A surprising METamorphosis: Autism genetics finds a common functional variant

Autism is a devastating neurodevelopmental syndrome characterized by fundamental impairments in reciprocal social interactions, delayed and deviant language development, and restricted interests and/or highly repetitive stereotyped behaviors. Approximately 13 in 10,000 individuals are affected. There are several related clinical disorders, including Asperger's syndrome and pervasive developmental disorder not otherwise specified, which, along with autism, are collectively known as autism spectrum disorders (ASDs) and increase the prevalence estimates to ≈60 in 10,000 (1). Although ASDs have been shown to have among the greatest heritability of any neuropsychiatric syndrome (1), specific genes causing or increasing the risk for social disability have been extremely difficult to identify. Nonetheless, over the past several years, a transformation has begun: After two decades of frustration, rare functional variants contributing to a small number of ASD cases have been identified (2), a convergence of linkage data from different studies and patient samples has begun to emerge (3), and promising results have recently been reported from association studies of common genetic polymorphisms (4). In addition, there have been dramatic advances in the understanding of the neurobiology of single-gene syndromes, such as Fragile X, in which affected individuals may also display an autism behavioral phenotype (5). In this issue of PNAS, Campbell et al. (6) now take the next step in solving the puzzle of ASD genetics. These investigators report a large-scale, methodologically rigorous candidate gene-association study and provide exciting genetic and molecular biological evidence pointing to a common functional variant in the promoter of the MET gene as the contributing risk factor. The identification of an association of a specific common functional allele, if replicated, would be an unprecidented advance in autism genetics.

The present study is notable for …

*E-mail: matthew.state{at}yale.edu