{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:43:35Z","timestamp":1765547015013,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T00:00:00Z","timestamp":1671235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health\u2014\u201cRicerca Corrente\u201d and 5 x mille\u201d"},{"name":"Research Plan PIACERI L.3 Starting Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>PHF21A (PHD finger protein 21A) gene, located in the short arm of chromosome 11, encodes for BHC80, a component of the Lysine Specific Demethylase 1, Corepressor of REST (LSD1-CoREST) complex. BHC80 is mainly expressed in the human fetal brain and skeletal muscle and acts as a modulator of several neuronal genes during embryogenesis. Data from literature relates PHF21A variants with Potocki\u2013Shaffer Syndrome (PSS), a contiguous gene deletion disorder caused by the haploinsufficiency of PHF21A, ALX4, and EXT2 genes. Clinical cardinal features of PSS syndrome are multiple exostoses (due to the EXT2 involvement), biparietal foramina (due to the ALX4 involvement), intellectual disability, and craniofacial anomalies (due to the PHF21A involvement). To date, to the best of our knowledge, a detailed description of PHF21A-related disorder clinical phenotype is not described in the literature; in fact, only 14 subjects with microdeletion frameshift or nonsense variants concerning only PHF21A gene have been reported. All reported cases did not present ALX4 or EXT2 variants, and their clinical features did not fit with PSS diagnosis. Herein, by using Exome sequencing, and Sanger sequencing of the region of interest, we describe a case of a child with a paternally inherited (mosaicism of 5%) truncating variant of the PHF21A gene (c.649_650del; p.Gln217ValfsTer6), and discuss the new evidence. In conclusion, these patients showed varied clinical expressions, mainly including the presence of intellectual disability, epilepsy, hypotonia, and dysmorphic features. Our study contributes to describing the genotype\u2013phenotype spectrum of patients with PHF21A-related disorder; however, the limited data in the literature have been unable to provide a precise diagnostic protocol for patients with PHF21A-related disorder.<\/jats:p>","DOI":"10.3390\/ijms232416130","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:25:46Z","timestamp":1671427546000},"page":"16130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["PHF21A Related Disorder: Description of a New Case"],"prefix":"10.3390","volume":"23","author":[{"given":"Ambra","family":"Butera","sequence":"first","affiliation":[{"name":"Department of Human Pathology of the Adult and Developmental Age, \u201cGaetano Barresi\u201d University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Gennaro","family":"Nicotera","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adult and Developmental Age, \u201cGaetano Barresi\u201d University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Di Rosa","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of the Adult and Developmental Age, \u201cGaetano Barresi\u201d University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastiano Antonino","family":"Musumeci","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-9692","authenticated-orcid":false,"given":"Girolamo Aurelio","family":"Vitello","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8999-3365","authenticated-orcid":false,"given":"Antonino","family":"Musumeci","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirella","family":"Vinci","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Gloria","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0160-9040","authenticated-orcid":false,"given":"Concetta","family":"Federico","sequence":"additional","affiliation":[{"name":"Department Biological, Geological and Environmental Sciences, University of Catania, Via Androne 81, 95124 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7568-5823","authenticated-orcid":false,"given":"Salvatore","family":"Saccone","sequence":"additional","affiliation":[{"name":"Department Biological, Geological and Environmental Sciences, University of Catania, Via Androne 81, 95124 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8667-8223","authenticated-orcid":false,"given":"Francesco","family":"Cal\u00ec","sequence":"additional","affiliation":[{"name":"Oasi Research Institute\u2014IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7420","DOI":"10.1073\/pnas.112008599","article-title":"A core\u2013BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes","volume":"99","author":"Hakimi","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.cell.2004.12.012","article-title":"Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1","volume":"119","author":"Shi","year":"2004","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.molcel.2005.08.027","article-title":"Regulation of LSD1 Histone Demethylase Activity by Its Associated Factors","volume":"19","author":"Shi","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1385\/JMN:29:3:227","article-title":"CoREST-Like Complexes Regulate Chromatin Modification and Neuronal Gene Expression","volume":"29","author":"Lakowski","year":"2006","journal-title":"J. Mol. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.neuroscience.2017.05.031","article-title":"Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells","volume":"370","author":"Porter","year":"2017","journal-title":"Neuroscience"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13229-019-0286-0","article-title":"Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism","volume":"10","author":"Kim","year":"2019","journal-title":"Mol. Autism."