FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

Reymundo Lozano, Catherine Gbekie, Paige M Siper, Shubhika Srivastava, Jeffrey M Saland, Swathi Sethuram, Lara Tang, Elodie Drapeau, Yitzchak Frank, Joseph D Buxbaum, Alexander Kolevzon, Reymundo Lozano, Catherine Gbekie, Paige M Siper, Shubhika Srivastava, Jeffrey M Saland, Swathi Sethuram, Lara Tang, Elodie Drapeau, Yitzchak Frank, Joseph D Buxbaum, Alexander Kolevzon

Abstract

FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

Keywords: ASD; Autism spectrum disorder; FOXP1; FOXP1 syndrome; Forkhead box protein 1.

Conflict of interest statement

AK receives research support from AMO Pharma and consults to Ovid Therapeutics, Acadia, Ritrova, and Alkermes. The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Facial characteristic of two individuals with FOXP1 sequence variants, ages 9 and 15, including prominent forehead, wide nasal bridge with a broad tip, down slanting palpebral fissures, mild ptosis, thick vermillion, and wide spacing between teeth

References

    1. Shu W, Yang H, Zhang L, Lu MM, Morrisey EE. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem. 2001;276(29):27488–27497. doi: 10.1074/jbc.M100636200.
    1. Dasen JS, De Camilli A, Wang B, Tucker PW, Jessell TM. Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1. Cell. 2008;134(2):304–316. doi: 10.1016/j.cell.2008.06.019.
    1. Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L, et al. Foxp1 is an essential transcriptional regulator of B cell development. Nat Immunol. 2006;7(8):819–826. doi: 10.1038/ni1358.
    1. Jepsen K, Gleiberman AS, Shi C, Simon DI, Rosenfeld MG. Cooperative regulation in development by SMRT and FOXP1. Genes Dev. 2008;22(6):740–745. doi: 10.1101/gad.1637108.
    1. Palmesino E, Rousso DL, Kao TJ, Klar A, Laufer E, Uemura O, et al. Foxp1 and lhx1 coordinate motor neuron migration with axon trajectory choice by gating Reelin signalling. PLoS Biol. 2010;8(8):e1000446. doi: 10.1371/journal.pbio.1000446.
    1. Shi C, Zhang X, Chen Z, Sulaiman K, Feinberg MW, Ballantyne CM, et al. Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1. J Clin Invest. 2004;114(3):408–418. doi: 10.1172/JCI200421100.
    1. Wang B, Weidenfeld J, Lu MM, Maika S, Kuziel WA, Morrisey EE, et al. Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development. 2004;131(18):4477–4487. doi: 10.1242/dev.01287.
    1. Araujo DJ, Anderson AG, Berto S, Runnels W, Harper M, Ammanuel S, et al. FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes Dev. 2015;29(20):2081–2096. doi: 10.1101/gad.267989.115.
    1. Pariani MJ, Spencer A, Graham JM, Jr, Rimoin DL. A 785kb deletion of 3p14.1p13, including the FOXP1 gene, associated with speech delay, contractures, hypertonia and blepharophimosis. Eur J Med Genet. 2009;52(2-3):123–127. doi: 10.1016/j.ejmg.2009.03.012.
    1. Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, et al. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet. 2010;87(5):671–678. doi: 10.1016/j.ajhg.2010.09.017.
    1. Meerschaut I, Rochefort D, Revencu N, Petre J, Corsello C, Rouleau GA, et al. FOXP1-related intellectual disability syndrome: a recognisable entity. J Med Genet. 2017;54(9):613–623. doi: 10.1136/jmedgenet-2017-104579.
    1. Chang SW, Mislankar M, Misra C, Huang N, Dajusta DG, Harrison SM, et al. Genetic abnormalities in FOXP1 are associated with congenital heart defects. Hum Mutat. 2013;34(9):1226–1230. doi: 10.1002/humu.22366.
    1. Bekheirnia MR, Bekheirnia N, Bainbridge MN, Gu S, Coban Akdemir ZH, Gambin T, et al. 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. Genet Med. 2017;19(4):412–420. doi: 10.1038/gim.2016.131.
    1. Horn D, Kapeller J, Rivera-Brugues N, Moog U, Lorenz-Depiereux B, Eck S, et al. Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Hum Mutat. 2010;31(11):E1851–E1860. doi: 10.1002/humu.21362.
    1. Carr CW, Moreno-De-Luca D, Parker C, Zimmerman HH, Ledbetter N, Martin CL, et al. Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency. Eur J Hum Genet. 2010;18(11):1216–1220. doi: 10.1038/ejhg.2010.96.
    1. Ţuţulan-Cunită AC, Papuc SM, Arghir A, Rötzer KM, Deshpande C, Lungeanu A, et al. 3p interstitial deletion: novel case report and review. J Child Neurol. 2012;27(8):1062–1066. doi: 10.1177/0883073811431016.
    1. Palumbo O, D'Agruma L, Minenna AF, Palumbo P, Stallone R, Palladino T, et al. 3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination. Gene. 2013;516(1):107–113. doi: 10.1016/j.gene.2012.12.073.
