Rare Deletions at the Neurexin 3 Locus in Autism Spectrum Disorder
Andrea K. Vaags,Anath C. Lionel,Anath C. Lionel,Daisuke Sato,McKinsey L. Goodenberger,Quinn Stein,Sarah Curran,Caroline Mackie Ogilvie,Joo Wook Ahn,Irene Drmic,Lili Senman,Christina Chrysler,Ann Thompson,Carolyn Russell,Aparna Prasad,Susan Walker,Dalila Pinto,Christian R. Marshall,Dimitri J. Stavropoulos,Lonnie Zwaigenbaum,Bridget A. Fernandez,Eric Fombonne,Patrick Bolton,David A. Collier,Jennelle C. Hodge,Wendy Roberts,Peter Szatmari,Stephen W. Scherer,Stephen W. Scherer +28 more
TLDR
This report presents clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3.Abstract:
The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3–31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.read more
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Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders.
Sacha B. Nelson,Vera Valakh +1 more
TL;DR: The contrasting evidence for primary defects in inhibition or excitation in ASDs is explored and the findings are integrated in terms of the brain's ability to maintain functional homeostasis.
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Advancing the understanding of autism disease mechanisms through genetics
TL;DR: Current understanding of the genetic architecture of ASD is reviewed and genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology are integrated.
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Genetics of autism spectrum disorders.
TL;DR: Findings demonstrate that ASD is etiologically heterogeneous and diverse genetic and genomic approaches provide evidence converging on disruption of key biological pathways, many of which are also implicated in other allied neurodevelopmental disorders.
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Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits
TL;DR: Neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.
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Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease
David Neil Cooper,Michael Krawczak,Constantin Polychronakos,Chris Tyler-Smith,Hildegard Kehrer-Sawatzki +4 more
TL;DR: The evidence for reduced penetrance being a widespread phenomenon in human genetics is summarized and some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease are explored.
References
More filters
Journal ArticleDOI
Detection of large-scale variation in the human genome.
A. John Iafrate,Lars Feuk,Miguel Rivera,Miguel Rivera,Marc L. Listewnik,Patricia K. Donahoe,Ying Qi,Stephen W. Scherer,Charles Lee,Charles Lee +9 more
TL;DR: This article identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals, and revealed that half of these regions overlap with genes, and many coincide with segmental duplications or gaps in human genome assembly.
Journal ArticleDOI
The Wellcome Trust Case Control Consortium, U.K.
TL;DR: This article reports that the magazine's award for Research Leader of the Year was given to the Wellcome Trust Case Control Consortium which conducted a huge genetic study to look at the genetic causes for various diseases.
Journal ArticleDOI
Integrating common and rare genetic variation in diverse human populations
David Altshuler,Richard A. Gibbs,Leena Peltonen,Emmanouil T. Dermitzakis,Stephen F. Schaffner,Fuli Yu,Penelope E. Bonnen,de Bakker Piw.,Panagiotis Deloukas,Stacey Gabriel,R. Gwilliam,Sarah E. Hunt,Michael Inouye,Xiaoming Jia,Aarno Palotie,Melissa Parkin,Pamela Whittaker,Kyle Chang,Alicia Hawes,Lora Lewis,Yanru Ren,D Wheeler,Donna M. Muzny,Chris P. Barnes,Katayoon Darvishi,Matthew E. Hurles,Joshua M. Korn,K. Kristiansson,Charles Lee,S A McCarrol,James Nemesh,Alon Keinan,Stephen B. Montgomery,Samuela Pollack,Alkes L. Price,Nicole Soranzo,Claudia Gonzaga-Jauregui,Verneri Anttila,Wendy Brodeur,Mark J. Daly,Stephen Leslie,Gil McVean,Loukas Moutsianas,Huy Nguyen,Qingrun Zhang,Ghori Mjr.,Ralph McGinnis,William M. McLaren,Fumihiko Takeuchi,Sharon R. Grossman,Ilya Shlyakhter,Elizabeth Hostetter,Pardis C. Sabeti,Clement Adebamowo,Morris W. Foster,Deborah R. Gordon,Julio Licinio,M C Manca,Patricia A. Marshall,Ichiro Matsuda,D Ngare,Vivian Ota Wang,D Reddy,Charles N. Rotimi,Charmaine D.M. Royal,Richard R. Sharp,Changqing Zeng,Lisa D. Brooks,Jean E. McEwen +68 more
TL;DR: An expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.
Journal ArticleDOI
Strong Association of De Novo Copy Number Mutations with Autism
Jonathan Sebat,B. Lakshmi,Dheeraj Malhotra,Jennifer Troge,Christa Lese-Martin,Tom Walsh,Boris Yamrom,Seungtai Yoon,Alexander Krasnitz,Jude Kendall,Anthony Leotta,Deepa Pai,Ray Zhang,Yoon-ha Lee,James W. Hicks,Sarah J. Spence,Annette Lee,Kaija Puura,Terho Lehtimäki,David H. Ledbetter,Peter K. Gregersen,Joel D. Bregman,James S. Sutcliffe,Vaidehi Jobanputra,Wendy K. Chung,Dorothy Warburton,Mary Claire King,David Skuse,Daniel H. Geschwind,T. Conrad Gilliam,Kenny Ye,Michael Wigler +31 more
TL;DR: Findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Journal ArticleDOI
Functional impact of global rare copy number variation in autism spectrum disorders
Dalila Pinto,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Tiago R. Magalhaes,Catarina Correia,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Geraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,Christine M. Freitag,John Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hakon Hakonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Katerina Papanikolaou,Jeremy R. Parr,Barbara Parrini,Tara Paton,Andrew Pickles,Marion Pilorge,Joseph Piven,Chris P. Ponting,David J. Posey,Annemarie Poustka,Fritz Poustka,Aparna Prasad,Jiannis Ragoussis,Katy Renshaw,Jessica Rickaby,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman Van Engeland,John B. Vincent,Fred R. Volkmar,Simon Wallace,Kai Wang,Zhouzhi Wang,Thomas H. Wassink,Caleb Webber,Rosanna Weksberg,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Jing Wu,Brian L. Yaspan,Danielle Zurawiecki,Lonnie Zwaigenbaum,Joseph D. Buxbaum,Rita M. Cantor,Edwin H. Cook,Hilary Coon,Michael L. Cuccaro,Bernie Devlin,Sean Ennis,Louise Gallagher,Daniel H. Geschwind,Michael Gill,Jonathan L. Haines,Joachim Hallmayer,Judith Miller,Anthony P. Monaco,John I. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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