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Baylor College of Medicine, Houston , TX

Principal Investigator: Arthur Beaudet, M.D.

Search for an Autism Gene on the Y Chromosome (funded through NAAR)

The male to female ratio in autism is 4:1 in the global autistic population. Despite this gender difference, male predisposition to autistic disorder has not been explained. The reduced rate at which people with autism have children makes vertical transmission uncommon and genetic analysis confusing. Furthermore, genome scans based on linkage analysis cannot study the non-recombining region of the Y chromosome and the lack of Y linkage in these studies does not rule out the possibility of susceptibility loci for autism on this chromosome. Dr. Beaudet proposes that a dysfunction of genes involved in synapse function and located on the Y chromosome can cause autism. To analyze for a Y chromosome effect in autism, Dr. Beaudet will screen Y chromosome haplotypes in subjects with autism and controls by using Y-polymorphic markers looking for specific haplogroups that could be associated with autism. Dr. Beaudet is also testing the hypothesis that the Y-linked SYBLI and NLGN4Y genes, whose products are molecules involved in the vesicular trafficking and synaptogenesis, are candidate genes for involvement in autism.

Arthur Beaudet

Beth Israel Deaconess Medical Center, Boston, MA

Principal Investigator: Christopher Walsh, M.D., Ph.D.

Recessive Genes for Autism and Mental Retardation (Co-funded with The Simons Foundation)

Twin studies suggest that autism has a large genetic component; however, few potential autism susceptibility genes have been identified. The goal of this project is to use special genetic populations to map and identify autism spectrum disorders (ASD) genes to better understand their classification, pathogenesis, and potential treatments. Preliminary data show that the large families and patterns of consanguinity that characterize special populations such as the Arabic countries of the Middle East facilitate the recognition of recessively inherited neurological disorders. The investigator will identify appropriate pedigrees that show children with autism, and in which parents are related to one another, suggesting that recessively acting genes may be causing ASD in those families. He will then take advantage of this consanguinity to map and hopefully clone these recessive ASD genes. The investigator will focus on Arabic populations of the Middle East since these populations also show “founder mutations” which are restricted to certain groups, and which further facilitate precise gene mapping. This study may provide new insights into patterns of inheritance and genetic causes of autism spectrum disorders.

Christopher A. Walsh Laboratory

Broad Institute, Massachusetts Institute of Technology, Cambridge , MA

Principal Investigators: David H. Skuse, M.D., Ph.D., Eric Lander, Ph.D, Pamela Sklar, M.D., Ph.D.

Confirmatory study of influence of EFHC2 genetic variant on complex phenotype in x-monosomic females

This research aims to identify genetic influences in the development and function of neural systems that may be disrupted in individuals with impaired social and cognitive functions by studying individuals with Turners syndrome, a condition in which one of the two X chromosomes normally found in females is missing or incomplete. Because individuals with Turner syndrome have similar social cognitive deficits as many individuals with autism, and because autism is a condition in which males outnumber females significantly, the results of this research may shed light on genetic vulnerability to autism. The goal is to map a genetic locus to the X-chromosome associated with emotion-processing deficits in individuals with Turner syndrome. Researchers intend to investigate through a replication study, the hypothesis that the EFHC2 gene contributes to social cognitive difficulties in Turner syndrome, and the hypothesis that specific allelic variants in the gene contribute to vulnerability to autism.

Broad Institute of MIT and Harvard

Lander Laboratory

Pamela Sklar

Children's Hospital, Boston, MA

Principal Investigator: Isaac Kohane, M.D, Ph.D.

Small RNAs and Editing in Autistic Brains

Autism is a common neurodevelopmental disorder characterized by a spectrum of social deficits, communication impairments, stereotyped interests, and repetitive behavior. Twin and family studies provide substantial evidence that autism is among the most heritable complex disorders, but the molecular mechanism underlying the majority of autism cases remains unknown. Understanding the genetic basis of autism is needed to improve diagnosis and provide critical targets for intervention and prevention. The long-term goal of this research is to characterize the genetic and molecular mechanisms that predispose to autism spectrum disorders (ASD). The objective of this research project is to investigate the involvement of RNA-mediated post-transcriptional regulation in ASD. MicroRNAs (miRNAs) and small nucleolar RNAs (snoRNAs) are gaining increasing recognition for their key role in orchestrating complex brain development. Both molecules are heavily involved in A-to-I editing, which is crucial for appropriate animal behavior. As the regulators affect multiple transcripts, each subject to sequence variation of its own, the investigators hypothesize that alterations in these upstream regulatory mechanisms can account for the broad phenotypic spectrum and complex inheritance pattern observed in autism.

