Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.

Cytogenetic imbalances are increasingly being realized as causes of autism. Here, we report a de novo translocation between the short arms of chromosomes 15 and 16 in a female with autism, epilepsy, and global developmental delay. FISH analysis identified a cryptic deletion of approximately 160 kb at the boundary of the first exon and first intron of the 1.7 Mb ataxin-2 binding protein-1 (A2BP1) gene, also called FOX1. Quantitative real time PCR (Q-PCR) analysis verified a deletion of exon 1 in the 5' promoter region of the A2BP1 gene. Reverse transcription PCR (qRT-PCR) showed reduced mRNA expression in the individual's lymphocytes, demonstrating the functional consequence of the deletion. A2BP1 codes for a brain-expressed RNA binding or splicing factor. Because of emerging evidence in the role of RNA processing and gene regulation in pervasive developmental disorders, we performed further screening of A2BP1 in additional individuals with autism from the Autism Genetics Resource Exchange (AGRE) collection. Twenty-seven SNPs were genotyped across A2BP1 in 206 parent-child trios and two regions showed association at P < or = 0.008 level. No additional deletions or clear mutations were identified in 88 probands by re-sequencing of all exons and surrounding intronic regions or quantitative PCR (Q-PCR) of exon 1. Although only nominal association was observed, and no obvious causal mutations were identified, these results suggest that A2BP1 may affect susceptibility or cause autism in a subset of patients. Further investigations in a larger sample may provide additional information regarding the involvement of this gene in the autistic phenotype.

This study demonstrates the utility of the Social Responsiveness Scale quantitative endophenotype to detect autism-related genetic loci using quantitative behavioral information that may more closely relate to underlying genetic factors.

The methyl-binding protein gene, MECP2, is a candidate for involvement in autism through its implication as a major causative factor in Rett syndrome that has similarities to autism. Rare mutations in MECP2 have also been identified in autistic individuals. We have examined the possible broader involvement of MECP2 as a predisposing factor in the disorder. Analysis of polymorphic markers spanning the gene and comprising both microsatellites and single nucleotide polymorphisms (SNPs) by the transmission disequilibrium test in two collections of families (219 in total), one in the USA and one in the UK, has provided evidence for significant association (P = 0.009) for a three-marker SNP haplotype of MECP2 with autism/autism spectrum disorders. This association is supported by association of both Single Sequence Repeat (SSR) and SNP single markers located at the 3′ end of the MECP2 locus and flanking sequence, the most significant being that of an indel marker located in intron 2 (P = 0.001 – Bonferroni corrected P = 0.006). This suggests that one or more functional variants of MECP2 existing at significant frequencies in the population may confer increased risk of autism/autism spectrum disorders and warrants further investigation in additional independent samples.