A study published in Science (2012) used multiplex targeted sequencing to identify recurrently mutated genes in autism spectrum disorders (ASDs). The researchers developed a modified molecular inversion probe (MIP) method for ultra-low-cost candidate gene resequencing in large cohorts. They sequenced 44 ASD candidate genes in 2,446 ASD probands and identified 27 de novo mutations in 16 genes, with 59% predicted to truncate proteins or disrupt splicing. The study estimated that mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. The data supported associations between specific genes and reciprocal subphenotypes, such as CHD8-macrocephaly and DYRK1A-microcephaly, and reinforced the importance of a β-catenin/chromatin remodeling network in ASD etiology. The study found a mutation burden in the 44 genes, with a higher rate of de novo mutations than expected. The burden was driven by severe disruptions, including coding indels, nonsense mutations, and splice-site disruptions. Five of the six genes with mutation burden were part of a β-catenin/chromatin remodeling network. The study also validated 23 inherited, severely disruptive variants in the 44 genes and found that de novo mutations in these genes were more common in ASD probands than in healthy controls. The study highlights the role of de novo mutations in six genes in approximately 1% of sporadic ASDs. It also suggests that these mutations may contribute to the genetic basis of ASD. The study's findings support the use of targeted sequencing for identifying de novo mutations in ASD and provide insights into the genetic mechanisms underlying the disorder. The study's methods and findings have implications for understanding the genetic basis of other complex disorders.A study published in Science (2012) used multiplex targeted sequencing to identify recurrently mutated genes in autism spectrum disorders (ASDs). The researchers developed a modified molecular inversion probe (MIP) method for ultra-low-cost candidate gene resequencing in large cohorts. They sequenced 44 ASD candidate genes in 2,446 ASD probands and identified 27 de novo mutations in 16 genes, with 59% predicted to truncate proteins or disrupt splicing. The study estimated that mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs. The data supported associations between specific genes and reciprocal subphenotypes, such as CHD8-macrocephaly and DYRK1A-microcephaly, and reinforced the importance of a β-catenin/chromatin remodeling network in ASD etiology. The study found a mutation burden in the 44 genes, with a higher rate of de novo mutations than expected. The burden was driven by severe disruptions, including coding indels, nonsense mutations, and splice-site disruptions. Five of the six genes with mutation burden were part of a β-catenin/chromatin remodeling network. The study also validated 23 inherited, severely disruptive variants in the 44 genes and found that de novo mutations in these genes were more common in ASD probands than in healthy controls. The study highlights the role of de novo mutations in six genes in approximately 1% of sporadic ASDs. It also suggests that these mutations may contribute to the genetic basis of ASD. The study's findings support the use of targeted sequencing for identifying de novo mutations in ASD and provide insights into the genetic mechanisms underlying the disorder. The study's methods and findings have implications for understanding the genetic basis of other complex disorders.