To explore the genetic contribution in autism spectrum disorders, Michael Wigler and his colleagues at Cold Spring Harbor Laboratory in New York studied genomic variation in the Simons Simplex Collection (SSC), a large cohort of families that have one child with autism and unaffected parents and siblings.

Their study confirmed a major contribution from spontaneous, or de novo, deletions and duplications of DNA and provided evidence that inherited ‘ultra-rare’ duplications may also play a role. Relative to boys, girls have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers.

In addition to confirming several previously observed loci, Wigler found many new candidate regions, adding substantially to the list of potential gene targets in autism.

To assess the contribution of single nucleotide variants and small insertions or deletions (indels), Wigler and his colleagues performed high-resolution exome sequencing and sequence analysis of nearly the entire SSC collection, about 2,500 families. The analysis revealed small de novo indels and point substitutions, which come mostly from the paternal line in an age-dependent manner.

They see significantly greater numbers of de novo mutations in affected versus unaffected children, and gene-disrupting mutations (nonsense, splice site and frame shifts) are twice as frequent in those with autism. Based on this work and similar studies from others, Wigler estimates that there are on the order of 500 strong autism susceptibility genes.