Isaac Kohane

Children's Hospital, Boston, MA

Principal Investigators: Michael E. Greenberg, Ph.D., Isaac Kohane, M.D, Ph.D., Louis M. Kunkel, Ph.D.

Genetic Studies of Autism Spectrum Disorders

This study will utilize genetics, bioinformatics, and neuroscience programs at Children's Hospital-Boston to address the genetic basis of autism spectrum disorders (ASD). One hypothesis of this study is that there are genetic variants that may predispose an individual to develop ASD, and that these genes can be identified by transmission disequilibrium testing (TDT) of candidate genes in pathways logically indicated based on gene expression and neuronal activity studies. Using TDT and trios (child with autism and their parents), and affected sib pairs (ASP) analysis, studies will be performed to look for association of ASD with candidate genes and for linkage peaks associated with ASD. Another hypothesis of this study is that there are differences in gene expression in the white blood cells of children with autism in comparison with normal children. Microarray analysis will be performed to study differences in gene expression in white blood cells of children with autism compared with that of normal children. Sparked by evidence that autism may be caused by defective synaptic maturation and the finding that activity-dependent gene transcription plays a role in synapse maturation, a third hypothesis of this study is that mutations of transcriptional regulators and their target genes may underlie some forms of autism.

Michael Greenberg

Isaac Kohane

Louis Kunkel

Massachusetts General Hospital, Boston, MA

Principal Investigator: Susan Santangelo, Sc.D.
Co-Investigators: Iain Fraser, MBCHB, D. Phil, Katherine Tsatsanis, Ph.D.

The Establishment of a Well-Characterized Cohort for Autism Studies at the Massachusetts General Hospital

This project will establish a well-characterized and documented patient sample and database that will allow investigators to begin a multidisciplinary, comprehensive program designed to elucidate underlying mechanisms important in the manifestation of autism. The investigators envision the establishment of a repository of genotypic and phenotypic information which will serve the needs of researchers interested in the neurobiology of the disorder. The patient sample and database will be developed from the patient population of the Learning and Developmental Disabilities Evaluation and Rehabilitation Service (LADDERS) program. In one year, 75 individuals with autism and their immediate family members who seek treatment at the LADDERS program will be recruited and expertly phenotyped with measures that will support a myriad of studies investigating the etiology of autism. A comprehensive database will be created that will contain all of the phenotypic and genetic information for these families. Both quantitative and qualitative phenotypes will be assessed for individuals with autism, their siblings and parents. All of the individuals with autism will be examined for evidence of gastrointestinal difficulties, immune dysfunction, and medical problems that may be associated with mitochondrial disorders. A permanent bank of cell lines will be established from recruited families to support gene mapping studies and DNA, RNA and protein level analyses in the future.

Susan Santangelo

Massachusetts Institute of Technology, Picower Institute for Learning and Memory, Cambridge, MA
2009- 2010

Principal Investigator: Damon Page, Ph.D.

MAPK3 as a Chr 16p11.2 Autism Candidate Gene

The chromosomal region of 16p11.2 has emerged from genetic screening in humans as a significant susceptibility locus for ASD. This interval contains 25 genes; however, the link between these genes and the symptoms of ASD is not clear. This project seeks to bridge this gap in our understanding by investigating the role of candidate genes from the 16p11.2 region in the development of brain and behavior, using the mouse as a model system. The first candidate gene that Dr. Page will focus on is MAPK3. He selected this gene as a candidate for the following reasons: 1) He had previously found that ERK, the Drosophila homologue of MAPK3, influences regionalized growth in the embryonic brain by controlling proliferation of specific populations of neural stem cells in response to activation of the receptor tyrosine kinase EGFR in these cells (Page, 2003), 2) MAPK3 is known to act in the PTEN/PI3K pathway to influence a variety of cellular processes relevant to growth (Cully et al., 2006). Dr. Page has found that haploinsufficiency for Pten leads to brain overgrowth as well as social behavioral deficits (Page et al., 2009), two phenotypes relevant to ASD. And, 3) MAPK3 acts in several additional pathways that have been implicated in ASD pathogenesis, including: Serotonin (Launay et al., 1996), Oxytocin (Blume et al., 2008) and IL-6/immune signaling (D'Arcangelo et al., 2000). Dr. Page’s studies indicate that Pten intersects with these pathways in the developing brain. Thus, the possibility that MAPK3 might act as an intermediary across these pathways is one worth exploring. As an initial investigation of the function of Mapk3 in ASD-relevant endophenotypes, Dr. Page will make use of assays of social approach behavior and brain growth.

