To collect standardized phenotypic and biological data in a sample of 200 families with affected relatives with autism.
To detect susceptibility loci for autism by performing genomic screening with 250 highly polymorphic microsatellite markers.
Autism is a rare (4/10,000) and severe developmental disorder associated with life-long handicaps. Twin studies agree in showing a strong genetic component with heritability estimates no less than 90%. The frequency of autism among siblings of autistic probands is a 100 times higher than the general population rate. Family studies also indicate that the autism phenotype extends beyond the traditional diagnostic boundaries to include characteristic patterns of cognitive (largely language-related) and social deficits. The evidence suggests the operation of several genes acting epistatically; however, there is currently no obvious candidate gene. The proposed research consists of a collaborative study of 200 families in which there are two or more affected relatives (siblings in most instances). An international consortium has been formed under the leadership of the coordinator. Affected relatives will be selected for meeting ICD-10 criteria for autism and for having a non-verbal IQ greater than 35. Standardized phenotypic measures of demonstrated reliability and validity will be employed. Workshops will be organized to train to the administration of these instruments and to maintain comparable and high levels of data quality throughout the project. All interviews and observations will be video or audio-taped to allow running checks on reliability across, as well as within, research groups; clinical data will be centralized in the coordinator's team. Blood samples will be taken from affected pairs, unaffected sibs and their parents and cell-lines will be produced in a centralized laboratory. Following DNA extraction, genomic screening will be performed on the affected sib-pair families using 250 highly polymorphic microsatellite markers spread across the human genome in order to detect susceptibility loci for autism. In addition to testing for linkage, an association study will follow as a confirmatory strategy for detecting autism-susceptibility genes, using both the multiply affected families and singletons samples. Similarly, the affected relative pairs findings will be followed by a quantitative trait locus (QTL) testing for a model of dimensional susceptibility to autism.