Phenotypic variability to medication management: an update on fragile X syndrome.
CGG trinucleotide repeat
CRISPR/Cas9
Clinical features
DNA methylation
FMR1 gene
Fragile X syndrome (FXS)
Variable expressivity
dCas9
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
07 Jul 2023
07 Jul 2023
Historique:
received:
21
03
2023
accepted:
03
07
2023
medline:
10
7
2023
pubmed:
8
7
2023
entrez:
7
7
2023
Statut:
epublish
Résumé
This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.
Identifiants
pubmed: 37420260
doi: 10.1186/s40246-023-00507-2
pii: 10.1186/s40246-023-00507-2
pmc: PMC10329374
doi:
Substances chimiques
FMR1 protein, human
0
Fragile X Mental Retardation Protein
139135-51-6
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
60Subventions
Organisme : This work was technically and financially supported by the Batterjee Medical College, Jeddah, Saudi Arabia for publishing this work.
ID : 23-MED-01
Organisme : This work was technically and financially supported by the Batterjee Medical College, Jeddah, Saudi Arabia for publishing this work.
ID : 23-MED-01
Informations de copyright
© 2023. The Author(s).
Références
Eur J Hum Genet. 2014 Oct;22(10):1185-9
pubmed: 24448548
Nat Neurosci. 2013 Nov;16(11):1530-6
pubmed: 23584741
Nat Rev Neurol. 2018 Jan;14(1):9-21
pubmed: 29192260
Front Neurol. 2020 Oct 30;11:581429
pubmed: 33193037
Expert Rev Mol Diagn. 2017 Nov;17(11):1023-1032
pubmed: 28929824
Pediatrics. 2017 Jun;139(Suppl 3):S183-S193
pubmed: 28814539
Neurobiol Dis. 2020 Mar;136:104740
pubmed: 31927143
Ann Saudi Med. 2000 Jan;20(1):16-9
pubmed: 17322735
Front Mol Neurosci. 2018 Mar 15;11:41
pubmed: 29599705
Front Mol Neurosci. 2017 Sep 12;10:290
pubmed: 28955201
Brain Sci. 2018 Dec 05;8(12):
pubmed: 30563047
Am J Med Genet. 1999 Apr 2;83(4):286-95
pubmed: 10208163
Dev Psychopathol. 2020 Oct;32(4):1335-1352
pubmed: 33161907
Brain Sci. 2023 Feb 07;13(2):
pubmed: 36831819
Genet Res (Camb). 2016 Jun 28;98:e11
pubmed: 27350105
Res Dev Disabil. 2014 May;35(5):1072-86
pubmed: 24629733
Intractable Rare Dis Res. 2014 Nov;3(4):110-7
pubmed: 25606361
J Mol Diagn. 2008 Jan;10(1):43-9
pubmed: 18165273
Clin Genet. 2018 Feb;93(2):216-222
pubmed: 28436599
J Neurol Psychiatry. 1943 Jul;6(3-4):154-7
pubmed: 21611430
PLoS One. 2011;6(8):e23648
pubmed: 21909353
Pediatrics. 2017 Jun;139(Suppl 3):S194-S206
pubmed: 28814540
Exp Mol Med. 2017 Apr 28;49(4):e322
pubmed: 28450738
Genet Test. 2003 Winter;7(4):339-43
pubmed: 15000813
Nat Med. 2017 Jun;23(6):674-677
pubmed: 28504725
