{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:17:16Z","timestamp":1760235436966,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"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>X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G &gt; A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.<\/jats:p>","DOI":"10.3390\/genes12091328","type":"journal-article","created":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T09:53:23Z","timestamp":1630058003000},"page":"1328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MED12 Mutation in Two Families with X-Linked Ohdo Syndrome"],"prefix":"10.3390","volume":"12","author":[{"given":"Luca","family":"Rocchetti","sequence":"first","affiliation":[{"name":"U.O. Genetica Medica della Romagna, Dipartimento di Patologia Clinica AUSL, 47522 Cesena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eloisa","family":"Evangelista","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigia","family":"De Falco","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Savarese","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Savarese","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Sensi","sequence":"additional","affiliation":[{"name":"U.O. Genetica Medica della Romagna, Dipartimento di Patologia Clinica AUSL, 47522 Cesena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Fico","sequence":"additional","affiliation":[{"name":"AMES-Centro Polidiagnostico Strumentale, Srl, 80013 Naples, Italy"},{"name":"Fondazione Genetica per la Vita Onlus, 80013 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103768","DOI":"10.1016\/j.ejmg.2019.103768","article-title":"MED12 Missense Mutation in a Three-Generation Family. Clinical Characterization of MED12-Related Disorders and Literature Review","volume":"63","author":"Rubinato","year":"2020","journal-title":"Eur. J. Med Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41436-020-01031-7","article-title":"De Novo Loss-of-Function Variants in X-Linked MED12 Are Associated with Hardikar Syndrome in Females","volume":"23","author":"Li","year":"2021","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41436-020-01040-6","article-title":"De Novo Variants in MED12 Cause X-Linked Syndromic Neurodevelopmental Disorders in 18 Females","volume":"23","author":"Polla","year":"2021","journal-title":"Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/pr.2016.162","article-title":"De Novo Mutations in Genes of Mediator Complex Causing Syndromic Intellectual Disability: Mediatorpathy or Transcriptomopathy?","volume":"80","author":"Rosello","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1055\/s-0037-1602386","article-title":"Clinical Variability in Familial X-Linked Ohdo Syndrome\u2013Maat-Kievit-Brunner Type with MED12 Mutation","volume":"06","author":"Patil","year":"2017","journal-title":"J. Pediatr. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1002\/ajmg.a.36162","article-title":"Clinical and Neurocognitive Characterization of a Family with a Novel MED12 Gene Frameshift Mutation","volume":"161","author":"Lesca","year":"2013","journal-title":"Am. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/ccr3.301","article-title":"Nonsyndromic X-linked Intellectual Deficiency in Three Brothers with a Novel MED12 Missense Mutation [c.5922G>T (p.Glu1974His)]","volume":"3","author":"Bouazzi","year":"2015","journal-title":"Clin Case Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.1002\/ajmg.a.37354","article-title":"Beyond Ohdo Syndrome: A Familial Missense Mutation Broadens the MED12 Spectrum","volume":"167","author":"Langley","year":"2015","journal-title":"Am. J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1038\/ejhg.2015.5","article-title":"Next-Generation Sequencing in X-Linked Intellectual Disability","volume":"23","author":"Tzschach","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/cge.13412","article-title":"The Power of the Mediator Complex-Expanding the Genetic Architecture and Phenotypic Spectrum of MED12 -Related Disorders","volume":"94","author":"Charzewska","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"van de Plassche, S.R., and de Brouwer, A.P.M. (2021). MED12-Related (Neuro)Developmental Disorders: A Question of Causality. Genes, 12.","DOI":"10.3390\/genes12050663"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1002\/ajmg.1320470618","article-title":"Two Additional Cases of the Ohdo Blepharophimosis Syndrome","volume":"47","author":"Brunner","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1002\/ajmg.a.36539","article-title":"Blepharophimosis, Short Humeri, Developmental Delay and Hirschsprung Disease: Expanding the Phenotypic Spectrum of MED12 Mutations","volume":"164","author":"Isidor","year":"2014","journal-title":"Am. J. Med. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ajhg.2013.01.007","article-title":"Mutations in MED12 Cause X-Linked Ohdo Syndrome","volume":"92","author":"Hoischen","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1002\/ajmg.a.31270","article-title":"Blepharophimosis-Mental Retardation (BMR) Syndromes: A Proposed Clinical Classification of the so-Called Ohdo Syndrome, and Delineation of Two New BMR Syndromes, One X-Linked and One Autosomal Recessive","volume":"140A","author":"Verloes","year":"2006","journal-title":"Am. J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2019.06.014","article-title":"Increasing Evidence of Pathogenic Role of the Mediator (MED) Complex in the Development of Cardiovascular Diseases","volume":"165","author":"Napoli","year":"2019","journal-title":"Biochimie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s13238-013-3048-3","article-title":"MED12 Mutations in Human Diseases","volume":"4","author":"Wang","year":"2013","journal-title":"Protein Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18473","DOI":"10.1073\/pnas.0509457102","article-title":"The Zebrafish Kohtalo\/Trap230 Gene Is Required for the Development of the Brain, Neural Crest, and Pronephric Kidney","volume":"102","author":"Hong","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.pbiomolbio.2018.07.010","article-title":"Mediator Complex Subunit Med12 Regulates Cardiac Jelly Development and AV Valve Formation in Zebrafish","volume":"138","author":"Segert","year":"2018","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13052-020-00865-w","article-title":"What Is the Impact of a Novel MED12 Variant on Syndromic Conotruncal Heart Defects? Analysis of Case Report on Two Male Sibs","volume":"46","author":"Amodeo","year":"2020","journal-title":"Ital. J. Pediatr"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1242\/dev.053660","article-title":"Med12 Is Essential for Early Mouse Development and for Canonical Wnt and Wnt\/PCP Signaling","volume":"137","author":"Rocha","year":"2010","journal-title":"Development"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:34Z","timestamp":1760165614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,27]]},"references-count":21,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091328"],"URL":"https:\/\/doi.org\/10.3390\/genes12091328","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,8,27]]}}}