The expression patterns of ASD genes converge on cortical projection neurons in layers 5/6 of the prefrontal cortex during mid-fetal development (Willsey et al., Cell, 2013)
While multiple genes contribute to ASD we expect them to converge on a smaller number of pathological mechanisms to result in a common phenotype. To identify this convergence we considered 9 genes identified by multiple de novo LoF mutations on exome sequencing in ASD families in light of human gene expression data derived from multiple brain regions across the timespan of human development (BrainSpan). We saw significant convergence in the prefrontal cortex during mid-fetal development. Further analysis showed that this signal was specific to cortical projection neurons in layers 5/6.
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 Devlin, Roeder, and Geschwind labs. Wigler, Eichler, and Daly labs independently replicated the findings in publications in the same month.
De novo copy number variation (CNV) in ASD (Sanders et al., Neuron, 2011)
Our analysis of CNVs in 1,124 families with ASD from the Simons Simplex Collection (SSC) replicated prior findings (Sebat et al., 2007) that de novo CNVs contribute to ASD, further clarified the allelic architecture of ASD, and identified the association of idiopathic autism with 7q11.23 duplications at the Williams syndrome deletion region. The deletions observed in Williams-Beuren syndrome lead to neuropsychiatric impairments but also a strikingly high socialization skills; it is remarkable that duplications of 7q11.23 (the same region) are associated with decreased socialization skills that characterize ASD. This work was performed in collaboration with the SSC Genotyping Consortium (SSCGC) led by Dr. State.
Role of histaminergic neurotransmission in TD (Ercan-Sencicek et al., NEJM, 2010)
Linkage analysis of a two-generation pedigree with multiple affected individuals with TD identified an 8Mbp locus (lod 2.05, max lod 2.10). PCR and Sanger sequencing analysis of all genes within the interval identified a segregating heterozygous nonsense mutation in the gene HDC that encodes L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. This mutation was not observed in 1,500 controls, nor in 720 TD cases. Enzymatic assay of the mutation revealed a dominant negative effect on histamine synthesis. This finding offers a clear, novel therapeutic target for TD treatment.
Association of SLITRK1 with Tourette Disorder (Abelson et al., Science, 2005)
Fine mapping with FISH of a de novo chr13 inversion in a child with sporadic TD identified a breakpoint in proximity to the gene SLITRK1. This gene was analyzed with PCR and Sanger sequencing in 174 unrelated TD cases identified a frameshift mutation and two independent variants that disrupted a co-expressed microRNA binding site; neither were observed in 1,800 controls. While overexpression of wild type human SLITRK1 enhances dendritic outgrowth in cultured mouse neurons no such outgrowth is observed when the frameshift mutation is overexpressed.