World J Pediatr. 2021 Dec;17(6):653-658
pubmed: 34738199
J Psychiatr Res. 2014 Dec;59:220-8
pubmed: 25300441
J Neurodev Disord. 2014;6(1):26
pubmed: 25147583
Front Psychiatry. 2018 Nov 13;9:564
pubmed: 30483160
Am J Med Genet. 2000 Sep 18;94(3):232-6
pubmed: 10995510
J Neurodev Disord. 2020 Apr 22;12(1):12
pubmed: 32316911
Science. 2016 Jan 22;351(6271):400-3
pubmed: 26721683
J Neurodev Disord. 2014 Mar 26;6(1):6
pubmed: 24669826
Cerebellum. 2022 Oct;21(5):851-860
pubmed: 34498198
Int J Dev Neurosci. 2014 Nov;38:155-60
pubmed: 25016068
J Neurodev Disord. 2022 Nov 25;14(1):56
pubmed: 36434514
J Neurol. 2016 Jul;263(7):1390-400
pubmed: 27159993
JAMA Neurol. 2014 Mar;71(3):355-9
pubmed: 24395328
EMBO Mol Med. 2015 Nov 26;7(12):1565-79
pubmed: 26612855
Am J Med Genet. 2000 Jun 5;92(4):229-36
pubmed: 10842286
Ann Genet. 1997;40(3):139-44
pubmed: 9401101
Front Synaptic Neurosci. 2017 Nov 06;9:15
pubmed: 29163124
Am J Med Genet A. 2013 Apr;161A(4):771-8
pubmed: 23444167
Cerebellum. 2016 Oct;15(5):623-31
pubmed: 27372099
Appl Clin Genet. 2021 Jul 05;14:305-312
pubmed: 34262328
Epilepsy Behav. 2011 Nov;22(3):581-3
pubmed: 21890420
PLoS One. 2011;6(7):e21728
pubmed: 21818263
Eur J Pharmacol. 2010 Nov 25;647(1-3):90-6
pubmed: 20816814
Mol Neurobiol. 2020 Mar;57(3):1748-1767
pubmed: 31836945
Psychopharmacology (Berl). 2011 May;215(2):291-300
pubmed: 21181121
Science. 2014 Feb 28;343(6174):1002-5
pubmed: 24578575
Cell. 1991 Aug 23;66(4):817-22
pubmed: 1878973
Genome Med. 2012 Dec 21;4(12):100
pubmed: 23259642
Hum Genomics. 2018 Apr 10;12(1):18
pubmed: 29631625
Mol Autism. 2013 Jun 03;4(1):16
pubmed: 23731516
Nat Rev Neurol. 2017 Jul;13(7):384-385
pubmed: 28574060
Genes (Basel). 2021 Nov 27;12(12):
pubmed: 34946857
F1000Res. 2017 Dec 8;6:2112
pubmed: 29259781
Neuron. 2013 Jan 23;77(2):243-50
pubmed: 23352161
Curr Opin Psychiatry. 2015 Mar;28(2):107-12
pubmed: 25602250
Am J Med Genet A. 2023 Feb;191(2):357-369
pubmed: 36349505
Intractable Rare Dis Res. 2021 Feb;10(1):11-16
pubmed: 33614370
Nat Biotechnol. 2016 Oct;34(10):1060-1065
pubmed: 27571369
Science. 2016 Jan 22;351(6271):407-411
pubmed: 26721686
Ital J Pediatr. 2017 Apr 19;43(1):39
pubmed: 28420439
Malays J Pathol. 2017 Aug;39(2):99-106
pubmed: 28866690
J Mol Diagn. 2016 Nov;18(6):834-841
pubmed: 27585064
Am J Med Genet. 1999 May 28;84(3):221-5
pubmed: 10331596
Brain Cogn. 2012 Feb;78(1):74-84
pubmed: 22070923
Mol Ther. 2020 Aug 5;28(8):1846-1857
pubmed: 32416058
Neurotherapeutics. 2015 Jul;12(3):584-608
pubmed: 25986746
Hum Genet. 2017 Jul;136(7):875-883