Damon Page

North Shore Long Island Jewish Research Institute, Manhasset , New York

Principal Investigator: Peter K. Gregersen, M.D.

Autism and Absolute Pitch

This project is based on the hypothesis that there are common genetic factors involved in autism and a rare cognitive ability in normal subjects known as absolute pitch (also called "perfect pitch"). This research will utilize an internet-based test which can detect absolute pitch ability without the need to know conventional musical designations for pitch. Using this test, individuals with autism and their family members will be formally tested for absolute pitch ability. Researchers will investigate whether genes that may carry predisposition to absolute pitch are also involved in genetic predisposition to autism. This project may provide insight into the genetics of autism by studying a readily measurable trait (absolute pitch) to identify candidate genes.

North Shore Long Island Jewish Health System

Princeton University , Princeton , NJ



Principal Investigators: Arnold J. Levine, Ph.D. & Daniel A. Notterman, MD


Autism and Single Nucleotide Polymorphisms in the IGF Pathway (Co-funded with

The Simons Foundation)



This project's goal is to test the frequencies of single nucleotide polymorphisms (SNPs) in selected genes that populate the IGF-1, mTor and p53 interrelated signal transduction pathways in individuals with autism spectrum disorder. The IGF-1, mTor and p53 networks are known to act in the central nervous system (CNS) and regulate cell growth and size, dendrite formation, metabolic capabilities, glucose and amino acid use, stress and cell/DNA damage. It has become apparent that there are connections between the IGF-1-PI3K-AKT (cell growth, anti-apoptotic), mTor (glucose and amino acid sensing, autophagy control, metabolic regulation) and the p53 (stresses of many kinds-oxidative, hypoxia, DNA damage, etc leading to apoptosis and senescence) pathways. These three inter-related networks play a role in cancer; they are involved in diabetes and glucose utilization by cells, and they affect longevity. Several lines of evidence suggest that this same critical set of genes can act in the CNS to contribute to autism. For example, 60% of individuals with either TSC-1 or TSC-2 mutations have autism; some individuals with mutations in the PTEN gene develop autism, and a knock-out of the PTEN gene activity in the CNS of mice alters the structure of the CNS and results in behavioral abnormalities in these mice. Thus, the genes in these networks are interesting candidates whose alleles might contribute to autism or ASD. Initially, the PIs will examine possible increased frequencies of SNPs and haplotypes from each gene separately. Later, combinations of SNPs, haplotypes and genes will be examined for enhanced frequency in the autistic group. When the PIs are confident that a SNP or a haplotype is contributing to the autistic phenotype, they will explore the molecular effect of the SNP. Looking for polymorphisms in these candidate genes will complement other ongoing studies to track down mutations that contribute to autism spectrum disorder.

Arnold Levine

Daniel Notterman

University College London , Behavioral and Brain Sciences Unit / Institute of Child Health, London , UK

Principal Investigator: David H. Skuse, M.D.

A Family Study of Genetic Susceptibility to Autistic Traits

Research has shown that not everyone who has the genetic susceptibility to autism will become autistic. It is believed that gene discovery in autism could be facilitated by use of endophenotypes in linkage and association studies. Endophenotypes are hidden indicators of genetic susceptibility reflecting underlying disruption to covert processes such as cognition, and they are not directly correlated with behavioral expression of risk. The goal of this research is to test the hypothesis that genetic susceptibility to a social-cognitive endophenotype in children with autism and their first degree relatives is due to allelic variance in the same risk haplotypes that are of relevance to Turner syndrome. The long term goal is to discover specific genes that influence development of social cognition in males and females and which increase susceptibility to autism in families with a child with autism.

UCL Institute of Child Health

University of Cambridge Autism Research Centre, Cambridge , UK

Principal Investigator: Simon Baron-Cohen, Ph.D.

A Genetic Study of Mathematical Talent and Asperger's Syndrome

Autism spectrum disorders often involve impaired empathy and intact or talent in systemizing. Research has suggested a link between talent in systemizing and the likelihood of autism in a family. This suggests that one of the genes involved in autism may be the gene (or genes) that underlie systemizing talent. This research attempts to identify genes associated with a well-defined example of systemizing talent, mathematical giftedness. Researchers will obtain DNA from large families where there are many gifted mathematicians, and will re-test any significant regions of the DNA in detail in a sample of mathematicians vs. non-mathematicians. Researchers are also studying DNA of people with Asperger Syndrome (AS) to see if the genes for systemizing are implicated in the genes for AS. Genetic research may improve early diagnosis of autism spectrum conditions.

