosaicism in individuals with Cornelia de Lange syndrome","volume":"50","author":"Huisman","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15459","DOI":"10.1038\/s41598-021-94958-z","article-title":"Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood","volume":"11","author":"Parenti","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/BF00595907","article-title":"Rubinstein-taybi syndrome in a mother and son","volume":"148","author":"Hennekam","year":"1989","journal-title":"Eur. J. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/ajmg.1320460309","article-title":"Apparent dominant transmission of the Rubinstein-Taybi syndrome","volume":"46","author":"Marion","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1002\/ajmg.a.33598","article-title":"Inheritance and variable expression in Rubinstein-Taybi syndrome","volume":"152","author":"Bartsch","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/ajmg.a.32948","article-title":"Somatic and germ-line mosaicism in Rubinstein-Taybi syndrome","volume":"149","author":"Chiang","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.gene.2012.12.105","article-title":"Germline mosaicism in Rubinstein-Taybi syndrome","volume":"518","author":"Tajir","year":"2013","journal-title":"Gene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"640992","DOI":"10.3389\/fgene.2021.640992","article-title":"Case Report: Low-Level Maternal Mosaicism of a Novel CREBBP Variant Causes Recurrent Rubinstein-Taybi Syndrome in Two Siblings of a Chinese Family","volume":"12","author":"Lin","year":"2021","journal-title":"Front. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ajhg.2020.01.019","article-title":"Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders","volume":"106","author":"Kerkhof","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1002\/ajmg.a.37800","article-title":"CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype","volume":"170","author":"Menke","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1136\/jmg.2009.070573","article-title":"Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome","volume":"47","author":"Thienpont","year":"2010","journal-title":"J. Med. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/6\/654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:46:08Z","timestamp":1760107568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/6\/654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,22]]},"references-count":27,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["genes15060654"],"URL":"https:\/\/doi.org\/10.3390\/genes15060654","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2024,5,22]]}}}