pubmed: 28508290
Front Psychiatry. 2021 May 21;12:643442
pubmed: 34093265
Eur J Hum Genet. 2021 Jan;29(1):173-183
pubmed: 32862204
Front Immunol. 2018 Sep 21;9:2009
pubmed: 30298064
Sci Rep. 2017 Jul 27;7(1):6732
pubmed: 28751638
Mol Psychiatry. 2005 Jul;10(7):631-6
pubmed: 15768049
Curr Res Virol Sci. 2022;3:
pubmed: 36330462
Clin Genet. 2009 Dec;76(6):511-23
pubmed: 19863547
Brain Sci. 2020 Sep 30;10(10):
pubmed: 33008014
Neuropsychiatr Dis Treat. 2019 Dec 27;15:3569-3581
pubmed: 31920317
Am J Hum Genet. 1969 May;21(3):231-44
pubmed: 5794013
Dev Neurosci. 2011;33(5):379-94
pubmed: 21893949
J Neurosci. 2014 Jul 23;34(30):9867-79
pubmed: 25057190
Biol Psychiatry. 2007 Apr 1;61(7):911-22
pubmed: 17217930
Ir J Med Sci. 2022 Nov 21;:
pubmed: 36409419
Science. 2006 Oct 6;314(5796):140-3
pubmed: 17023662
Cell. 2013 Feb 28;152(5):1173-83
pubmed: 23452860
Am J Med Genet A. 2008 Apr 1;146A(7):803-12
pubmed: 18286595
J Med Genet. 2014 May;51(5):309-18
pubmed: 24591415
J Med Genet. 2013 Oct;50(10):641-52
pubmed: 23785127
Curr Pediatr Rev. 2019;15(4):251-258
pubmed: 31241016
J Hum Genet. 2017 Feb;62(2):269-275
pubmed: 27784894
Hum Genet. 1997 Aug;100(2):224-9
pubmed: 9254854
Nat Rev Drug Discov. 2019 Jun;18(6):421-446
pubmed: 30846871
RNA. 2002 Dec;8(12):1482-8
pubmed: 12515381
Pediatrics. 2009 Aug;124(2):527-33
pubmed: 19581269
Cell Stem Cell. 2015 Aug 6;17(2):213-20
pubmed: 26212079
Hum Genomics. 2022 Jul 19;16(1):22
pubmed: 35854334
J Autism Dev Disord. 2016 Jun;46(6):2088-2099
pubmed: 26864160
J Autism Dev Disord. 2014 Apr;44(4):981-7
pubmed: 24052275
J Neurodev Disord. 2017 Jun 12;9:14
pubmed: 28616097
J Neurosci Res. 2007 Oct;85(13):2813-23
pubmed: 17387691
Eur J Hum Genet. 2017 Apr;25(4):423-431
pubmed: 28176767
Mol Ther Nucleic Acids. 2016;5:e349
pubmed: 28131272
Am J Med Genet A. 2015 Oct;167A(10):2485-7
pubmed: 25988754
J Child Neurol. 2005 Oct;20(10):790-5
pubmed: 16417872
Int J Pediatr. 2017;2017:9318346
pubmed: 28751920
Epilepsia. 1999 Aug;40(8):1092-9
pubmed: 10448821
Eur J Hum Genet. 2013 Aug;21(8):816-23
pubmed: 23211703
Am J Med Genet A. 2009 Oct;149A(10):2152-7
pubmed: 19764037
J Neurodev Disord. 2019 Dec 26;11(1):41
pubmed: 31878865
Prim Care Companion CNS Disord. 2013;15(2):
pubmed: 23930232
Science. 2012 Aug 17;337(6096):816-21
pubmed: 22745249
Hum Genet. 2017 Oct;136(10):1313-1327
pubmed: 28866801
J Hum Genet. 2018 Apr;63(4):509-516
pubmed: 29379191
J Child Adolesc Psychopharmacol. 2011 Dec;21(6):565-9
pubmed: 22136091
Mol Genet Genomic Med. 2018 Apr 6;:
