Four independent studies have uncovered different autism-associated variants in the gene contactin­associated protein-like 2 (CNTNAP2), making this gene the first to have multiple variants associated with autism. The striking pervasiveness and diversity of the variants suggest that CNTNAP2 plays a crucial role in autism, leading Aravinda Chakravarti and his colleagues to embark on a detailed study of the gene.

CNTNAP2 encodes a cell adhesion protein that regulates signaling between neurons at the synapse. It is highly expressed in neurons that control language and language development, difficulties with which are a hallmark of autism. Disrupting the gene’s activity may impair synapse formation in these neurons, thereby affecting language ability.

Chakravarti’s approach is to gather DNA samples from a large group of people with autism who share similar abilities and disabilities, such as the age at which they spoke their first word. This pre-selection makes the data set more precisely tuned to uncover genes related to traits of the same intensity and improves the chance of finding variants by statistical analysis.

CNTNAP2 is a large gene comprising more than 3 million base pairs. Chakravarti’s team has searched for new associations and small structural variants in this gene, using families from both the National Institute for Mental Health’s consortium and the Simons Simplex Collection. The researchers found one variant that shows consistent association in both data sets.

Chakravarti and collaborator Mark Daly of Harvard Medical School have identified common variants of the SEMA5A gene that are potential risk factors for autism. They are conducting a meta-analysis of all available genome-scan data to uncover novel genes linked to autism. More recently, they have sequenced certain coding regions of the human genome in severely affected individuals, and have identified multiple mutations in the CTNND2 (delta-catenin) gene that are associated with autism.