Contribution of SHANK3 Mutations to Autism Spectrum Disorder
Rainald Moessner,Christian R. Marshall,James S. Sutcliffe,Jennifer Skaug,Dalila Pinto,John B. Vincent,Lonnie Zwaigenbaum,Bridget A. Fernandez,Wendy Roberts,Peter Szatmari,Stephen W. Scherer +10 more
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TLDR
The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.Abstract:
Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.read more
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Journal ArticleDOI
Synaptic, transcriptional and chromatin genes disrupted in autism
Silvia De Rubeis,Xin-Xin He,Arthur P. Goldberg,Christopher S. Poultney,Kaitlin E. Samocha,A. Ercument Cicek,Yan Kou,Li Liu,Menachem Fromer,Menachem Fromer,R. Susan Walker,Tarjinder Singh,Lambertus Klei,Jack A. Kosmicki,Shih-Chen Fu,Branko Aleksic,Monica Biscaldi,Patrick Bolton,Jessica M. Brownfeld,Jinlu Cai,Nicholas G. Campbell,Angel Carracedo,Angel Carracedo,Maria H. Chahrour,Andreas G. Chiocchetti,Hilary Coon,Emily L. Crawford,Lucy Crooks,Sarah Curran,Geraldine Dawson,Eftichia Duketis,Bridget A. Fernandez,Louise Gallagher,Evan T. Geller,Stephen J. Guter,R. Sean Hill,R. Sean Hill,Iuliana Ionita-Laza,Patricia Jiménez González,Helena Kilpinen,Sabine M. Klauck,Alexander Kolevzon,Irene Lee,Jing Lei,Terho Lehtimäki,Chiao-Feng Lin,Avi Ma'ayan,Christian R. Marshall,Alison L. McInnes,Benjamin M. Neale,Michael John Owen,Norio Ozaki,Mara Parellada,Jeremy R. Parr,Shaun Purcell,Kaija Puura,Deepthi Rajagopalan,Karola Rehnström,Abraham Reichenberg,Aniko Sabo,Michael Sachse,Stephen Sanders,Chad M. Schafer,Martin Schulte-Rüther,David Skuse,David Skuse,Christine Stevens,Peter Szatmari,Kristiina Tammimies,Otto Valladares,Annette Voran,Li-San Wang,Lauren A. Weiss,A. Jeremy Willsey,Timothy W. Yu,Timothy W. Yu,Ryan K. C. Yuen,Edwin H. Cook,Christine M. Freitag,Michael Gill,Christina M. Hultman,Thomas Lehner,Aarno Palotie,Aarno Palotie,Aarno Palotie,Gerard D. Schellenberg,Pamela Sklar,Matthew W. State,James S. Sutcliffe,Christopher A. Walsh,Christopher A. Walsh,Stephen W. Scherer,Michael E. Zwick,Jeffrey C. Barrett,David J. Cutler,Kathryn Roeder,Bernie Devlin,Mark J. Daly,Mark J. Daly,Joseph D. Buxbaum +99 more
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
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Advances in autism genetics: on the threshold of a new neurobiology
TL;DR: Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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Structural variation of chromosomes in autism spectrum disorder.
Christian R. Marshall,Abdul Noor,John B. Vincent,Anath C. Lionel,Lars Feuk,Jennifer Skaug,Mary Shago,Rainald Moessner,Dalila Pinto,Yan Ren,Bhooma Thiruvahindrapduram,Andreas Fiebig,Stefan Schreiber,Jan M. Friedman,Cees E.J. Ketelaars,Yvonne J. Vos,Can Ficicioglu,Susan J. Kirkpatrick,Rob Nicolson,Leon Sloman,Anne Summers,Clare A. Gibbons,Ahmad S. Teebi,David Chitayat,Rosanna Weksberg,Ann Thompson,Cathy Vardy,Vicki Crosbie,Sandra Luscombe,Rebecca Baatjes,Lonnie Zwaigenbaum,Wendy Roberts,Bridget A. Fernandez,Peter Szatmari,Stephen W. Scherer +34 more
TL;DR: The results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility.
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Neuroligins and Neurexins Link Synaptic Function to Cognitive Disease
TL;DR: This work has shown that alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.
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Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Joseph T. Glessner,Kai Wang,Guiqing Cai,Olena Korvatska,Cecilia E. Kim,Shawn Wood,Haitao Zhang,Annette Estes,Camille W. Brune,Jonathan P. Bradfield,Marcin Imielinski,Edward C. Frackelton,Jennifer Reichert,Emily L. Crawford,Jeffrey Munson,Patrick M. A. Sleiman,Rosetta M. Chiavacci,Kiran Annaiah,Kelly A. Thomas,Cuiping Hou,Wendy Glaberson,James H. Flory,Frederick G. Otieno,Maria Garris,Latha Soorya,Lambertus Klei,Joseph Piven,Kacie J. Meyer,Evdokia Anagnostou,Takeshi Sakurai,Rachel M. Game,Danielle S. Rudd,Danielle Zurawiecki,Christopher J. McDougle,Lea K. Davis,Judith Miller,David J. Posey,Shana M. Michaels,Alexander Kolevzon,Jeremy M. Silverman,Raphael Bernier,Susan E. Levy,Robert T. Schultz,Geraldine Dawson,Thomas Owley,William M. McMahon,Thomas H. Wassink,John A. Sweeney,John I. Nurnberger,Hilary Coon,James S. Sutcliffe,Nancy J. Minshew,Struan F.A. Grant,Maja Bucan,Edwin H. Cook,Joseph D. Buxbaum,Bernie Devlin,Gerard D. Schellenberg,Hakon Hakonarson +58 more
TL;DR: Several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls, and duplications 55 kilobases upstream of complementary DNA AK123120 indicate that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
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TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
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