Genomic Profiling and Functional Mutation Analysis in Autism Spectrum Disorders
Principal Investigator: MATTHEW W contact STATE
Abstract: DESCRIPTION (provided by applicant): This proposal is in response to a request for applications to address "Genomic Profiling of Mental Disorders," and proposes intensive genomic profiling and functional analysis of Contactin Associated Protein 2 (CNTNAP2) as well as the presynaptic cytomatrix protein Piccolo (PCLO), in an effort to clarify their roles in Autism Spectrum Disorders (ASD). In addition, the application proposes to deeply sequence genes in the Contactin and Contactin Associated pathways, as well as genes coding for proteins known to interact with PCLO. We propose to leverage ongoing collaborations among the State, De Camilli and Giraldez labs at Yale to allow for rapid functional assays (both in vitro and in vivo) of identified rare sequence mutations, which will be used to clarify genomic findings and to confirm the relevance of rare mutations for disease risk. The organizing principles supporting this application are as follows: 1) Rare genetic variation is likely to play a significant role in the etiology of ASD;2) Methods of detecting rare (MAF<5%) and very rare (MAF<1%) variation in large numbers of patients and controls are now economically and technically feasible;3) Rare and very rare variations, including those in highly conserved coding regions, are widespread throughout the genomes of both affected and unaffected individuals;4) Rare and very rare alleles of intermediate effect will likely require association as opposed to linkage strategies to evaluate disease risk;and 5) That among the most pressing issues at this stage in the success of genomic profiling of mental disorders are differentiating disease-related mutations from low frequency neutral mutations and addressing the methodolgical challenges of assessing disease association in the case of rare and very rare alleles. This application proposes to address these issues as follows: 1) Deep-resequencing using next generation technologies to identify rare and very rare mutations in a large, extremely well-characterized and carefully ethnically matched case-control sample;2) To use quantitative ASD phenotyping in addition to categorical diagnoses in an effort to enhance the power of case-control association of rare variants;3) To leverage well established association methodologies, including genomic control, mutation burden analyses for very rare mutations, correction for multiple comparisons and replication samples, to decrease type 1 error;4) To use both in vitro and in vivo methods to evaluate the functional consequences of rare mutations identified in cases and controls, specifically in the genes CNTNAP2 and PCLO;and importantly, 5) To test the hypothesis that functional assays stratifying rare functional from neutral variation in CNTNAP2 will clarify the results of association analyses, as has been successfully employed in other rare variant studies (1). PUBLIC HEALTH RELEVANCE: This study seeks to identify the role of specific genes in Autism Spectrum Disorders. The research plan utilizes high throughput sequencing technologies and combines these with molecular in vitro and in vivo biological studies in an effort to clarify the precise contribution of two brain expressed molecules Contactin Associated Protein 2 and Picollo as well as related genes to Autism and related conditions.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
- The genetics of child psychiatric disorders: focus on autism and Tourette syndromeMatthew W State
Department of Child Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA
Neuron 68:254-69. 2010....
- Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsyGaia Novarino
Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
Science 338:394-7. 2012..Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome...
- Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autismA Jeremy Willsey
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA
Cell 155:997-1007. 2013..This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology. ..
- Recent challenges to the psychiatric diagnostic nosology: a focus on the genetics and genomics of neurodevelopmental disordersYoung Shin Kim
Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA, Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea and Department of Psychiatry, University of California, San Francisco, CA, USA
Int J Epidemiol 43:465-75. 2014....
- MicroRNAs as genetic sculptors: fishing for cluesCarter M Takacs
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
Semin Cell Dev Biol 21:760-7. 2010..This review will focus on the role that the teleost Danio rerio (zebrafish) has played in shaping our understanding of miRNA function in vertebrates...
- The genetics of autism: key issues, recent findings, and clinical implicationsPaul El-Fishawy
Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA
Psychiatr Clin North Am 33:83-105. 2010..This article reviews the origins of the common versus rare variant debate, highlights recent findings in the field, and addresses the clinical implications of common and rare variant discoveries...
- Selection-free zinc-finger-nuclease engineering by context-dependent assembly (CoDA)Jeffry D Sander
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA
Nat Methods 8:67-9. 2011..The simplicity and efficacy of CoDA will enable broad adoption of ZFN technology and make possible large-scale projects focused on multigene pathways or genome-wide alterations...
- The conundrums of understanding genetic risks for autism spectrum disordersMatthew W State
Program on Neurogenetics, Departments of Child Psychiatry, Psychiatry and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
Nat Neurosci 14:1499-506. 2011....