    1. Le Fevre AK, Taylor S, Malek NH, Horn D, Carr CW, Abdul-Rahman OA, et al. FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am J Med Genet A. 2013;161A(12):3166–3175. doi: 10.1002/ajmg.a.36174.
    1. Lloveras E, Vendrell T, Fernández A, Castells N, Cueto A, del Campo M, et al. Intrachromosomal 3p insertion as a cause of reciprocal pure interstitial deletion and duplication in two siblings: further delineation of the emerging proximal 3p deletion syndrome. Cytogenet Genome Res. 2014;144(4):290–293. doi: 10.1159/000375184.
    1. Dimitrov BI, Ogilvie C, Wieczorek D, Wakeling E, Sikkema-Raddatz B, van Ravenswaaij-Arts CM, et al. 3p14 deletion is a rare contiguous gene syndrome: report of 2 new patients and an overview of 14 patients. Am J Med Genet A. 2015;167(6):1223–1230. doi: 10.1002/ajmg.a.36556.
    1. Song H, Makino Y, Noguchi E, Arinami T. A case report of de novo missense FOXP1 mutation in a non-Caucasian patient with global developmental delay and severe speech impairment. Clin Case Rep. 2015;3(2):110–113. doi: 10.1002/ccr3.167.
    1. Sollis E, Graham SA, Vino A, Froehlich H, Vreeburg M, Dimitropoulou D, et al. Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. Hum Mol Genet. 2016;25(3):546–557. doi: 10.1093/hmg/ddv495.
    1. Sollis E, Deriziotis P, Saitsu H, Miyake N, Matsumoto N, Hoffer MJV, et al. Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders. Hum Mutat. 2017;38(11):1542–1554. doi: 10.1002/humu.23303.
    1. Siper PM, De Rubeis S, Trelles MDP, Durkin A, Di Marino D, Muratet F, et al. Prospective investigation of FOXP1 syndrome. Mol Autism. 2017;8:57. doi: 10.1186/s13229-017-0172-6.
    1. Myers A, du Souich C, Yang CL, Borovik L, Mwenifumbo J, Rupps R, et al. FOXP1 haploinsufficiency: phenotypes beyond behavior and intellectual disability? Am J Med Genet A. 2017;173(12):3172–3181. doi: 10.1002/ajmg.a.38462.
    1. Johnson TB, Mechels K, Anderson RH, Cain JT, Sturdevant DA, Braddock S, et al. Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. Sci Rep. 2018;8(1):16161. doi: 10.1038/s41598-018-34437-0.
    1. Yamamoto-Shimojima K, Okamoto N, Matsumura W, Okazaki T, Yamamoto T. Three Japanese patients with 3p13 microdeletions involving FOXP1. Brain and Development. 2019;41(3):257–262. doi: 10.1016/j.braindev.2018.10.016.
    1. Vuillaume ML, Cogné B, Jeanne M, Boland A, Ung DC, Quinquis D, et al. Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability. Clin Chim Acta. 2018;485:218–223. doi: 10.1016/j.cca.2018.06.048.
    1. Mutlu-Albayrak H, Karaer K. Vocal cord immobility as a cause of aphonia in a child with 3p13p12 deletion syndrome encompassing FOXP1 gene. Int J Pediatr Otorhinolaryngol. 2019;117:179–181. doi: 10.1016/j.ijporl.2018.11.024.
    1. Urreizti R, Damanti S, Esteve C, Franco-Valls H, Castilla-Vallmanya L, Tonda R, et al. A de novo FOXP1 truncating mutation in a patient originally diagnosed as C syndrome. Sci Rep. 2018;8(1):694. doi: 10.1038/s41598-017-19109-9.
    1. Blanco Sánchez T, Duat Rodríguez A, Cantarín Extremera V, Lapunzina P, Palomares Bralo M, Nevado Blanco J. Clinical phenotype of a patient with FOXP1 deletion. An Pediatr (Barc) 2015;82(4):280–281. doi: 10.1016/j.anpedi.2014.06.007.
    1. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43(6):585–589. doi: 10.1038/ng.835.
    1. Lozano R, Vino A, Lozano C, Fisher SE, Deriziotis P. A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment. Eur J Hum Genet. 2015;23(12):1702–1707. doi: 10.1038/ejhg.2015.66.
    1. Zombor M, Kalmár T, Maróti Z, Zimmermann A, Máté A, Bereczki C, et al. Co-occurrence of mutations in FOXP1 and PTCH1 in a girl with extreme megalencephaly, callosal dysgenesis and profound intellectual disability. J Hum Genet. 2018;63(11):1189–1193. doi: 10.1038/s10038-018-0508-x.
    1. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399–407. doi: 10.1038/gim.2013.32.
    1. Schluth-Bolard C, Diguet F, Chatron N, Rollat-Farnier PA, Bardel C, Afenjar A, et al. Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders. J Med Genet. 2019;56(8):526–535. doi: 10.1136/jmedgenet-2018-105778.
    1. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133(1):1–9. doi: 10.1007/s00439-013-1358-4.
    1. D.Carmichael J. The Pituitary. 4. 2017. Anterior pituitary failure; pp. 245–247.
    1. Ren J, Han L, Tang J, Liu Y, Deng X, Liu Q, et al. Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function. PLoS Biol. 2019;17(5):e3000270. doi: 10.1371/journal.pbio.3000270.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться