Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.

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...

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Autores principales:	Maria Tropeano, Joo Wook Ahn, Richard J B Dobson, Gerome Breen, James Rucker, Abhishek Dixit, Deb K Pal, Peter McGuffin, Anne Farmer, Peter S White, Joris Andrieux, Evangelos Vassos, Caroline Mackie Ogilvie, Sarah Curran, David A Collier
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49c7f56bc6bd4332b987a49bb5d588de
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spelling	oai:doaj.org-article:49c7f56bc6bd4332b987a49bb5d588de2021-11-18T07:48:54ZMale-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.1932-620310.1371/journal.pone.0061365https://doaj.org/article/49c7f56bc6bd4332b987a49bb5d588de2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637818/?tool=EBIhttps://doaj.org/toc/1932-6203Copy 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.Maria TropeanoJoo Wook AhnRichard J B DobsonGerome BreenJames RuckerAbhishek DixitDeb K PalPeter McGuffinAnne FarmerPeter S WhiteJoris AndrieuxEvangelos VassosCaroline Mackie OgilvieSarah CurranDavid A CollierPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e61365 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Tropeano Joo Wook Ahn Richard J B Dobson Gerome Breen James Rucker Abhishek Dixit Deb K Pal Peter McGuffin Anne Farmer Peter S White Joris Andrieux Evangelos Vassos Caroline Mackie Ogilvie Sarah Curran David A Collier Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
description	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.
format	article
author	Maria Tropeano Joo Wook Ahn Richard J B Dobson Gerome Breen James Rucker Abhishek Dixit Deb K Pal Peter McGuffin Anne Farmer Peter S White Joris Andrieux Evangelos Vassos Caroline Mackie Ogilvie Sarah Curran David A Collier
author_facet	Maria Tropeano Joo Wook Ahn Richard J B Dobson Gerome Breen James Rucker Abhishek Dixit Deb K Pal Peter McGuffin Anne Farmer Peter S White Joris Andrieux Evangelos Vassos Caroline Mackie Ogilvie Sarah Curran David A Collier
author_sort	Maria Tropeano
title	Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
title_short	Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
title_full	Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
title_fullStr	Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
title_full_unstemmed	Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
title_sort	male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/49c7f56bc6bd4332b987a49bb5d588de
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_version_	1718422907936309248

Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.

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