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Summary: Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0–2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10−9), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release. : Insertions and deletions (indels) have proven especially difficult to detect in exome sequencing data. Dong et al. now identify indels in exome data for 787 autism spectrum disorder (ASD) families. They demonstrate association between de novo indels that alter the reading frame and ASD. Furthermore, by observing clustering of indels in unrelated probands, they uncover two additional ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

Loss of synapses correlates with cognitive decline in Alzheimer’s disease (AD). However, molecular mechanisms underlying the synaptic dysfunction and loss are not well understood. In this study, microarray analysis of brain tissues from five AD cases revealed a reduced expression of a group of related genes, all of which are involved in synaptic vesicle (SV) trafficking. By contrast, several synaptic genes with functions other than vesicle trafficking remained unchanged. Quantitative RT-PCR confirmed and expanded the microarray findings. Furthermore, immunoblotting showed that the protein level of at least one of these gene products, dynamin I, correlated with its reduced transcript. Immunhistochemical analysis exhibited an altered distribution of dynamin I immunolabeling in AD neurons. Microarray analysis of transgenic mice with mutated amyloid precursor protein showed that although the transcript levels for some of the SV trafficking-related genes are also decreased, the change in dynamin did not replicate the AD pattern. The results suggest a link among SV vesicle-trafficking pathways, synaptic malfunction, and AD pathogenesis.