{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:05:01Z","timestamp":1753891501963,"version":"3.41.2"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>We aimed to report on previously unappreciated clinical features associated with <jats:italic>FOXP1<\/jats:italic>-related intellectual disability (ID) syndrome, a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and language delay, with or without autistic features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole-exome sequencing (WES) to molecularly characterize an individual presenting with ID, epilepsy, autism spectrum disorder, behavioral problems, and facial dysmorphisms as major features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>WES allowed us to identify a previously unreported <jats:italic>de novo<\/jats:italic> splice site variant, c.1429-1G&amp;gt;T (NM_032682.6), in the <jats:italic>FOXP1<\/jats:italic> gene (OMIM<jats:sup>*<\/jats:sup>605515) as the causative event underlying the phenotype. Clinical reassessment of the patient and revision of the literature allowed us to refine the phenotype associated with <jats:italic>FOXP1<\/jats:italic> haploinsufficiency, including hyperkinetic movement disorder and flat angiomas as associated features. Interestingly, the patient also has an asymmetric face and choanal atresia and a novel <jats:italic>de novo<\/jats:italic> variant of the <jats:italic>CHD7<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We suggest that <jats:italic>FOXP1<\/jats:italic>-related ID syndrome may also predispose to the development of hyperkinetic movement disorders and flat angiomas. These features could therefore require specific management of this condition.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1207176","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T09:12:12Z","timestamp":1689412332000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Case report: Expanding the phenotype of FOXP1-related intellectual disability syndrome and hyperkinetic movement disorder in differential diagnosis with epileptic seizures"],"prefix":"10.3389","volume":"14","author":[{"given":"Carlo Alberto","family":"Cesaroni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzia","family":"Pollazzon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Rizzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Cappelletti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Pizzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Frattini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlotta","family":"Spagnoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano Giuseppe","family":"Caraffi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Zuntini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Trimarchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Niceta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livia","family":"Garavelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Fusco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"B1","unstructured":""},{"key":"B2","doi-asserted-by":"publisher","first-page":"27488","DOI":"10.1074\/jbc.M100636200","article-title":"Characterization of a new subfamily of winged-helix\/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors","volume":"276","author":"Shu","year":"2001","journal-title":"J Biol Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.ejmg.2009.03.012","article-title":"A 785kb deletion of 3p14.1p13, including the FOXP1 gene, associated with speech delay, contractures, hypertonia and blepharophimosis","volume":"52","author":"Pariani","year":"2009","journal-title":"Eur J Med Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"E1851","DOI":"10.1002\/humu.21362","article-title":"Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits","volume":"31","author":"Horn","year":"2010","journal-title":"Hum Mutat"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/ejhg.2010.96","article-title":"Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency","volume":"18","author":"Carr","year":"2010","journal-title":"Eur J Hum Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1177\/0883073811431016","article-title":"3p interstitial deletion: novel case report and review","volume":"27","author":"Tutulan-Cunit\u0103","year":"2012","journal-title":"J Child Neurol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.gene.2012.12.073","article-title":"3p141 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination","volume":"516","author":"Palumbo","year":"2013","journal-title":"Gene."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1002\/ajmg.a.36556","article-title":"3p14 deletion is a rare contiguous gene syndrome: report of 2 new patients and an overview of 14 patients","volume":"167","author":"Dimitrov","year":"2015","journal-title":"Am J Med Genet A"},{"key":"B9","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.cca.2018.06.048","article-title":"Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability","volume":"485","author":"Vuillaume","year":"2018","journal-title":"Clin Chim Acta"},{"key":"B10","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.ijporl.2018.11.024","article-title":"Vocal cord immobility as a cause of aphonia in a child with 3p13p12 deletion syndrome encompassing FOXP1 gene","volume":"117","author":"Mutlu-Albayrak","year":"2019","journal-title":"Int J Pediatr Otorhinolaryngol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.braindev.2018.10.016","article-title":"Three Japanese patients with 3p13 microdeletions involving FOXP1","volume":"41","author":"Yamamoto-Shimojima","year":"2019","journal-title":"Brain Develop."},{"key":"B12","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.ajhg.2010.09.017","article-title":"De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment","volume":"87","author":"Hamdan","year":"2010","journal-title":"Am J Hum Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/ng.835","article-title":"Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations","volume":"43","author":"O'Roak","year":"2011","journal-title":"Nat Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3166","DOI":"10.1002\/ajmg.a.36174","article-title":"FOXP1 mutations cause intellectual disability and a recognizable phenotype","author":"Le Fevre","year":"2013","journal-title":"Am J Med Genet A"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1038\/ejhg.2015.66","article-title":"novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment","volume":"23","author":"Lozano","year":"2015","journal-title":"Eur J Hum Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1002\/ccr3.167","article-title":"A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment","volume":"3","author":"Song","year":"2015","journal-title":"Clin