Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, ... Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypical, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). For a discussion of genetic heterogeneity of autism, see 209850.
Using denaturing high-performance liquid chromatography (DHPLC) analysis to detect DNA sequence variants, Bacchelli et al. (2003) excluded 9 candidate disease genes at the 2q locus between markers D2S2370 and D2S364. The authors ... - Associations Pending Confirmation Using denaturing high-performance liquid chromatography (DHPLC) analysis to detect DNA sequence variants, Bacchelli et al. (2003) excluded 9 candidate disease genes at the 2q locus between markers D2S2370 and D2S364. The authors identified 4 rare nonsynonymous variants in the cAMP-GEFII gene (RAPGEF4; 606058) in 5 IMGSAC families that segregated with the autistic phenotype and were not observed among controls. However, the significance of these findings was unclear since, overall, the frequency of the variants was low in the autistic families. Ramoz et al. (2004) screened 9 candidate genes across chromosome 2q31 for polymorphisms in 411 pedigrees including 671 autistic children and detected an association with 2 SNPs in introns 3 and 16 of SLC25A12 (-21A/G, dbSNP rs2056202 and +70A/G, dbSNP rs229813, respectively). By genotyping 158 Irish child-parent rios (442 individuals) and transmission disequilibrium test (TDT) analysis, Segurado et al. (2005) found significant association between autism and both C alleles as well as the 2-marker haplotype. Segurado et al. (2005) noted that they reported sense strand SNPs, while Ramoz et al. (2004) reported the reverse strand. Liu et al. (2009) reported an association between autism spectrum disorders and SNPs in or near the DLX1 (600029) and DLX2 (126255) genes on chromosome 2q32. In a sample of 138 multiplex families with autism spectrum disorders, the common T allele of dbSNP rs4519482 near the DLX2 gene was significantly associated with autism after correction for multiple testing (p = 0.0046). This association was confirmed in a second sample of 169 families (p = 0.034; combined corrected p value of 0.0005). Common alleles of dbSNP rs788172, dbSNP rs788173, and dbSNP rs813720 in or near the DLX1 gene were associated with autism spectrum disorders in the combined sample (p values of 0.0005 to 0.016). A haplotype of 5 SNPs in or near DLX1 and DLX2 was overtransmitted in the 2 multiplex family cohorts and in the combined sample (corrected p value of 0.00007). Further testing in 306 simplex families replicated the association at dbSNP rs4519482 (p = 0.033) and the haplotype, but p values were not significant after correction for multiple testing. Ionita-Laza et al. (2012) focused on a chromosome 2q replicated linkage region that is associated with autism spectrum disorder and that has been sequenced in 3 independent datasets. Ionita-Laza et al. (2012) found that variants in one gene, LRP2 (600073), residing on 2q were associated with autism spectrum disorder in 2 datasets (the combined variable threshold test p value is 1.2 x 10(-5)). Using a cluster detection method, they showed that in the discovery and replication datasets, variants associated with autism spectrum disorder clustered preponderantly in 25-kb windows (adjusted p values are p1 = 0.003 and p2 = 0.002), and the 2 windows are highly overlapping. Furthermore, for the third dataset, a 25-kb region similar to those in the other 2 datasets showed significant evidence of enrichment of rare disease-risk variants. The region implicated by all 3 studies is involved in ligand binding, suggesting that subtle alterations in either LRP2 expression or LRP2 primary sequence modulate the uptake of LRP2 ligands. Ionita-Laza et al. (2012) suggested that BMP4 (112262) is a ligand of particular interest given its role in forebrain development, and modest changes in BMP4 binding, which occurs in LRP2 near the mutation cluster, might subtly affect development and could lead to autism-associated phenotypes.