19411
Defining the Contribution of Different Classes of De Novo Mutation to Autism
Objectives: We sought to make precise estimates of the contributions of different types of de novo mutations in different classes of idiopathic autism.
Methods: We used comparative genomic hybridization (CGH) over ~1,000 families, whole exome sequencing (WES) over ~2,500 families and whole genome sequencing (WGS) over 40 families from the Simons Simplex Collection (SSC), each with a single affected child.
Results: We found that children with ASD have an increased incidence of DN missense, 'likely gene-disrupting' (LGD), and copy number variant (CNV) mutations compared to unaffected siblings. We estimated that 70% of DN CNV, 42% of DN LGD and 13% of DN missense mutations contributed to 6%, 9% and 12% of diagnoses in simplex families, respectively. DN mutation in coding sequence contributes to nearly 30% of all simplex and 45% of female diagnoses. We found a list of ~40 genes with DN LGD mutations in more than one affected child. Males with DN LGDs or DN CNVs have lower IQ. The gene targets of DN LGDs in ASD males with lower IQ overlap with targets in ASD females and with individuals having intellectual disability or schizophrenia, but not significantly with targets in ASD males having higher IQ. We estimate the number of vulnerable genes in which LGD mutation can cause ASD in females or lower IQ ASD in males to be ~400, with a similar number of genes vulnerable to missense mutation. LGD targets are enriched for chromatin modifiers and FMRP-associated genes in both affected males of lower IQ and females. Embryonically expressed genes are significantly enriched in DN targets, LGD and missense, only in affected females.
Conclusions: WES and CGH have proven to be powerful tools for understanding the genetic architecture of ASD and for identifying ASD genes. But larger family collections will be necessary to identify the majority of the ASD genes and to characterize DN mutation in non-coding regions through WGS.