Autism Research Centre

Simon Baron-Cohen

University of Cambridge, Cambridge, UK

Principal Investigator: Lindsey Kent, MBChB., PhD. MRC Psych

Investigation of Imprinted Chromosomal Regions and Mitochondrial Haplotypes in Autism

Autism is a developmental condition that may impair social development, communication, and may be accompanied by narrow interests and repetitive activity. Twin and family studies demonstrate a genetic contribution to autistic spectrum disorders (ASD’s). Although substantial effort is aimed at identifying these susceptibility genes, there is no unequivocal evidence to implicate a particular gene. This study proposes two novel approaches to investigating possible genetic risk factors. Firstly, ASD’s are known to occur in a number of disorders which arise from individuals possessing extra genetic material such as chromosomal duplications. The overgrowth condition known as Beckwith Weidemann syndrome (BWS) can occur in individuals who inherit two copies of a part of chromosome 11 from their father. The researcher has recently found that a number of these BWS individuals also have autism, suggesting that an autism susceptibility gene may be present on chromosome 11, although may only be expressed when inherited from the father. Secondly, there is evidence from several case reports to suggest that variation in the mitochondrial genome may be associated with autism but the role of the mitochondrial genetic code has not been widely investigated in ASD’s. Mitochondria supply cells with sufficient energy for a wide range of cellular processes. Polymorphisms within mitochondrial genes may therefore have functional consequences on cellular functions. This study will investigate these mechanisms in 300 autism probands parent trios and 230+ Asperger syndrome trios, as well as a control sample in the mitochondrial studies.

University of Cambridge

University of Cambridge Autism Research Centre, Cambridge , UK

Principal Investigator: Emma Weisblatt, Ph.D.

DNA Collection from a Cohort of Children with Asperger's Syndrome, PDD-NOS and High-Functioning Autism and their Families

This project involves the collection of DNA samples from 100 to 150 probands of high-functioning patients with autism spectrum diagnoses and their parents and siblings. Researchers will use a candidate gene approach to contribute to the search for autism susceptibility genes. One of the major aims of this research is to investigate phenotypic markers, such as sensory processing differences or electrophysiological differences, for use in genetic studies. These will help to identify subgroups of patients with autism who may differ in their underlying neurobiological characteristics.

Autism Research Centre

Emma Weisblatt

University of Oxford, Welcome Trust Centre for Human Genetics, Oxford, UK

Principal Investigators: Anthony Bailey, M.D., Anthony Monaco, M.D., Ph.D.

Identifying and Understanding the Actions of Autism Susceptibility Genes (Co-funded with the Simons Foundation)

Autism spectrum disorders usually arise through the inheritance of a relatively small number of susceptibility genes, but these genes cause a very variable behavioral phenotype that can include milder but related difficulties in relatives. The investigators have identified several candidate susceptibility genes within replicated regions of linkage on chromosomes 7 and 2 and will type dense genetic markers in these genes and regions in a new set of families to identify the specific genetic variants that predispose to autism. They have already assessed relatives using interview measures of socio-communication difficulties and repetitive/rigid behaviors and will administer specific tests of social cognition and face recognition. The investigators will be able to dimensionalize the autism phenotype in two independent ways and use this information to aid in gene identification. Once susceptibility genes are identified they will investigate their molecular function. Additionally the investigators will use magnetoencephalography in a stratified sample of relatives to understand how the brain basis of a typical social difficulty (face processing) varies across the behavioral phenotype and how this relates to changes in the way the brain processes language information.

Wellcome Trust Center for Human Genetics

Anthony Monaco

University of Oxford , Wellcome Trust Centre for Human Genetics, Oxford , UK

Principal Investigators: Anthony Bailey, M.D., Anthony Monaco, M.D., Ph.D.

Identifying and Understanding the Actions of Autism Susceptibility Genes

This research involves the search of the top two regions of peak linkage (currently on chromosomes 2q and 7q) for Single Nucleotide Polymorphisms (SNPs) that may be in linkage disequilibrium with autism susceptibility alleles. Dr. Monaco's most current analysis of linkage on chromosome 7q with regards to parent of origin effects indicates that there may be two genes in this region of chromosome 7q, one paternally linked and the other maternally linked in separate areas. To pursue this finding, the NLM Family Foundation is supporting the search for the paternally and maternally linked regions on chromosome 7q with high density SNPs to test for association. Knowledge of parent of origin effects will allow Dr. Monaco to test genes in the two regions for imprinting (expression from only one chromosome depending on its parent of origin) using both molecular and bioinformatics approaches, thus speeding up his localization and identification of autism susceptibility genes.

Wellcome Trust Center for Human Genetics

Anthony Monaco

Copyright © 2011 Nancy Lurie Marks Family Foundation
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