Autism Speaks
Autism Genetic Resource Exchange
Re: AGRE Catalog, 13th Edition

Dear Colleagues:

It is a great pleasure to introduce the 13th edition of the AGRE Pedigree Catalog. AGRE is an unprecedented resource for the study of autism genetics. Complex neuropsychiatric diseases such as autism are best approached by collaborative research efforts that pool large sample sizes to accelerate the pace of research. The goal of AGRE is to facilitate more rapid progress in the identification of the genetic underpinnings of autism spectrum disorders by making this information available to the scientific community. This substantial collection, which has now grown to 1308 multiplex and simplex pedigrees, has clearly moved the field in that direction.

AGRE is a DNA repository and family registry, housing a database of genotypic and phenotypic information that is available to autism researchers worldwide. In this 13th edition, there are 44 new pedigrees. As they become available, additional family pedigrees will be posted on our online catalog which, based on the expanding nature of the resource, provides the most up-to-date availability of pedigrees and biomaterials. Cell lines have been established for the majority of families in this collection and serum is available on a subset of the subjects until stocks are depleted.

Although most of the AGRE families have had extensive evaluations by a variety of pediatricians, psychiatrists, and other neurodevelopmental specialists, these assessments are not uniform. Therefore, one of our goals is to provide uniform, research-reliable, diagnostic and neurogenetic evaluations. Our first priority, however, is collecting a large cohort of multiplex families, so as to provide additional power to genetic studies and allow for replication of findings.

The diagnosis of autism has been made using the standard Autism Diagnostic Interview-Revised (ADI-R) algorithm (see accompanying letter from Dr. Catherine Lord). In addition, AGRE provides two other diagnostic classifications (Not Quite Autism and Broad Spectrum) to characterize those individuals on the broader autism spectrum who do not meet full ADI-R criteria. Please refer to the description of Affected Status Categories for full details on how our three diagnostic categories are defined. All of our clinical raters are trained by a certified ADI trainer and undergo reliability reviews throughout the data collection process to ensure the highest standards of data collection. All of our diagnoses are scored and validated through the Internet System for Assessing Autistic Children (ISAAC), thereby eliminating manual scoring errors.

ADI-R information and pedigree configurations are available for all families in our collection. Ethnicity data have been collected on 1232 of the 1308 families and further data continue to be gathered. Autism Diagnostic Observation Schedule (ADOS) evaluations are currently available for 1091 families. Detailed birth and medical histories, physical and neurological examinations (including basic dysmorphology assessments), as well as family and medical information for parents and unaffected siblings, are available for 361 families.

We have prioritized karyotyping for those families with suspected chromosome 15 duplications. To date, 616 families have been karyotyped, 226 analyzed for SNRPN duplications at 15q12, and 374 for telomere analyses for small-scale deletions and duplications by Dr. Christa Lese Martin’s laboratory at Emory University. These data are posted on the registered and password-protected portion of the AGRE researcher website.

Families who have undergone the physician’s assessments and/or were noted to have possible non-idiopathic autism (e.g., significant chromosomal abnormalities, prematurity, associated co-morbid disorders, etc.) are included in the collection, but these families are flagged in the registered researchers’ edition of the pedigree catalog so that they can easily be identified, and included or removed, as per individual researcher protocols. In addition, more detailed descriptions of the flag or other potential exclusionary criteria are listed in the pedigree note. As more families undergo this phase of assessment, the flagged families table will be updated.

To date, 99% of these families have been screened for Fragile X by Drs. Ted Brown and Sally Nolin at the Institute for Basic Research using the PCR technique. Five of these families have members with the full Fragile X mutation.

In order to rule out other chromosomal abnormalities, karyotyping and FISH analyses were being conducted in the laboratory of Dr. Christa Lese Martin, in collaboration with Dr. David Ledbetter, at Emory University. This work had been funded by a grant from the National Institute of Mental Health (NIMH) to UCLA and collaborating investigators. The results of these analyses will be posted to the AGRE website soon. Currently, AGRE provides high density SNP data which can be used for in silico chromosomal analysis. However, significant findings such as the 16p11 duplications and deletions are undergoing validation by fluorescent in situ hybridization (FISH).

A genome scan has been completed on approximately 50% of the multiplex families in AGRE using the James Weber version 6 microsatellite marker set, with additional markers selected from the Marshfield Database by Dr. Conrad Gilliam, formerly at Columbia University. The genotypic database can be accessed by AGRE-approved researchers. Additional fine-mapping data on 11 chromosomes are also available for 316 families. Additional genome scan data carried out by the Center for Inherited Disease Research (CIDR) is available for 117 families. The majority of these families are non-overlapping with the Columbia genome scan families. The availability of this resource is particularly important for the replication of past genome scan results and for helping to further narrow loci. Candidate gene data from participating investigators are also available for download. Single Nucleotide Polymorphism (SNP) data generated by participating researchers are currently available, including SNP data from the 10K Affymetrix arrays for 426 families. These data were generated as part of the Autism Genome Project efforts. 

A release of 5.0 Affymetrix data is available for 751 families.  Because of the size of this data set, AGRE cannot make it available for download via the AGRE website.  Please contact the researcher liaison for account information for the AGRE FTP site. Finally, AGRE is also making SNP data generated on the Illumina 550K platform for 943 families available on the AGRE FTP site. This data was generated in the lab of Dr. Hakon Hakonarsen at the Children’s Hospital of Philadelphia.

Another interesting feature of this collection is the high number of multiple births. Some investigators may not want to use this subgroup of individuals for genetic studies because of potential environmental confounds. However, these samples are still made available to researchers. Zygosity has been confirmed for the majority of the multiple births in our collection.

To obtain access to the AGRE collection, researchers must receive approval from the AGRE Steering Committee by completing the Researcher Access application and the signing of the Researcher Distribution Agreement found on the AGRE website. A copy of the researcher’s current IRB approval or exemption must accompany their application. When an application is approved, a username and password will be issued by the AGRE Researcher Liaison that will allow the researcher to access the “Approved Researchers” section of the website.

Biomaterial orders are processed by the AGRE Researcher Liaison in the Los Angeles office. DNA and clinical information are made available to AGRE-approved researchers for analysis.

The Autism Speaks website (http://www.autismspeaks.org ) receives requests from new multiplex families each month, indicating that many families are still eager to participate in our research program. Because these samples are made available to any qualified researcher at a fraction of what it would actually cost them to ascertain an equivalent sample size on their own, AGRE provides a cost-effective and efficient way to replicate and expand on initial findings in autism research. In addition, we hope that this resource will foster collaboration among groups working in autism genetics and will lead to the imminent creation of a central repository and database where all data will be made public.

We welcome your interest and participation in the AGRE research program. If you have questions, please feel free to contact Clara Lajonchere, Ph.D., Vice President of Clinical Research, clara@agre.org, or Vlad Kustanovich, Ph.D., AGRE Researcher Liaison, vlad@agre.org, at 323-297-4731.

Sincerely yours,

In this section, please visit the the following pages for further information:
[AGRE Program Description]  
[About the AGRE Diagnostic Procedures]
[How to Access AGRE Data and BioMaterials]
[AGRE Steering Commitee]