An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder.
Adult
Autism Spectrum Disorder
/ diagnosis
Calcium-Binding Proteins
/ genetics
Comparative Genomic Hybridization
Computational Biology
/ methods
DNA Copy Number Variations
Exons
Female
Gene Expression Profiling
Gene Regulatory Networks
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genome, Mitochondrial
Genomics
/ methods
Heterozygote
Humans
Infant
Male
Neural Cell Adhesion Molecules
/ genetics
Penetrance
Phenotype
Sequence Deletion
Exome Sequencing
NRXN1
ASD
mtDNA
penetrance
rare variants
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
24
07
2020
revised:
05
11
2020
accepted:
13
11
2020
pubmed:
22
1
2021
medline:
22
9
2021
entrez:
21
1
2021
Statut:
ppublish
Résumé
Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole-exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion-transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10
Identifiants
pubmed: 33476483
doi: 10.1111/jcmm.16161
pmc: PMC7933976
doi:
Substances chimiques
Calcium-Binding Proteins
0
NRXN1 protein, human
0
Neural Cell Adhesion Molecules
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2459-2470Subventions
Organisme : Italian Ministry of Health
ID : GR-2013-02357561
Organisme : Università di Bologna
Informations de copyright
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Références
Genet Med. 2019 Apr;21(4):816-825
pubmed: 30190612
Am J Hum Genet. 2014 May 1;94(5):677-94
pubmed: 24768552
Cell. 2019 Aug 8;178(4):850-866.e26
pubmed: 31398340
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Nat Genet. 2017 Jul;49(7):978-985
pubmed: 28504703
Am J Hum Genet. 2012 Jan 13;90(1):133-41
pubmed: 22209245
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
J Neurodev Disord. 2018 Jun 1;10(1):18
pubmed: 29859039
Nat Genet. 1999 Oct;23(2):147
pubmed: 10508508
Cell. 2020 Feb 6;180(3):568-584.e23
pubmed: 31981491
Neuron. 2000 May;26(2):443-55
pubmed: 10839362
Nature. 2012 Apr 04;485(7397):246-50
pubmed: 22495309
Nat Genet. 2019 Dec;51(12):1679-1690
pubmed: 31784728
J Cell Mol Med. 2021 Mar;25(5):2459-2470
pubmed: 33476483
Nat Genet. 2019 Jan;51(1):106-116
pubmed: 30559488
Nature. 2011 Oct 26;478(7370):483-9
pubmed: 22031440
Hum Mol Genet. 2013 Jan 15;22(2):384-90
pubmed: 23077218
Genet Med. 2017 Jan;19(1):53-61
pubmed: 27195815
Eur J Hum Genet. 2017 Jun;25(7):863-868
pubmed: 28422133
Cell. 2017 Nov 2;171(4):745-769
pubmed: 29100073
Clin Genet. 2020 Feb;97(2):338-346
pubmed: 31674007
PLoS Genet. 2013;9(8):e1003709
pubmed: 23990802
J Neurosci. 2008 Jul 9;28(28):7047-56
pubmed: 18614673
BMC Genomics. 2018 Feb 5;19(1):120
pubmed: 29402227
Bioinformatics. 2016 Jan 15;32(2):292-4
pubmed: 26428292
Am J Hum Genet. 2014 Mar 6;94(3):415-25
pubmed: 24581740
Br J Psychiatry. 2005 Dec;187:568-72
pubmed: 16319410
PLoS Genet. 2018 Feb 14;14(2):e1007210
pubmed: 29444077
Nat Med. 2015 Feb;21(2):185-91
pubmed: 25621899
Nat Neurosci. 2011 Jan;14(1):19-21
pubmed: 21170055
Am J Hum Genet. 2018 Jun 7;102(6):1031-1047
pubmed: 29754769
J Med Genet. 2013 Dec;50(12):819-22
pubmed: 24065355
Biol Psychiatry. 2010 Aug 15;68(4):320-8
pubmed: 20346443
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Patient Educ Couns. 2018 Feb;101(2):352-361
pubmed: 28803755
Nat Genet. 2017 Apr;49(4):515-526
pubmed: 28191889
Cell. 2019 Mar 21;177(1):162-183
pubmed: 30901538
MMWR Surveill Summ. 2020 Mar 27;69(4):1-12
pubmed: 32214087
Neurol Sci. 2020 Mar;41(3):699-703
pubmed: 31814071
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
Bioinformatics. 2014 Nov 1;30(21):3115-7
pubmed: 25028726
Nat Genet. 2010 Mar;42(3):203-9
pubmed: 20154674
Nature. 2014 Nov 13;515(7526):209-15
pubmed: 25363760
Mol Syst Biol. 2014 Dec 30;10:774
pubmed: 25549968
J Autism Dev Disord. 2007 Oct;37(9):1679-90
pubmed: 17146701
Nature. 2014 Nov 13;515(7526):216-21
pubmed: 25363768
Genet Med. 2011 Jul;13(7):680-5
pubmed: 21681106
Nat Genet. 2015 Jun;47(6):582-8
pubmed: 25961944
Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13039-13044
pubmed: 30478036
Mamm Genome. 2006 Jul;17(7):723-31
pubmed: 16845472
Nat Commun. 2019 Oct 15;10(1):4679
pubmed: 31616000
Nucleic Acids Res. 2016 Jul 8;44(W1):W64-9
pubmed: 27084948
J Neurosci. 2010 Nov 10;30(45):15102-12
pubmed: 21068316
Brain. 2014 Feb;137(Pt 2):335-53
pubmed: 24369379
Biol Psychiatry. 2018 May 1;83(9):722-730
pubmed: 29290371
J Med Genet. 2020 May;57(5):347-355
pubmed: 31932357
Neuron. 2013 Jan 23;77(2):259-73
pubmed: 23352163
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15161-5
pubmed: 25288738