Case Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3172","DOI":"10.1002\/ajmg.a.38462","article-title":"FOXP1 haploinsufficiency: phenotypes beyond behavior and intellectual disability?","volume":"173","author":"Myers","year":"2017","journal-title":"Am J Med Genet A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1002\/humu.23303","article-title":"Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders","volume":"38","author":"Sollis","year":"2017","journal-title":"Hum Mutat"},{"key":"B19","doi-asserted-by":"publisher","first-page":"16161","DOI":"10.1038\/s41598-018-34437-0","article-title":"Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1","volume":"8","author":"Johnson","year":"2018","journal-title":"Sci Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/s41598-017-19109-9","article-title":"A de novo FOXP1 truncating mutation in a patient originally diagnosed as C syndrome","volume":"8","author":"Urreizti","year":"2018","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1093\/hmg\/ddv495","article-title":"Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder","volume":"25","author":"Sollis","year":"2016","journal-title":"Hum Mol Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13229-017-0172-6","article-title":"Prospective investigation of FOXP1 syndrome","volume":"8","author":"Siper","year":"2017","journal-title":"Mol Autism."},{"key":"B23","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s11689-021-09358-1","article-title":"FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring","volume":"13","author":"Lozano","year":"2021","journal-title":"J Neurodev Disord"},{"key":"B24","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/gim.2016.131","article-title":"Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene","volume":"19","author":"Bekheirnia","year":"2017","journal-title":"Genet Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.ajhg.2020.06.018","article-title":"Enhanced MAPK1 function causes a neurodevelopmental disorder within the RASopathy clinical spectrum","volume":"107","author":"Motta","year":"2020","journal-title":"Am J Hum Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.01.015","article-title":"SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females","author":"Radio","year":"2021","journal-title":"Am J Hum Genet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ajhg.2020.11.015","article-title":"SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling","volume":"108","author":"Lin","year":"2021","journal-title":"Am J Hum Genet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1303.3997","author":"Li","year":"2013","journal-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM"},{"key":"B30","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"B31","doi-asserted-by":"publisher","first-page":"E2393","DOI":"10.1002\/humu.22376","article-title":"dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations","volume":"34","author":"Liu","year":"2013","journal-title":"Hum Mutat"},{"key":"B32","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat Genet"},{"key":"B34","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am J Hum Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"lqaa032","DOI":"10.1093\/nargab\/lqaa032","article-title":"Phen2Gene: rapid phenotype-driven gene prioritization for rare diseases","volume":"2","author":"Zhao","year":"2020","journal-title":"NAR Genom Bioinform"},{"key":"B36","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines","volume":"41","author":"Tavtigian","year":"2020","journal-title":"Hum Mutat."},{"key":"B38","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1136\/jmedgenet-2017-104579","article-title":"FOXP1-related intellectual disability syndrome: a recognisable entity","volume":"54","author":"Meerschaut","year":"2017","journal-title":"J Med Genet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13229-021-00469-z","article-title":"Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms","volume":"12","author":"Trelles","year":"2021","journal-title":"Mol Autism"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e0127671","DOI":"10.1371\/journal.pone.0127671","article-title":"Foxp1 regulates cortical radial migration and neuronal morphogenesis in developing cerebral cortex","volume":"10","author":"Li","year":"2015","journal-title":"PLoS ONE"},{"key":"B41","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.neuroscience.2003.11.036","article-title":"Foxp1 gene expression in projection neurons of the mouse striatum","volume":"124","author":"Tamura","year":"2004","journal-title":"Neuroscience."},{"key":"B42","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.neuroscience.2018.07.017","article-title":"Differential and overlapping pattern of Foxp1 and Foxp2 expression in the striatum of adult mouse brain","volume":"388","author":"Fong","year":"2018","journal-title":"Neuroscience."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1016\/j.celrep.2020.02.030","article-title":"Single-cell analysis of Foxp1-Driven mechanisms essential for striatal development","volume":"30","author":"Anderson","year":"2020","journal-title":"Cell Rep"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1101\/gad.267989.115","article-title":"FoxP1 orchestration of ASD-relevant signaling pathways in the striatum","volume":"29","author":"Araujo","year":"2015","journal-title":"Genes Dev"},{"key":"B45","doi-asserted-by":"publisher","first-page":"6575","DOI":"10.1523\/JNEUROSCI.3612-16.2017","article-title":"Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease","volume":"37","author":"Louis Sam Titus","year":"2017","journal-title":"J Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e2112852119","DOI":"10.1073\/pnas.2112852119","article-title":"Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome","volume":"119","author":"Wang","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1007\/s00415-017-8722-6","article-title":"Movement disorders in mitochondrial disease","volume":"265","author":"Ghaoui","year":"2018","journal-title":"J Neurol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e70873","DOI":"10.1371\/journal.pone.0070873","article-title":"FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells","volume":"8","author":"Grundmann","year":"2013","journal-title":"PLoS ONE"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1207176\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T09:12:18Z","timestamp":1689412338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1207176\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":48,"alternative-id":["10.3389\/fneur.2023.1207176"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1207176","relation":{},"ISSN":["1664-2295"],"issn-type":[{"type":"electronic","value":"1664-2295"}],"subject":[],"published":{"date-parts":[[2023,7,14]]},"article-number":"1207176"}}