Mental retardation (MR) is the most common developmental disability in the United States affecting between 1 % to 3% of the population. Structural brain injury, chromosomal anomalies, malformation syndromes, and teratogens cause MR in some individuals, but often the etiology is unknown. Research efforts to identify the genetic basis of these non-specific, non-syndromic types of MR have been restricted by the lack of informative family pedigrees and the complexity of intellectual traits. The preliminary results of this proposal traverse these limitations by using five nuclear families from a large founder population to establish genetic linkage between an autosomal recessive, non-specific MR phenotype and a disease locus on the subtelomeric region of chromosome 3p (chr 3pter). Based on these findings there are four main reasons to pursue positional cloning efforts to identify the causative gene: First, the terminal ends of human chromosomes are "hot-spots" in the etiopathogenesis of MR. Second, breakpoint mapping in individuals with syndromic MR and cytogenetic deletions on chr 3pter confirms that a gene for MR resides within our linked candidate interval. Third, several positional candidate genes in the region encode for proteins that are crucial for normal brain development, neuronal adhesion and molecular signaling. Fourth, a virtual contig of the region estimates that the size of the interval is amenable to physical mapping. The long-term objective of this study is to identify the genes on chr 3pter that cause delayed acquisition of higher cognitive skills. The specific aims are the following: 1). Collect affected sib pairs and families with MR. 2). Refine the minimal critical region (MCR) that contains a gene for MR by identifying key recombinants. 3). Construct a high-resolution physical map (contig) of the MCR. 4). Isolate the genes within the contig and evaluate these candidates for disease-causing mutations. The identification of a gene for general intelligence will advance our understanding of the developmental neurobiology of MR and open avenues for better interventions and effective treatments to reduce its physical, financial and emotional burden.