Identification of a de novo FOXP1 mutation and incidental discovery of inherited genetic variants contributing to a case of autism spectrum disorder and epilepsy.
Autism Spectrum Disorder
/ genetics
Epilepsy
/ genetics
Exome
/ genetics
Forkhead Transcription Factors
/ genetics
Genetic Predisposition to Disease
/ genetics
High-Throughput Nucleotide Sequencing
/ methods
Humans
Incidental Findings
Intellectual Disability
/ genetics
Male
Mutation
/ genetics
Phenotype
Repressor Proteins
/ genetics
Exome Sequencing
/ methods
Young Adult
COMT
FOXP1
SLC6A4
structural variants
whole genome/exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
27
01
2019
revised:
08
04
2019
accepted:
22
04
2019
pubmed:
22
5
2019
medline:
16
7
2020
entrez:
22
5
2019
Statut:
ppublish
Résumé
Autism spectrum disorder is commonly co-diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD. We present a next-generation sequencing-based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post-translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions. A de novo variant was identified within the FOXP1 3' untranslated regulatory region using exome sequencing. Additionally, inherited variants that likely contribute to the current and potential future traits were identified within the COMT, SLC6A4, CYP2C19, and CYP2D6 genes. This study aims to elucidate how a collection of variant genotypes could potentially impact neural development resulting in a unique phenotype including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic treatments for ASD-related symptoms.
Sections du résumé
BACKGROUND
Autism spectrum disorder is commonly co-diagnosed intellectual disability, language disorder, anxiety, and epilepsy, however, symptom management is difficult due to the complex genetic nature of ASD.
METHODS
We present a next-generation sequencing-based case study with both de novo and inherited genetic variants and highlight the impact of structural variants on post-translational regulation of protein expression. Since management of symptoms has classically been through pharmaceutical therapies, a pharmacogenomics screen was also utilized to determine possible drug/gene interactions.
RESULTS
A de novo variant was identified within the FOXP1 3' untranslated regulatory region using exome sequencing. Additionally, inherited variants that likely contribute to the current and potential future traits were identified within the COMT, SLC6A4, CYP2C19, and CYP2D6 genes.
CONCLUSION
This study aims to elucidate how a collection of variant genotypes could potentially impact neural development resulting in a unique phenotype including ASD and epilepsy. Each gene's contribution to neural development is assessed, and the interplay of these genotypes is discussed. The results highlight the utility of exome sequencing in conjunction with pharmacogenomics screening when evaluating possible causes of and therapeutic treatments for ASD-related symptoms.
Identifiants
pubmed: 31111659
doi: 10.1002/mgg3.751
pmc: PMC6625142
doi:
Substances chimiques
FOXP1 protein, human
0
Forkhead Transcription Factors
0
Repressor Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00751Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
Algorithms Mol Biol. 2011 Nov 24;6:26
pubmed: 22115189
Indian J Psychiatry. 2011 Oct;53(4):289-99
pubmed: 22303036
Am J Med Genet A. 2013 Dec;161A(12):3166-75
pubmed: 24214399
Am J Hum Genet. 2010 Nov 12;87(5):671-8
pubmed: 20950788
J Neurophysiol. 2012 Jan;107(1):417-23
pubmed: 22031777
Nat Commun. 2015 Apr 14;6:6778
pubmed: 25868900
Nucleic Acids Res. 2014 Sep;42(15):9543-52
pubmed: 25081214
BMC Res Notes. 2012 Jul 02;5:337
pubmed: 22748135
Ochsner J. 2013 Winter;13(4):533-40
pubmed: 24358002
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Cell Rep. 2012 Feb 23;1(2):167-78
pubmed: 22574288
BMC Med Genet. 2007 Jun 25;8:38