pubmed: 29624914
Am J Med Genet. 1994 Jul 15;51(4):509-12
pubmed: 7943031
Am J Med Genet A. 2013 Aug;161A(8):1897-903
pubmed: 23824974
Genes Brain Behav. 2005 Aug;4(6):393-8
pubmed: 16098137
Intractable Rare Dis Res. 2016 Aug;5(3):145-57
pubmed: 27672537
Curr Treat Options Neurol. 2019 Feb 27;21(3):12
pubmed: 30809735
Nat Rev Neurosci. 2021 May;22(5):275-289
pubmed: 33828309
Am J Hum Genet. 2009 Oct;85(4):503-14
pubmed: 19804849
Cell. 2014 Oct 23;159(3):647-61
pubmed: 25307932
Am J Med Genet A. 2014 Jul;164A(7):1648-58
pubmed: 24700618
Hum Mol Genet. 2002 Feb 15;11(4):371-8
pubmed: 11854169
J Dev Behav Pediatr. 2020 Dec;41(9):724-728
pubmed: 32947579
Noncoding RNA Res. 2020 Dec 03;6(1):1-7
pubmed: 33426406
J Dev Behav Pediatr. 2016 Oct;37(8):619-28
pubmed: 27560971
Southeast Asian J Trop Med Public Health. 1999;30 Suppl 2:114-8
pubmed: 11400746
Neuropharmacology. 2005 Dec;49(7):1053-66
pubmed: 16054174
Science. 2013 Feb 15;339(6121):823-6
pubmed: 23287722
J Autism Dev Disord. 2008 Jan;38(1):184-9
pubmed: 17340199
Dev Med Child Neurol. 2019 Feb;61(2):121-127
pubmed: 30084485
J Neurodev Disord. 2023 Jan 9;15(1):1
pubmed: 36624400
ACS Chem Biol. 2018 Feb 16;13(2):389-396
pubmed: 29210569
J Intellect Disabil Res. 2009 Jun;53(6):559-70
pubmed: 19504727
Nat Rev Dis Primers. 2017 Sep 29;3:17065
pubmed: 28960184
Nature. 2018 Jan 11;553(7687):217-221
pubmed: 29258297
Science. 2013 Feb 15;339(6121):819-23
pubmed: 23287718
Science. 2016 Jan 22;351(6271):403-7
pubmed: 26721684
Cell. 1991 May 31;65(5):905-14
pubmed: 1710175
J Intellect Disabil Res. 2016 Jan;60(1):54-67
pubmed: 26449367
Tunis Med. 2008 Nov;86(11):973-7
pubmed: 19213487
J Mol Diagn. 2009 Jul;11(4):324-9
pubmed: 19460941
Cell. 2018 Feb 22;172(5):979-992.e6
pubmed: 29456084
Eur J Med Genet. 2009 Jul-Aug;52(4):170-3
pubmed: 19361583
J Appl Res Intellect Disabil. 2017 Sep;30(5):970-974
pubmed: 27456465
Epilepsy Res. 2009 Jul;85(1):114-7
pubmed: 19394799
Cell. 2016 Sep 22;167(1):219-232.e14
pubmed: 27662090
Am J Hum Genet. 2000 Jun;66(6):1729-35
pubmed: 10793008
Cell. 2020 Apr 2;181(1):136-150
pubmed: 32243786
BMC Neurol. 2009 Oct 13;9:53
pubmed: 19822023
Int J Mol Sci. 2020 Jun 20;21(12):
pubmed: 32575683
Gac Med Mex. 2020;156(1):60-66
pubmed: 32026885
Biomed Res Int. 2014;2014:195793
pubmed: 24987673
J Clin Invest. 2012 Dec;122(12):4314-22
pubmed: 23202739
Cell. 2017 Jan 12;168(1-2):20-36
pubmed: 27866654
Mol Biol Rep. 2019 Aug;46(4):4185-4193
pubmed: 31098807
Intractable Rare Dis Res. 2016 Aug;5(3):158-67
pubmed: 27672538