Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential intere...
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2009
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oai:doaj.org-article:ef6efa22e8c1433a95092439816543662021-11-25T05:53:20ZGenome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.1553-73901553-740410.1371/journal.pgen.1000536https://doaj.org/article/ef6efa22e8c1433a95092439816543662009-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19557195/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.Maja BucanBrett S AbrahamsKai WangJoseph T GlessnerEdward I HermanLisa I SonnenblickAna I Alvarez RetuertoMarcin ImielinskiDexter HadleyJonathan P BradfieldCecilia KimNicole B GidayaIngrid LindquistTed HutmanMarian SigmanVlad KustanovichClara M LajonchereAndrew SingletonJunhyong KimThomas H WassinkWilliam M McMahonThomas OwleyJohn A SweeneyHilary CoonJohn I NurnbergerMingyao LiRita M CantorNancy J MinshewJames S SutcliffeEdwin H CookGeraldine DawsonJoseph D BuxbaumStruan F A GrantGerard D SchellenbergDaniel H GeschwindHakon HakonarsonPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 5, Iss 6, p e1000536 (2009) |
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Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Maja Bucan Brett S Abrahams Kai Wang Joseph T Glessner Edward I Herman Lisa I Sonnenblick Ana I Alvarez Retuerto Marcin Imielinski Dexter Hadley Jonathan P Bradfield Cecilia Kim Nicole B Gidaya Ingrid Lindquist Ted Hutman Marian Sigman Vlad Kustanovich Clara M Lajonchere Andrew Singleton Junhyong Kim Thomas H Wassink William M McMahon Thomas Owley John A Sweeney Hilary Coon John I Nurnberger Mingyao Li Rita M Cantor Nancy J Minshew James S Sutcliffe Edwin H Cook Geraldine Dawson Joseph D Buxbaum Struan F A Grant Gerard D Schellenberg Daniel H Geschwind Hakon Hakonarson Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| description |
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts. |
| format |
article |
| author |
Maja Bucan Brett S Abrahams Kai Wang Joseph T Glessner Edward I Herman Lisa I Sonnenblick Ana I Alvarez Retuerto Marcin Imielinski Dexter Hadley Jonathan P Bradfield Cecilia Kim Nicole B Gidaya Ingrid Lindquist Ted Hutman Marian Sigman Vlad Kustanovich Clara M Lajonchere Andrew Singleton Junhyong Kim Thomas H Wassink William M McMahon Thomas Owley John A Sweeney Hilary Coon John I Nurnberger Mingyao Li Rita M Cantor Nancy J Minshew James S Sutcliffe Edwin H Cook Geraldine Dawson Joseph D Buxbaum Struan F A Grant Gerard D Schellenberg Daniel H Geschwind Hakon Hakonarson |
| author_facet |
Maja Bucan Brett S Abrahams Kai Wang Joseph T Glessner Edward I Herman Lisa I Sonnenblick Ana I Alvarez Retuerto Marcin Imielinski Dexter Hadley Jonathan P Bradfield Cecilia Kim Nicole B Gidaya Ingrid Lindquist Ted Hutman Marian Sigman Vlad Kustanovich Clara M Lajonchere Andrew Singleton Junhyong Kim Thomas H Wassink William M McMahon Thomas Owley John A Sweeney Hilary Coon John I Nurnberger Mingyao Li Rita M Cantor Nancy J Minshew James S Sutcliffe Edwin H Cook Geraldine Dawson Joseph D Buxbaum Struan F A Grant Gerard D Schellenberg Daniel H Geschwind Hakon Hakonarson |
| author_sort |
Maja Bucan |
| title |
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| title_short |
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| title_full |
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| title_fullStr |
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| title_full_unstemmed |
Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| title_sort |
genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/ef6efa22e8c1433a9509243981654366 |
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