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/ajmg.a.33245","article-title":"Potocki-Shaffer syndrome: Comprehensive clinical assessment, review of the literature, and proposals for medical management","volume":"152A","author":"Swarr","year":"2010","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.2217\/epi-2016-0090","article-title":"Yin\u2013yang actions of histone methylation regulatory complexes in the brain","volume":"8","author":"Garay","year":"2016","journal-title":"Epigenomics"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Trajkova, S., Di Gregorio, E., Ferrero, G., Carli, D., Pavinato, L., Delplancq, G., Kuentz, P., and Brusco, A. (2020). New Insights into Potocki-Shaffer Syndrome: Report of Two Novel Cases and Literature Review. Brain Sci., 10.","DOI":"10.3390\/brainsci10110788"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, X., Xu, H., Shi, W., Wang, F., Xu, F., Zhang, Y., Gan, J., Tian, X., Chen, B., and Dai, M. (2021). 11p11.12p12 duplication in a family with intellectual disability and craniofacial anomalies. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-00945-8"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41431-018-0289-x","article-title":"De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies","volume":"27","author":"Hamanaka","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/S0002-9297(07)62963-2","article-title":"Haploinsufficiency of ALX4 as a Potential Cause of Parietal Foramina in the 11p11.2 Contiguous Gene\u2013Deletion Syndrome","volume":"67","author":"Wu","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1002\/ajmg.a.37344","article-title":"A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies","volume":"167","author":"Labonne","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/(SICI)1096-8628(19960329)62:3<319::AID-AJMG22>3.0.CO;2-M","article-title":"Interstitial deletion of 11 (P11.2p12): A newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2)","volume":"62","author":"Potocki","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/sj.ejhg.5201366","article-title":"Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki\u2013Shaffer syndrome","volume":"13","author":"Wakui","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/ajmg.a.35671","article-title":"A 137-kb deletion within the Potocki-Shaffer syndrome interval on chromosome 11p11.2 associated with developmental delay and hypotonia","volume":"161","author":"Montgomery","year":"2012","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/ajmg.a.37988","article-title":"Potocki-Shaffer syndrome in a child without intellectual disability-The role of PHF21A in cognitive function","volume":"173","author":"McCool","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ajhg.2012.05.005","article-title":"Translocations Disrupting PHF21A in the Potocki-Shaffer-Syndrome Region Are Associated with Intellectual Disability and Craniofacial Anomalies","volume":"91","author":"Kim","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Musumeci, A., Cal\u00ec, F., Scuderi, C., Vinci, M., Vitello, G.A., Musumeci, S.A., Chiavetta, V., Federico, C., Amore, G., and Saccone, S. (2022). Identification of a Novel Missense Mutation of POLR3A Gene in a Cohort of Sicilian Patients with Leukodystrophy. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092276"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/nature06034","article-title":"Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression","volume":"448","author":"Lan","year":"2007","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature13772","article-title":"Synaptic, transcriptional and chromatin genes disrupted in autism","volume":"515","author":"He","year":"2014","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum disorder","volume":"515","author":"Iossifov","year":"2014","journal-title":"Nature"},{"key":"ref_23","first-page":"318","article-title":"Novel Pathogenic Variant (c.1171A>T) in PHF21A in a Female with Intellectual Disability and Craniofacial Anomalies","volume":"13","author":"Lee","year":"2022","journal-title":"Mol. Syndr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.cell.2019.12.036","article-title":"Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism","volume":"180","author":"Satterstrom","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1038\/s41436-021-01159-0","article-title":"Combining exome\/genome sequencing with data repository analysis reveals novel gene\u2013disease associations for a wide range of genetic disorders","volume":"23","author":"Kandaswamy","year":"2021","journal-title":"Genet. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.visres.2017.03.007","article-title":"Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy","volume":"139","author":"Ung","year":"2017","journal-title":"Vis. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S1474-4422(15)00250-1","article-title":"The genetic landscape of the epileptic encephalopathies of infancy and childhood","volume":"15","author":"McTague","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Spoto, G., Saia, M.C., Amore, G., Gitto, E., Loddo, G., Mainieri, G., Nicotera, A.G., and Di Rosa, G. (2021). Neonatal Seizures: An Overview of Genetic Causes and Treatment Options. Brain Sci., 11.","DOI":"10.3390\/brainsci11101295"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"826225","DOI":"10.3389\/fneur.2022.826225","article-title":"KCNQ2-Related Neonatal Epilepsy Treated With Vitamin B6: A Report of Two Cases and Literature Review","volume":"13","author":"Amore","year":"2022","journal-title":"Front. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:43:27Z","timestamp":1760147007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,17]]},"references-count":29,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232416130"],"URL":"https:\/\/doi.org\/10.3390\/ijms232416130","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,12,17]]}}}