Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity

Although there is considerable evidence for a strong genetic component to i diopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either n umerous genes of weak effect and/or sample heterogeneity. Because decreasin g sample heterogeneity would increase the power to identify genes, the effe ct on evidence for linkage of restricting a sample of autism-affected relat ive pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD , for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or mor e individuals with autism or related disorders, a maximal multipoint hetero geneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric lin kage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysi s to the subset of families (n = 49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD scor e of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indi cate that the restricted sample comprises a population that is more genetic ally homogeneous, which could therefore increase the likelihood of position al cloning of susceptibility loci.