pubmed: 17592645
Nature. 2012 Nov 1;491(7422):56-65
pubmed: 23128226
OMICS. 2019 Jan;23(1):36-44
pubmed: 30566377
Mol Syndromol. 2012 Apr;2(3-5):213-216
pubmed: 22670142
J Anal Toxicol. 2007 Jan-Feb;31(1):31-6
pubmed: 17389081
Clin Chim Acta. 2017 Jun;469:63-68
pubmed: 28343847
Eur J Clin Pharmacol. 2016 Feb;72(2):175-84
pubmed: 26514968
Patient Prefer Adherence. 2015 Jan 22;9:161-72
pubmed: 25653508
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
J Neurosci. 2011 Jan 19;31(3):809-18
pubmed: 21248104
Mol Psychiatry. 2015 May;20(5):632-9
pubmed: 25266127
J Neurochem. 2010 May;113(4):836-47
pubmed: 20175877
Mol Autism. 2017 Oct 24;8:57
pubmed: 29090079
Cell. 2014 Oct 23;159(3):487-98
pubmed: 25417102
Neuropharmacology. 2011 Sep;61(3):382-6
pubmed: 21251917
Biol Psychiatry. 2017 May 15;81(10):838-847
pubmed: 27450033
Future Sci OA. 2016 Mar 21;2(2):FSO114
pubmed: 28031961
Child Adolesc Psychiatry Ment Health. 2018 Jul 16;12:37
pubmed: 30026806
Sci Rep. 2017 Aug 18;7(1):8735
pubmed: 28821725
Sci Rep. 2016 Jul 07;6:28998
pubmed: 27383233
Neuron. 2018 May 2;98(3):495-511.e6
pubmed: 29656876
Eur J Med Genet. 2009 Mar-Jun;52(2-3):123-7
pubmed: 19332160
Hum Brain Mapp. 2015 Mar;36(3):1093-101
pubmed: 25394948
BMC Med Genet. 2013 Jul 30;14:78
pubmed: 23895108
CPT Pharmacometrics Syst Pharmacol. 2018 Aug;7(8):525-533
pubmed: 30169917
Int J Neuropsychopharmacol. 2016 Dec 30;19(12):
pubmed: 27639091
Stem Cell Reports. 2017 Nov 14;9(5):1530-1545
pubmed: 29141232
Br J Clin Pharmacol. 2016 Aug;82(2):399-411
pubmed: 27096250
J Med Genet. 2017 Sep;54(9):613-623
pubmed: 28735298
Cleve Clin J Med. 2016 Nov;83(11):810-817
pubmed: 27824534
Mol Genet Genomic Med. 2019 Jul;7(7):e00751
pubmed: 31111659
Handb Exp Pharmacol. 2006;(175):59-73
pubmed: 16722230
PLoS One. 2018 Apr 5;13(4):e0195094
pubmed: 29621262
Int J Clin Pharm. 2016 Apr;38(2):388-94
pubmed: 26830411
Br J Psychiatry. 2009 Jul;195(1):7-14
pubmed: 19567888
Neuroscience. 2011 Dec 1;197:1-7
pubmed: 22001683
Eur J Neurosci. 2014 Apr;39(7):1107-13
pubmed: 24712990
Fly (Austin). 2012 Apr-Jun;6(2):80-92
pubmed: 22728672
Drug Metab Dispos. 2010 Sep;38(9):1393-6
pubmed: 20570945
Development. 2017 Dec 15;144(24):4645-4657
pubmed: 29061638
Soc Cogn Affect Neurosci. 2014 Aug;9(8):1232-8
pubmed: 23748501
Curr Protoc Hum Genet. 2017 Oct 18;95:9.24.1-9.24.28
pubmed: 29044471
Exp Biol Med (Maywood). 2017 Feb;242(4):436-440
pubmed: 27895094
Nat Genet. 2016 Apr;48(4):367-73
pubmed: 26878724
J Comp Neurol. 1996 Jun 24;370(2):247-61
pubmed: 8808733
Mol Genet Genomic Med. 2016 Dec 26;5(2):130-140
pubmed: 28361099
ScientificWorldJournal. 2013;2013:730210
pubmed: 23365548
Mol Psychiatry. 2019 May;24(5):726-745
pubmed: 30279456
J Neurosci. 2017 Nov 8;37(45):10917-10931
pubmed: 28978667
Neuron. 2012 Apr 26;74(2):285-99
pubmed: 22542183
Brain Imaging Behav. 2016 Jun;10(2):548-58
pubmed: 26149196
Genet Med. 2011 Mar;13(3):255-62
pubmed: 21173700
Eur J Hum Genet. 2010 Nov;18(11):1216-20
pubmed: 20571508
Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5
pubmed: 24234437
Am J Hum Genet. 2006 Nov;79(5):965-72
pubmed: 17033973
J Oral Biol Craniofac Res. 2016 May-Aug;6(2):129-34
pubmed: 27195211
Gen Hosp Psychiatry. 2008 Jul-Aug;30(4):372-7
pubmed: 18585543
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Fertil Steril. 2016 Jan;105(1):134-43.e1-3
pubmed: 26450530
J Clin Pharm Ther. 2015 Dec;40(6):672-9
pubmed: 26343256
Nucleic Acids Res. 2013 Apr 1;41(6):e73
pubmed: 23325845
Neuropharmacology. 2008 Nov;55(6):932-60
pubmed: 18824000
Cereb Cortex. 2015 Sep;25(9):2529-41
pubmed: 24658585
Drug Metab Pharmacokinet. 2012;27(1):55-67
pubmed: 22185816
Int J Mol Med. 2018 Nov;42(5):2353-2362
pubmed: 30226572
Neuroscience. 2004;124(2):261-7
pubmed: 14980377
Drug Metab Dispos. 1995 Apr;23(4):441-8
pubmed: 7600909
PLoS One. 2015 May 26;10(5):e0127671
pubmed: 26010426