Noncoding mutations in neurodevelopmental disorders

项目总结

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) affect >1% of the population and are comprised of multiple phenotypes including autism, intellectual disability, and other developmental delays. Over the last ten years, there has been considerable progress in understand the contribution of rare protein- coding variants in NDDs. However, the role of rare noncoding variation has been less clear due to the limited number of individuals with whole-genome sequencing (WGS) data previously available. We were one of the first to identify aggregate enrichment for promoters and enhancers in the first 516 families assessed by WGS; signals that have now been seen by multiple additional groups. Currently, we have analyzed ~2,700 families with autism and identified enrichment in a top enhancer. In Aim 1 of proposed studies we will expand this work to analyze 10,719 families with NDDs to identify specific noncoding regions using statistical tests to identify enrichment based on sequence context (fitDNM), enriched clustering of variants (GRUMP), and a transmission-disequilibrium based test, respectively. We will perform massively parallel reporter assays (MPRA) to follow up specific noncoding variants in the enriched elements and combine this with deep phylogenetic assessment using existing and new reference genomes (ACES). Our recent work suggests that dosage sensitivity is an important characteristic to consider when testing specific promoters and enhancers for enrichment in NDDs. In Aim 2, we will build a copy number map from 92,081 individuals, without NDDs, from the Centers for Common Disease Genomics dataset. We will specifically assess 1,327,879 noncoding regulatory regions for dosage-sensitivity in the human genome. As in Aim 1, we will follow up identified elements using MPRA and our ACES phylogenetic workup. The primary goal of proposed studies is to improve our understanding of noncoding variants in NDDs. We will do this by 1) identifying noncoding regulatory regions with enrichment of variation in NDDs and 2) developing a dosage sensitivity map of noncoding regulatory regions to inform studies of NDDs. This unique proposal, with its mirrored aims, focuses on noncoding variation as opposed to the majority NDD focus on protein- coding regions and it tests dosage in a large high-quality WGS dataset. This work will be integral to the genetic understanding of NDDs and the consequences of noncoding variation. It will also provide key insights into their role in the overall genetic architecture of NDDs.