De novo copy number variation (CNV) in ASD (Sanders et al., Neuron, 2015)
Our analysis of CNVs in 2,591 families with ASD from the Simons Simplex Collection (SSC) replicated prior findings (Sebat et al., 2007, Sanders et al. 2011) that de novo CNVs contribute to ASD. By integrating exome data (Iossifov et al. 2014, De Rubeis et al. 2014) and additional de novo CNV data (Pinto et al. 2014) we identified 65 ASD associated risk genes and six ASD associated CNV risk loci. These genes form a protein-protein interaction network that is enriched for chromatin regulators and genes involved in the synapse. By comparing the intersection of CNV and exome data we show that small de novo CNVs contain one critical gene that mediates the ASD risk (e.g. NRXN1), while large de novo CNVs contain multiple risk genes of individually low effect (e.g. 22q11.2). We also find evidence that supports the presence of a female protective effect (FPE): 1) A higher burden of de novo CNVs are observed in affected females than affected males; and 2) That the ASD risk genes are shared between males and females, rather than being specific to one sex. This work was performed in collaboration with the SSC Genomic Consortium (SSCGC) and the Autism Sequencing Consortium (ASC).
De novo insertion/deletions (indels) mutations in ASD (Dong et al., Cell Reports, 2014)
Analysis of 787 families with ASD from the Simons Simplex Collection (SSC) with exome sequencing showed that de novo frameshift mutations have a similar risk profile to de novo loss of function mutations in ASD. By indentifying multiple frameshift mutations we implicate the genes RIMS1 and KMT2E (also called MLL5) as ASD risk factors. This work was performed in collaboration with State, Devlin and Roeder labs.
De novo mutations identify 27 ASD genes (Iossifov et al., Nature, 2014)
Analysis of 2,508 families with ASD from the Simons Simplex Collection (SSC) with exome sequencing showed robust association of de novo loss of function (LoF) mutations with ASD. Twenty seven genes with multiple de novo LoF mutations were identified and found to be ASD risk loci with a false discovery rate of <10%. This work was performed in collaboration with State, Wigler, and Eichler labs.
De novo loss of function (LoF) mutations in ASD (Sanders et al., Nature, 2012)
Analysis of 225 families with ASD from the Simons Simplex Collection (SSC) with exome sequencing demonstrated that de novo mutations that disrupt one copy of a gene (loss of function mutations) are associated with ASD. Furthermore by identifying genes with multiple de novo LoF mutations we were able to demonstrate that the specific genes were associated with ASD, including the gene SCN2A. Finally we estimated that about 1,000 genes are likely to increase the risk for ASD when disrupted in this manner. This work was performed in collaboration with State, Devlin, Roeder, and Geschwind labs. Wigler, Eichler, and Daly labs independently replicated the findings in publications in the same month.