title: Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
abstract: Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.
authors: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK. maria.tropeano@kcl.ac.uk
authors: Maria
authors: M
authors: Tropeano
authors: Joo Wook
authors: JW
authors: Ahn
authors: Richard J B
authors: RJ
authors: Dobson
authors: Gerome
authors: G
authors: Breen
authors: James
authors: J
authors: Rucker
authors: Abhishek
authors: A
authors: Dixit
authors: Deb K
authors: DK
authors: Pal
authors: Peter
authors: P
authors: McGuffin
authors: Anne
authors: A
authors: Farmer
authors: Peter S
authors: PS
authors: White
authors: Joris
authors: J
authors: Andrieux
authors: Evangelos
authors: E
authors: Vassos
authors: Caroline Mackie
authors: CM
authors: Ogilvie
authors: Sarah
authors: S
authors: Curran
authors: David A
authors: DA
authors: Collier
mesh_terms: D002648:Child; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D010641:Phenotype
references: Mol Psychiatry. 2011 Mar;16(3):293-306
references: 20048751
references: Nat Rev Genet. 2008 Dec;9(12):911-22
references: 19002143
references: Mol Psychiatry. 2005 Jul;10(7):657-68, 616
references: 15838535
references: Hum Mol Genet. 2007 Mar 1;16(5):453-62
references: 17185386
references: Nat Genet. 2008 Dec;40(12):1392-3
references: 19029974
references: Am J Hum Genet. 2009 Feb;84(2):148-61
references: 19166990
references: Nat Genet. 2004 Sep;36(9):949-51
references: 15286789
references: Nature. 2004 Dec 23;432(7020):988-94
references: 15616553
references: PLoS Genet. 2010 May 20;6(5):e1000962
references: 20502679
references: Genome Res. 2006 Aug;16(8):949-61
references: 16809666
references: Am J Hum Genet. 2009 Apr;84(4):524-33
references: 19344873
references: Nature. 2008 Sep 11;455(7210):237-41
references: 18668038
references: Nat Genet. 2000 Jun;25(2):228-31
references: 10835643
references: Am J Med Genet A. 2010 Nov;152A(11):2820-6
references: 20830801
references: Nat Genet. 2008 Oct;40(10):1166-74
references: 18776908
references: Biol Psychiatry. 2010 Feb 1;67(3):283-6
references: 19880096
references: Psychol Med. 1986 May;16(2):461-5
references: 3726017
references: Mol Psychiatry. 2013 Feb;18(2):183-9
references: 22042228
references: Am J Hum Genet. 2003 Jul;73(1):34-48
references: 12802786
references: Mol Psychiatry. 2011 Jan;16(1):17-25
references: 19786961
references: Neuron. 2011 Jun 9;70(5):898-907
references: 21658583
references: Mol Psychiatry. 2008 Feb;13(2):173-86, 115
references: 17848917
references: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9270-4
references: 20439718
references: Nat Genet. 2006 Mar;38(3):343-9
references: 16444274
references: Am J Hum Genet. 2011 May 13;88(5):523-35
references: 21529752
references: Neuron. 2011 Jun 9;70(5):863-85
references: 21658581
references: Mol Psychiatry. 2005 Dec;10(12):1097-103
references: 16103888
references: Hum Mol Genet. 2009 Apr 15;18(8):1497-503
references: 19181681
references: Epidemiol Rev. 2008;30:67-76
references: 18480098
references: Hum Mutat. 2007 Jul;28(7):674-82
references: 17480035
references: Nat Rev Neurosci. 2001 Jun;2(6):408-16
references: 11389474
references: Epigenetics. 2011 Jul;6(7):857-61
references: 21617370
references: J Med Genet. 2009 Apr;46(4):223-32
references: 18550696
references: Hum Mol Genet. 2007 Oct 15;16(20):2517-28
references: 17673452
references: Mol Cytogenet. 2010 Oct 13;3:19
references: 20942916
references: J Clin Psychol. 1984 Nov;40(6):1365-7
references: 6511949
references: Neuron. 2011 Jun 9;70(5):886-97
references: 21658582
references: PLoS Genet. 2011 Jun;7(6):e1002118
references: 21698135
references: Nat Rev Genet. 2006 Feb;7(2):85-97
references: 16418744
references: Dev Med Child Neurol. 2008 Jan;50(1):15-8
references: 18173623
references: Am J Hum Genet. 2010 May 14;86(5):707-18
references: 20398883
references: Mol Cytogenet. 2010 Apr 15;3:9
references: 20398301
references: Science. 2004 Jul 23;305(5683):525-8
references: 15273396
references: Hum Mol Genet. 2006 Oct 15;15(20):3024-33
references: 16959794
references: Lancet. 2010 Oct 23;376(9750):1401-8
references: 20888040
references: PLoS One. 2012;7(4):e34813
references: 22523559
references: Annu Rev Genomics Hum Genet. 2002;3:199-242
references: 12142364
references: Biochem Biophys Res Commun. 2008 Dec 26;377(4):1091-6
references: 18983980
references: Hum Mol Genet. 2001 Dec 1;10(25):2933-44
references: 11741836
references: Am J Hum Genet. 2012 Jan 13;90(1):133-41
references: 22209245
references: Nat Genet. 2011 Aug 14;43(9):838-46
references: 21841781
references: Cereb Cortex. 2011 May;21(5):1134-46
references: 20943668
references: Handb Exp Pharmacol. 2011;(201):299-323
references: 21103974
references: Trends Genet. 2009 Apr;25(4):152-5
references: 19285746
references: BMC Genomics. 2009 Dec 08;10:588
references: 19995423
references: J Am Acad Child Adolesc Psychiatry. 2012 Aug;51(8):756-8
references: 22840545
references: Nat Genet. 2010 Mar;42(3):203-9
references: 20154674
references: Am J Hum Genet. 2011 May 13;88(5):536-47
references: 21529751
references: Brain. 2010 Jan;133(Pt 1):23-32
references: 19843651
references: Mol Psychiatry. 2008 Feb;13(2):187-96
references: 17579608
references: PLoS Biol. 2011 Jun;9(6):e1001081
references: 21695109
references: Science. 2005 Nov 4;310(5749):819-23
references: 16272115
references: Mol Cell Biol. 2000 Jun;20(11):4135-48
references: 10805755
references: Nat Genet. 2006 Feb;38(2):218-22
references: 16429159
references: Hum Mol Genet. 2010 Sep 1;19(17):3477-81
references: 20587603
references: Nature. 2008 Sep 11;455(7210):232-6
references: 18668039
references: Learn Mem. 2000 Sep-Oct;7(5):279-86
references: 11040259
references: Brain Res. 2001 Feb 23;892(2):336-43
references: 11172781
references: Hum Mol Genet. 2003 Dec 1;12(23):3151-9
references: 14532331
references: Epilepsia. 2012 Feb;53(2):308-18
references: 22242659
references: Eur J Hum Genet. 2011 Mar;19(3):280-6
references: 21150890
references: J Neurosci. 2011 Jun 15;31(24):9043-54
references: 21677187
references: Science. 2007 Apr 20;316(5823):445-9
references: 17363630
references: Neuron. 2004 Oct 14;44(2):279-93
references: 15473967
references: Schizophr Res. 2008 Dec;106(2-3):125-31
references: 18829262
references: Genome Res. 2009 Sep;19(9):1682-90
references: 19592680